BACKGROUND Over the years,the numbers of treatment options for colorectal cancer(CRC)have increased,leading to notable improvements in the overall survival of CRC patients.Although therapy may initially yield positive...BACKGROUND Over the years,the numbers of treatment options for colorectal cancer(CRC)have increased,leading to notable improvements in the overall survival of CRC patients.Although therapy may initially yield positive results,the development of drug resistance can result in treatment failure and cancer recurrence.This resistance is often attributed to the presence of cancer stem cells(CSCs).These CSCs not only contribute to therapeutic resistance but also play crucial roles in the initiation and development of tumor metastasis.AIM To investigate the antitumor effects of SH-4-54,which are mediated by targeting CSCs relative to treatment outcomes.METHODS CSCs were enriched by culturing CRC cells in serum-free medium.Hallmarks of stemness and IL-6/JAK2/STAT3 signaling were detected by Western blotting.Indicators of CSC malignancy,including proliferation,invasion,and tumor formation,were measured.RESULTS In this study,we employed SH-4-54,which exhibits anticancer activity in solid tumors through targeting the SH2 domain of both the signal transducer and activator of transcription(STAT)3 and the STAT5,and evaluated its effects on stemness and chemoresistance in colorectal CSCs.As expected,SH-4-54 treatment inhibited the phosphorylation of STAT3(p-STAT3)and decreased the percentage of ALDH1A1-positive CRC cells.The addition of SH-4-54 dissociated colorectal spheroids and decreased the expression of stemness markers,including ALDH1A1,CD44 and Nanog.SH-4-54 treatment decreased IL-6/JAK2/STAT3 signaling by inhibiting p-STAT3 and thus inhibited spheroid formation by SW480 and LoVo cells.Moreover,SH-4-54 treatment inhibited indicators of malignancy,including cell proliferation,invasion,and tumor formation,in CSCs in vitro and in vivo.Notably,SH-4-54 treatment significantly increased chemosensitivity to oxaplatin.CONCLUSION Taken together,these results indicate that SH-4-54 is a promising molecule that exerts antitumor effects on colorectal CSCs by inhibiting STAT3 signaling.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive and fatal malignancies,with a 5-year survival rate of<15%.Despite significant advancements in targeted therapies and immunotherapy,these approache...Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive and fatal malignancies,with a 5-year survival rate of<15%.Despite significant advancements in targeted therapies and immunotherapy,these approaches benefit only a limited subset of patients,leaving chemotherapy as the primary treatment modality for most patients.Chemotherapy is an essential adjunct to surgical resection,the only potentially curative option,playing a crucial role in reducing the tumor burden,delaying disease progression,and alleviating symptoms.However,its long-term efficacy is frequently undermined by the development of chemoresistance,wherein tumor cells adopt diverse strategies to evade or repair chemotherapy-induced damage.Addressing this critical barrier is imperative for improving the clinical outcomes of PDAC.This review comprehensively examines the multifaceted mechanisms of chemoresistance in PDAC and highlights innovative strategies designed to enhance chemosensitivity,thereby offering new hope for overcoming these challenges and improving patient survival.展开更多
Colorectal cancer(CRC)is the third most common malignancy.However,the efficacy of current treatment strategies remains limited.In recent years,monomeric compounds from traditional Chinese medicine have received extens...Colorectal cancer(CRC)is the third most common malignancy.However,the efficacy of current treatment strategies remains limited.In recent years,monomeric compounds from traditional Chinese medicine have received extensive attention in cancer therapy.Rosmarinic acid(RA),a natural phenolic acid,has multiple biological activities and exhibits anti-oncogenic effects in several cancers.Liu et al previously uncovered that RA could serve as a dual-action therapeutic agent in CRC.By suppressing nuclear factor-kappa B signaling via direct inhibition of inhibitory kappa B kinase beta,RA not only impedes tumor progression but also synergizes with first-line chemotherapeutics(5-fluorouracil/oxaliplatin)to reverse drug resistance.The authors demonstrate RA’s capacity to downregulate nuclear factor-kappa B-driven oncogenes and enhance chemotherapeutic cytotoxicity in vitro through integrative approaches,including molecular docking,luciferase assays,and functional validation.While these findings position RA as a cost-effective adjuvant in precision oncology,critical clinical translational gaps remain,including optimizing RA’s in vivo bioavailability,validating systemic safety in combinatorial regimens,and elucidating its immunomodulatory effects within the tumor microenvironment.This underscores the urgency of bridging phytochemistry and clinical oncology,advocating for biomarker-driven animal studies and phase I trials to translate RA’s potential into actionable CRC therapies.By addressing these hurdles,RA could emerge as a paradigm-shifting agent,harmonizing natural product efficacy with modern therapeutic precision.展开更多
BACKGROUND Chemotherapy is an essential treatment for colorectal cancer(CRC)patients after surgery,but many patients do not benefit from chemotherapy because tumour heterogeneity results in varied responses.AIM To stu...BACKGROUND Chemotherapy is an essential treatment for colorectal cancer(CRC)patients after surgery,but many patients do not benefit from chemotherapy because tumour heterogeneity results in varied responses.AIM To study the effectiveness of in vitro chemosensitivity tests adenosine tripho-sphate-based tumour chemotherapy sensitivity test(ATP-TCA)for tailoring po-stoperative chemotherapy regimens for patients with CRC.METHODS Between January 2015 to December 2021,a total of 1549 CRC patients underwent surgery and in vitro chemosensitivity testing using ATP-TCA.A subset of 405 patients who met the survival assessment criteria were followed to collect data on overall survival(OS)and disease-free survival(DFS).Cox regression analysis revealed independent prognostic factors that affect OS and DFS for those re-ceiving oxaliplatin(L-OPH)and fluoropyrimidine-based regimens,aiding in the development of clinical predictive models.The relationships between the ATP-TCA results and clinical outcomes were analysed using the Kaplan-Meier method.RESULTS Tumour heterogeneity and resistance to multiple drugs were observed in 1549 patients.The sensitivity to 5-fluorouracil(5-FU)combined with L-OPH was tested among 1474 of these patients,yielding a sensitivity rate of 11.9%.ATP-TCA results were identified as an independent prognostic factor for DFS[P=0.002,hazard ratio(95%confidence interval):4.98(1.81-13.72)]in patients with resectable CRC.Compared with drug-resistant patients,sensitive CRC patients treated with 5-FU and L-OPH had significantly prolonged DFS(P=0.027).Further Kaplan-Meier analysis indicated that ATP-TCA sensitivity was significantly associated with improved OS(P=0.048)and DFS(P=0.003)in patients with stage III CRC.CONCLUSION The response of CRC patients to the combination regimen of 5-FU and L-OPH is heterogeneous.This study confirmed that the ATP-TCA is a valuable tool for predicting clinical outcomes,such as DFS,in patients with resectable CRC receiving chemotherapy.Although further validation with multicentre data is still necessary,these findings support that the ATP-TCA may function as a guiding tool for personalized chemotherapy administration,thereby optimizing treatment opportunities for patients.展开更多
The authors prove the local existence and uniqueness of weak solution of a hyperbolic-parabolic system and establish the global existence of the weak solution for this system for the spatial dimension n = 1.
To establish a method to evaluate the effects of chemosensitizer onP-glycoprotein using ^(99m)Tc-MIBI, and observe the changes of ^(99m)Tc-MIBI uptake kinetics andP-glycoprotein levels after using verapamil in MDR hum...To establish a method to evaluate the effects of chemosensitizer onP-glycoprotein using ^(99m)Tc-MIBI, and observe the changes of ^(99m)Tc-MIBI uptake kinetics andP-glycoprotein levels after using verapamil in MDR human breast cells MCF-7/Adr. Methods: MDR breastcarcinoma cells, MCF-7/Adr, were incubated and different protocols were performed. Protocol Ⅰ: achemosensitizer, verapamil (10 μmol/L), was added into cell culture medium, while in control group,the same volume of DMEM was given. Cells were harvested after 2 h incubation with ^(99m)Tc-MIBI.Protocol Ⅱ: Verapamil (10 μmol/L) was added into cell culture medium and incubated for 20 min, 40min, 60 min, 80 min, 8 h, 24 h, 48 h and 72 h respectively. Cells were harvested after 2 hincubation with ^(99m)Tc-MIBI. The radioactivity of the cells was measured and P-glycoproteinexpression levels were determined with immunohistochemical stain. Results: Protocol Ⅰ: After 2hincubation with verapamil the cellular uptake of ^(99m)Tc-MIBI was remarkably higher than controlgroup (t=2.33, P 【 0.05), but there was no difference in P-glycoprotein expression levels betweentwo groups (P 】 0.05). Protocol Ⅱ: In verapamil group, ^(99m)Tc-MIBI uptake was increased withincubation time prolonging (F=58.2, P 【 0.05). When verapamil incubation time surpassed 8 h the^(99m)Tc-MIBI uptake negatively correlated to the P-glycoprotein expression levels (r=-0.73, P 【0.01). However, when incubation time was less than 80 min, there was no correlation between^(99m)Tc-MIBI accumulation and P-glycoprotein levels (r=0.16, P 】 0.05). Conclusion: ^(99m)Tc-MIBImay be used to evaluate the qualitative as well as quantitative change of P-glycoprotein expressionlevels induced by the chemosensitizer, verapamil.展开更多
Objective Our previous study has revealed that iASPP is elevated in human head and neck squamous cell carcinoma(HNSCC)and iASPP overexpression signifcantly correlates with tumor malignant progression and poor survival...Objective Our previous study has revealed that iASPP is elevated in human head and neck squamous cell carcinoma(HNSCC)and iASPP overexpression signifcantly correlates with tumor malignant progression and poor survival of HNSCC.This study investigated the function of iASPP playing in proliferation and invasion of HNSCC in vitro.Methods HNSCC cell line Tu686 transfected with Lentiviral vector-mediated iASPP-specific shRNA and control shRNA were named the shRNA-iASPP group and shRNA-NC group,respectively.The non-infected Tu686 cells were named the CON group.CCK-8 assay,flow cytometry,transwell invasion assay were performed to detect the effects of iASPP inhibition in vitro.Results Our results demonstrated that the proliferation of shRNA-iASPP cells at the time of 72 h(F=32.459,P=0.000),96 h(F=51.407,P=0.000),120 h(F=35.125,P=0.000)post-transfection,was significantly lower than that of shRNANC cells and CON cells.The apoptosis ratio of shRNA-iASPP cells was 9.42%±0.39%(F=299.490,P=0.000),which was significantly higher than that of CON cells(2.80%±0.42%)and shRNA-NC cells(3.18%±0.28%).The percentage of shRNA-iASPP cells in G0/G1 phase was 74.65%±1.09%(F=388.901,P=0.000),which was strikingly increased,compared with that of CON cells(55.19%±1.02%)and shRNA-NC cells(54.62%±0.88%).The number of invading cells was 56±4 in the shRNA-iASPP group(F=84.965,P=0.000),which decreased significantly,compared with the CON group(111±3)and the shRNA-NC group(105±8).The survival rate of shRNA-iASPP cells administrated with paclitaxel was highly decreased,compared with CON cells and shRNA-NC cells(F=634.841,P=0.000).Conclusion These results suggest iASPP may play an important role in progression and aggressive behavior of HNSCC and may be an efficient chemotherapeutic target for the treatment of HNSCC.展开更多
AIM:To investigate the predictive clinical value of in vitro 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay for directing chemosensitivity in patients with gastric cancer. METHODS:Results of ...AIM:To investigate the predictive clinical value of in vitro 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay for directing chemosensitivity in patients with gastric cancer. METHODS:Results of a total of 353 consecutive patients with gastric cancer treated with MTT-directed chemotherapy or physician’s empirical chemotherapy from July 1997 to April 2003 were reviewed and analyzed retrospectively. RESULTS:The overall 5-year survival rate of MTT- sensitive group (MSG) and control group (CG) was 47.5% and 45.1%, respectively. The results of subgroup analysis with Cox proportional-hazards model were favorable for the MSG-sensitive group. However, no statistically significant difference in survival rate was observed between the two groups. CONCLUSION:Individualized chemotherapy based on in vitro MTT assay is beneficial, but needs to be confirmed by further randomized controlled trials.展开更多
Metabolomics is a field of study in systems biology that involves the identification and quantification of metabolites present in a biological system. Analyzing metabolic differences between unperturbed and perturbed ...Metabolomics is a field of study in systems biology that involves the identification and quantification of metabolites present in a biological system. Analyzing metabolic differences between unperturbed and perturbed networks, such as cancerous and noncancerous samples, can provide insight into underlying disease pathology, disease prognosis and diagnosis. Despite the large number of review articles concerning metabolomics and its application in cancer research, biomarker and drug discovery, these reviews do not focus on a specific type of cancer. Metabolomics may provide biomarkers useful for identification of early stage gastric cancer, potentially addressing an important clinical need. Here, we present a short review on metabolomics as a tool for biomarker discovery in human gastric cancer, with a primary focus on its use as a predictor of anticancer drug chemosensitivity, diagnosis, prognosis, and metastasis.展开更多
Although gastric cancer(GC)is one of the leading causes of cancer-related death,major therapeutic advances have not been made,and patients with GC still face poor outcomes.The prognosis of GC also remains poor because...Although gastric cancer(GC)is one of the leading causes of cancer-related death,major therapeutic advances have not been made,and patients with GC still face poor outcomes.The prognosis of GC also remains poor because the molecular mechanisms of GC progression are incompletely understood.MicroRNAs(miRNAs)are noncoding RNAs that are associated with gastric carcinogenesis.Studies investigating the regulation of gene expression by miRNAs have made considerable progress in recent years,and abnormalities in miRNA expression have been shown to be associated with the occurrence and progression of GC.miRNAs contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors,affecting cell proliferation,apoptosis,motility,and invasion.Moreover,a number of miRNAs have been shown to be associated with tumor type,tumor stage,and patient survival and therefore may be developed as novel diagnostic or prognostic markers.In this review,we discuss the involvement of miRNAs in GC and the mechanisms through which they regulate gene expression and biological functions.Then,we review recent research on the involvement of miRNAs in GC prognosis,their potential use in chemotherapy,and their effects on Helicobacter pylori infections in GC.A greater understanding of the roles of miRNAs in gastric carcinogenesis could provide insights into the mechanisms of tumor development and could help to identify novel therapeutic targets.展开更多
AIM： To examine the effects of cyclin D1 antisense oligodexoyneucleotides （ASODN） on growth and chemosensitivity of gastric carcinoma cell lines SGC7901 and its mechanism. METHODS： Phosphorothioate modified cyclin...AIM： To examine the effects of cyclin D1 antisense oligodexoyneucleotides （ASODN） on growth and chemosensitivity of gastric carcinoma cell lines SGC7901 and its mechanism. METHODS： Phosphorothioate modified cyclin D1 ASODN was encapsulated by LipofectAMINE2000 （LF2000） and transfected into cells, the dose-effect curves and growth curves were observed. 5-FU, MTX, CDDP of different concentrations were given after transfecting cells with cyclin D1 ASODN for 24 h, the dose-effect responses were observed and IC50s were calculated. The mRNA expression of cyclin D1, thymidylate synthase （TS）, thymidine phosphorylase （TP） and dihydrofolate reductase （DHFR） was detected by reverse transcription-PCR （RTPCR） at 24 h and 48 h after transfection. RESULTS： Dose-dependent inhibitory effect was caused by cyclin D1 ASODN in SGC7901 cells. Transfecting gastric carcinoma cells with 0.2 μmol/L cyclin D1 ASODN for 24 h could inhibit growth significantly and reduce expression of cyclin D1 mRNA. Cyclin D1 ASODN could increase the chemosensitivity to 5-FU, MTX, CDDP in cells, The IC50s of different chemotherapeutic agents in ASODN plus chemotherapy groups were significantly lower than those in controls. Transfection with cyclin D1 ASODN leaded to an increase in TS and DHFR mRNA and a decrease in TP mRNA as determined by RT-PCR at 24 h, the alterations were more significant at 48 h. CONCLUSIONS： Cyclin D1 ASODN can decrease mRNA expression of cyclin D1, inhibit growth and enhance the chemosensitivity by changing the expression of enzymes related to metabolism of chemotherapeutic agents in SGC7901 gastric carcinoma cells.展开更多
AIM: To evaluate the significance of BNIP3 in the pathogenesis of pancreatic cancer, we analyzed the relationship between the expression of BNIP3 and survival rate of the patients with pancreatic cancer, or chemosensi...AIM: To evaluate the significance of BNIP3 in the pathogenesis of pancreatic cancer, we analyzed the relationship between the expression of BNIP3 and survival rate of the patients with pancreatic cancer, or chemosensitivities in pancreatic cancer cell lines, particularly for gemcitabine, the first-line anti-tumor drug for pancreatic cancer. METHODS: To compare the expression level of BNIP3 with the resistance to gemcitabine, eight pancreatic cancer cell lines were subjected to gemcitabine treatment and the quantitative real-time RT-PCR method was used to evaluate BNIP3 expression. Immunohistochemical analysis was also performed using 22 pancreatic cancer specimens to study relationship between BNIP3 expression and survival rate. RESULTS: Although no significantly positive association between BNIP3 mRNA level and gemcitabine chemosensitivity was observed, pancreatic cancer cell lines that were sensitive to gemcitabine treatment tended to show high levels of BNIP3 expression. The converse, an absence of BNIP3 expression, was not correlated with gemcitabine resistance. We further compared the BNIP3 expression profiles of resected primary pancreaticcancer specimens with the prognosis of the patients, and found a tendency of favorable prognosis and low BNIP3 expression. CONCLUSION: High levels of BNIP3 expression cannot be used as one of the predicting factors for gemcitabine chemosensitivity, and some yet to be known factors will have to fill the gap for the accurate prediction of pancreatic cancer chemosensitivity to gemcitabine. However, BNIP3 expression may have an impact on prediction of prognosis of patients with pancreatic cancer.展开更多
Objective To investigate and compare the biological characteristics and sensitivity to chemotherapy and radiotherapy of intrahepatic and extrahepatic cholangiocarcinoma cells in vitro.Methods The intrahepatic and extr...Objective To investigate and compare the biological characteristics and sensitivity to chemotherapy and radiotherapy of intrahepatic and extrahepatic cholangiocarcinoma cells in vitro.Methods The intrahepatic and extrahepatic cholangiocarcinoma cell lines were established,and cells with steady passage were chosen to study the biological characteristics including morphology,growth dynamics,chromosome,and levels of cancer antigen(CA)125,CA19-9,alpha-fetoprotein(AFP),and carcino-embryonic antigen(CEA).Meanwhile,MTT assay was used to determine the sensitivity of both kinds of cells to 6 chemotherapeutic drugs,including cisplatin,paclitaxel,harringtonine,5-fluorouracil,vincristine,and aclacimomycin,and the inhibitory rate of cells under the irradiation of 10 Gy ray was also measured.Results The intrahepatic cholangiocarcinoma cells were mostly fusiform in shape,and extrahepatic cholangiocarcinoma cells were mostly round or polygon in shape.Their doubling time was 26.3 hours and 23.1 hours,respectively.Their average number of chromosomes was 59(range,38-84)and 67(range,49-103),respectively.The chromosome karyotypes of most intrahepatic cholangiocarcinoma cells were hyperdiploid and hypotriploid,while hypertriploid was predominant in extrahepatic cholangiocarcinoma cells.The level of CA 125 in supernatant of extrahepatic cholangiocarcinoma cells increased obviously,while levels of other determined tumor markers in both kinds of cells were all within normal range.The intrahepatic cholangiocarcinoma cells were low sensitive to cisplatin and paclitaxel,but not sensitive to the other 4 chemotherapeutic drugs.The extrahepatic cholangiocarcinoma cells were high sensitive to cisplatin,but not sensitive to the other 5 drugs.Both kinds of cells had poor sensitivity to radiotherapy.Conclusions Intrahepatic and extrahepatic cholangiocarcinoma cells show differences in shape,doubling time,chromosome karyotype,tumor marker level,and chemosensitivity,whereas they both have poor radiosensitivity.Though they are similar in histopathology,they have different growth characteristics and have discrepancy in treatment and prognosis.展开更多
Objective:We aimed to develop a novel anti-HIF-1αintrabody to decrease gemcitabine resistance in pancreatic cancer patients.Methods:Surface plasmon resonance and glutathione S-transferase pull-down assays were conduc...Objective:We aimed to develop a novel anti-HIF-1αintrabody to decrease gemcitabine resistance in pancreatic cancer patients.Methods:Surface plasmon resonance and glutathione S-transferase pull-down assays were conducted to identify the binding affinity and specificity of anti-HIF-1αVHH212[a single-domain antibody(nanobody)].Molecular dynamics simulation was used to determine the protein-protein interactions between hypoxia-inducible factor-1α(HIF-1α)and VHH212.The real-time polymerase chain reaction(PCR)and Western blot analyses were performed to identify the expressions of HIF-1αand VEGF-A in pancreatic ductal adenocarcinoma cell lines.The efficiency of the VHH212 nanobody in inhibiting the HIF-1 signaling pathway was measured using a dual-luciferase reporter assay.Finally,a PANC-1 xenograft model was developed to evaluate the anti-tumor efficiency of combined treatment.Immunohistochemistry analysis was conducted to detect the expressions of HIF-1αand VEGF-A in tumor tissues.Results:VHH212 was stably expressed in tumor cells with low cytotoxicity,high affinity,specific subcellular localization,and neutralization of HIF-1αin the cytoplasm or nucleus.The binding affinity between VHH212 and the HIF-1αPAS-B domain was 42.7 n M.Intrabody competitive inhibition of the HIF-1αheterodimer with an aryl hydrocarbon receptor nuclear translocator was used to inhibit the HIF-1/VEGF pathway in vitro.Compared with single agent gemcitabine,co-treatment with gemcitabine and a VHH212-encoding adenovirus significantly suppressed tumor growth in the xenograft model with 80.44%tumor inhibition.Conclusions:We developed an anti-HIF-1αnanobody and showed the function of VHH212 in a preclinical murine model of PANC-1 pancreatic cancer.The combination of VHH212 and gemcitabine significantly inhibited tumor development.These results suggested that combined use of anti-HIF-1αnanobodies with first-line treatment may in the future be an effective treatment for pancreatic cancer.展开更多
The molecular basis for enhanced chemosensitivity of testicular germ cell tumors （GCT） has been an area of great interest, as it could potentially give us therapeutic leads in other resistant malignancies. Thus far,...The molecular basis for enhanced chemosensitivity of testicular germ cell tumors （GCT） has been an area of great interest, as it could potentially give us therapeutic leads in other resistant malignancies. Thus far, however, the increased sensitivity of C＆T has been variously attributed to multiple factors -- an inability to detoxify cisplatin, a lack of export pumps, an inability to repair the DNA damage, an intact apoptotic cascade and lack of p53 mutation; but a unifying underlying etiology leading to the aforementioned processes and having a translational implication has so far been elusive. Herein, we offer evidence to support a potential significant role for the previously demonstrated low hypoxia inducible factor-la （HIF-la） expression in mediating the general exquisite chemosensitivity of testicular GCT, through the aforementioned processes. This molecular mechanism based hypothesis could have a significant translational implication in platinum refractory GCT as well as other platinum resistant malignancies.展开更多
AIM： To determine the functional significance of TC21 in esophageal squamous cell carcinoma （ESCC）. METHODS： TC21 siRNA transfection was carried out using Hyperfectamine to knock down TC21, and tran- scripts were ...AIM： To determine the functional significance of TC21 in esophageal squamous cell carcinoma （ESCC）. METHODS： TC21 siRNA transfection was carried out using Hyperfectamine to knock down TC21, and tran- scripts were analyzed by reverse transcription-poly- merase chain reaction and protein by Western blotting.We demonstrated the effect of TC21 downregulation of cell signaling in esophageal cancer cells by assess- ing the phosphorylation status of its downstream tar- gets, phosphoinositide 3-kinase （PI3K）, phosphatase and tensin homolog （PTEN）, protein kinase B （pAl〈t）, nuclear factor-KB （NF-~B） and cyclinD1 using specific antibodies. Cell survival analysis after cisplatin treat- ment was carried out by cell viability assay and cell cycle analysis using flow cytometry. RESULTS： TC21 knockdown in human ESCC cell line TEl3 cells, showed only a marginal increase （14.2%） in cell death compared with control cells. The expres- sions of the signaling proteins PI3K and pAkt, transcrip- tion factor NF-KB, and cell cycle protein cyclin D1 were markedly decreased in response to TC21 downregula- tion, whereas the level of pPTEN, an antagonist of PI3K, was increased. In addition, we evaluated the potential of TC21 as a putative target for sensitizing ESCC cells to the chemotherapeutic agent cisplatin. Increased cell death （38.4%） was observed in cells treated with cis- platin after TC21 knockdown compared with cells which were treated with cisplatin alone （20% cell death）. CONCLUSION： Results suggest that TC21 mediates its effects via the PI3K-Akt pathway, NF-KB and cyclin D1, and enhances chemoresistance in esophageal cancer cells.展开更多
Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However, a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, ...Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However, a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, even in the absence of a response to modern targeted therapies and immunotherapies; accordingly, determining predictive biomarkers of the response to chemotherapies for metastatic melanoma remains a priority to guide treatment in these patients. We report a case study of a patient with B-Raf proto-oncogene serine/threonine kinase-mutated metastatic melanoma harbouring many genetic mutations. The patient did not respond to prior targeted therapies or immunotherapies but experienced a dramatic objective radiological and clinical response to subsequent dacarbazine-based chemotherapy. In the era of targeted therapies and immunotherapies for metastatic melanoma, cytotoxic chemotherapies may still represent an interesting therapeutic weapon in a well-deined subgroup of patients presenting with speciic genetic and molecular features.展开更多
AIM: To investigate the effect of Girdin knockdown on the chemosensitivity of colorectal cancer cells to oxaliplatin and the possible mechanisms involved.
Objective:The aim of the study was to identify specific chemosensitivity drugs for various molecular subtypes of breast tumors in Chinese women,by detecting the expression of drug resistance genes and by using the dru...Objective:The aim of the study was to identify specific chemosensitivity drugs for various molecular subtypes of breast tumors in Chinese women,by detecting the expression of drug resistance genes and by using the drug sensitivity test on different molecular subtypes of breast cancers.Methods:The expression of drug resistance genes including Topo Ⅱ,GST-π,P-gp,LRP,and CD133 were detected with immunohistochemistry in a tissue microarray.Drug sensitivity tests included those for paclitaxel,epirubicin,carboplatin,vinorelbine,and fluorouracil and were conducted on primary cancer tissue cells and cell lines,including the T47 D,BT-474,and MDA-MB-231 cells and human breast cancer xenografts in nude mice.Results:The different drug resistant genes Topo Ⅱ,GST-π,P-gp,and LRP were differentially expressed among different molecular subtypes of breast cancers(P<0.05).Positive expression of CD133 was highest in basal-like breast cancer(P<0.05).Kaplan-Meier survival analysis showed that positive expressions of Topo Ⅱ and CD133 both correlated with shorter disease-free survival(DFS)(P<0.05)and overall survival(P<0.05),and positive expression of LRP correlated only with shorter DFS(P<0.05).BT-474 showed chemosensitivity to paclitaxel and epirubicin,while MDA-MB-231 showed chemosensitivities to paclitaxel,epirubicin,carboplatin,and fluorouracil(T/C≤50%).The basal-like and HER2+breast cancer primary cells showed chemosensitivities to paclitaxel and epirubicin with significant differences compared with luminal breast cancer primary cells(P<0.05).Conclusions:The differential expression of drug resistance genes and the differential chemosensitivities of drugs in different molecular subtype of breast cancers suggested that individual treatment should be given for each type of breast cancer.展开更多
Pancreatic cancer is one of the most aggressive malignancies with poor prognosis and high mortality.Recent studies showed that microRNAs are dysregulated and involved in the initiation and progression of pancreatic ca...Pancreatic cancer is one of the most aggressive malignancies with poor prognosis and high mortality.Recent studies showed that microRNAs are dysregulated and involved in the initiation and progression of pancreatic cancer.In this study,we found that miR-708 was significantly downregulated in pancreatic cancer tissues and cell lines.Lentivirus-mediated overexpression of miR-708 could significantly inhibit the proliferation and invasion,while enhanced chemosensitivity to gemcitabine in both Panc-1 and SW1990 cells.Luciferase reporter assay showed that miR-708 bound the 3’-untranslated region of survivin and suppressed the expression of survivin in pancreatic cancer cells.In pancreatic cancer tissues,survivin protein was highly expressed and negatively correlated with miR-708 expression.Furthermore,the restoration of survivin expression could partially antagonize proliferation inhibition and apoptosis induction by miR-708 in pancreatic cancer cells.The Panc-1 cells with overexpression of miR-708 also showed decreased proliferation capability in nude mouse model compared with parental cells.In conclusion,our results suggest that miR-708 inhibits pancreatic cancer and could be a novel potential candidate to treat pancreatic cancer.展开更多
文摘BACKGROUND Over the years,the numbers of treatment options for colorectal cancer(CRC)have increased,leading to notable improvements in the overall survival of CRC patients.Although therapy may initially yield positive results,the development of drug resistance can result in treatment failure and cancer recurrence.This resistance is often attributed to the presence of cancer stem cells(CSCs).These CSCs not only contribute to therapeutic resistance but also play crucial roles in the initiation and development of tumor metastasis.AIM To investigate the antitumor effects of SH-4-54,which are mediated by targeting CSCs relative to treatment outcomes.METHODS CSCs were enriched by culturing CRC cells in serum-free medium.Hallmarks of stemness and IL-6/JAK2/STAT3 signaling were detected by Western blotting.Indicators of CSC malignancy,including proliferation,invasion,and tumor formation,were measured.RESULTS In this study,we employed SH-4-54,which exhibits anticancer activity in solid tumors through targeting the SH2 domain of both the signal transducer and activator of transcription(STAT)3 and the STAT5,and evaluated its effects on stemness and chemoresistance in colorectal CSCs.As expected,SH-4-54 treatment inhibited the phosphorylation of STAT3(p-STAT3)and decreased the percentage of ALDH1A1-positive CRC cells.The addition of SH-4-54 dissociated colorectal spheroids and decreased the expression of stemness markers,including ALDH1A1,CD44 and Nanog.SH-4-54 treatment decreased IL-6/JAK2/STAT3 signaling by inhibiting p-STAT3 and thus inhibited spheroid formation by SW480 and LoVo cells.Moreover,SH-4-54 treatment inhibited indicators of malignancy,including cell proliferation,invasion,and tumor formation,in CSCs in vitro and in vivo.Notably,SH-4-54 treatment significantly increased chemosensitivity to oxaplatin.CONCLUSION Taken together,these results indicate that SH-4-54 is a promising molecule that exerts antitumor effects on colorectal CSCs by inhibiting STAT3 signaling.
基金supported by grants from the CAMS Innovation Fund for Medical Sciences(No.2024-I2M-ZD-001)National Key R&D Program of China(No.2023YFC2413400)+5 种基金National Natural Science Foundation of China(No.82272917,No.62133006,No.82203158,No.82473086,No.82473096,and No.82403006)Beijing Natural Science Foundation(No.7242104,No.7244385,and No.L248053)Research and Translational Application of Clinical Characteristic Diagnosis and Treatment Techniques in the Capital(No.Z221100007422070)Beijing Science and Technology Plan(No.Z231100007223006)National High Level Hospital Clinical Research Funding(No.2022-PUMCH-B-004)the Postdoctoral Fellowship Program of CPSF(No.GZB20240074).
文摘Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive and fatal malignancies,with a 5-year survival rate of<15%.Despite significant advancements in targeted therapies and immunotherapy,these approaches benefit only a limited subset of patients,leaving chemotherapy as the primary treatment modality for most patients.Chemotherapy is an essential adjunct to surgical resection,the only potentially curative option,playing a crucial role in reducing the tumor burden,delaying disease progression,and alleviating symptoms.However,its long-term efficacy is frequently undermined by the development of chemoresistance,wherein tumor cells adopt diverse strategies to evade or repair chemotherapy-induced damage.Addressing this critical barrier is imperative for improving the clinical outcomes of PDAC.This review comprehensively examines the multifaceted mechanisms of chemoresistance in PDAC and highlights innovative strategies designed to enhance chemosensitivity,thereby offering new hope for overcoming these challenges and improving patient survival.
文摘Colorectal cancer(CRC)is the third most common malignancy.However,the efficacy of current treatment strategies remains limited.In recent years,monomeric compounds from traditional Chinese medicine have received extensive attention in cancer therapy.Rosmarinic acid(RA),a natural phenolic acid,has multiple biological activities and exhibits anti-oncogenic effects in several cancers.Liu et al previously uncovered that RA could serve as a dual-action therapeutic agent in CRC.By suppressing nuclear factor-kappa B signaling via direct inhibition of inhibitory kappa B kinase beta,RA not only impedes tumor progression but also synergizes with first-line chemotherapeutics(5-fluorouracil/oxaliplatin)to reverse drug resistance.The authors demonstrate RA’s capacity to downregulate nuclear factor-kappa B-driven oncogenes and enhance chemotherapeutic cytotoxicity in vitro through integrative approaches,including molecular docking,luciferase assays,and functional validation.While these findings position RA as a cost-effective adjuvant in precision oncology,critical clinical translational gaps remain,including optimizing RA’s in vivo bioavailability,validating systemic safety in combinatorial regimens,and elucidating its immunomodulatory effects within the tumor microenvironment.This underscores the urgency of bridging phytochemistry and clinical oncology,advocating for biomarker-driven animal studies and phase I trials to translate RA’s potential into actionable CRC therapies.By addressing these hurdles,RA could emerge as a paradigm-shifting agent,harmonizing natural product efficacy with modern therapeutic precision.
基金Supported by the National Natural Science Foundation of China,No.U24A20765 and No.T2321005Jiangsu Provincial Science and Technology Plan Special Fund,No.BM2023003+5 种基金Jiangsu Provincial Medical Key Discipline,No.ZDXK202247the Priority Academic Program Development of the Jiangsu Higher Education InstitutesJiangsu Engineering Research Center on Drug Evaluation and Translation of Organoids/Organ Chip(2024)the Science and Technology Plan of Suzhou,No.SKYD2023183the Research Project Established by Chinese Pharmaceutical Association Hospital Pharmacy Department,No.CPA-Z05-ZC-2023002Gusu Health Talent Research Project,No.GSWS2022015.
文摘BACKGROUND Chemotherapy is an essential treatment for colorectal cancer(CRC)patients after surgery,but many patients do not benefit from chemotherapy because tumour heterogeneity results in varied responses.AIM To study the effectiveness of in vitro chemosensitivity tests adenosine tripho-sphate-based tumour chemotherapy sensitivity test(ATP-TCA)for tailoring po-stoperative chemotherapy regimens for patients with CRC.METHODS Between January 2015 to December 2021,a total of 1549 CRC patients underwent surgery and in vitro chemosensitivity testing using ATP-TCA.A subset of 405 patients who met the survival assessment criteria were followed to collect data on overall survival(OS)and disease-free survival(DFS).Cox regression analysis revealed independent prognostic factors that affect OS and DFS for those re-ceiving oxaliplatin(L-OPH)and fluoropyrimidine-based regimens,aiding in the development of clinical predictive models.The relationships between the ATP-TCA results and clinical outcomes were analysed using the Kaplan-Meier method.RESULTS Tumour heterogeneity and resistance to multiple drugs were observed in 1549 patients.The sensitivity to 5-fluorouracil(5-FU)combined with L-OPH was tested among 1474 of these patients,yielding a sensitivity rate of 11.9%.ATP-TCA results were identified as an independent prognostic factor for DFS[P=0.002,hazard ratio(95%confidence interval):4.98(1.81-13.72)]in patients with resectable CRC.Compared with drug-resistant patients,sensitive CRC patients treated with 5-FU and L-OPH had significantly prolonged DFS(P=0.027).Further Kaplan-Meier analysis indicated that ATP-TCA sensitivity was significantly associated with improved OS(P=0.048)and DFS(P=0.003)in patients with stage III CRC.CONCLUSION The response of CRC patients to the combination regimen of 5-FU and L-OPH is heterogeneous.This study confirmed that the ATP-TCA is a valuable tool for predicting clinical outcomes,such as DFS,in patients with resectable CRC receiving chemotherapy.Although further validation with multicentre data is still necessary,these findings support that the ATP-TCA may function as a guiding tool for personalized chemotherapy administration,thereby optimizing treatment opportunities for patients.
文摘The authors prove the local existence and uniqueness of weak solution of a hyperbolic-parabolic system and establish the global existence of the weak solution for this system for the spatial dimension n = 1.
文摘To establish a method to evaluate the effects of chemosensitizer onP-glycoprotein using ^(99m)Tc-MIBI, and observe the changes of ^(99m)Tc-MIBI uptake kinetics andP-glycoprotein levels after using verapamil in MDR human breast cells MCF-7/Adr. Methods: MDR breastcarcinoma cells, MCF-7/Adr, were incubated and different protocols were performed. Protocol Ⅰ: achemosensitizer, verapamil (10 μmol/L), was added into cell culture medium, while in control group,the same volume of DMEM was given. Cells were harvested after 2 h incubation with ^(99m)Tc-MIBI.Protocol Ⅱ: Verapamil (10 μmol/L) was added into cell culture medium and incubated for 20 min, 40min, 60 min, 80 min, 8 h, 24 h, 48 h and 72 h respectively. Cells were harvested after 2 hincubation with ^(99m)Tc-MIBI. The radioactivity of the cells was measured and P-glycoproteinexpression levels were determined with immunohistochemical stain. Results: Protocol Ⅰ: After 2hincubation with verapamil the cellular uptake of ^(99m)Tc-MIBI was remarkably higher than controlgroup (t=2.33, P 【 0.05), but there was no difference in P-glycoprotein expression levels betweentwo groups (P 】 0.05). Protocol Ⅱ: In verapamil group, ^(99m)Tc-MIBI uptake was increased withincubation time prolonging (F=58.2, P 【 0.05). When verapamil incubation time surpassed 8 h the^(99m)Tc-MIBI uptake negatively correlated to the P-glycoprotein expression levels (r=-0.73, P 【0.01). However, when incubation time was less than 80 min, there was no correlation between^(99m)Tc-MIBI accumulation and P-glycoprotein levels (r=0.16, P 】 0.05). Conclusion: ^(99m)Tc-MIBImay be used to evaluate the qualitative as well as quantitative change of P-glycoprotein expressionlevels induced by the chemosensitizer, verapamil.
基金Supported by Beijing Medical Health Public Welfare Foundation(grant no.YWJKJJHKYJJ-B17468 and running period:2017.09.01-2020.09.01)
文摘Objective Our previous study has revealed that iASPP is elevated in human head and neck squamous cell carcinoma(HNSCC)and iASPP overexpression signifcantly correlates with tumor malignant progression and poor survival of HNSCC.This study investigated the function of iASPP playing in proliferation and invasion of HNSCC in vitro.Methods HNSCC cell line Tu686 transfected with Lentiviral vector-mediated iASPP-specific shRNA and control shRNA were named the shRNA-iASPP group and shRNA-NC group,respectively.The non-infected Tu686 cells were named the CON group.CCK-8 assay,flow cytometry,transwell invasion assay were performed to detect the effects of iASPP inhibition in vitro.Results Our results demonstrated that the proliferation of shRNA-iASPP cells at the time of 72 h(F=32.459,P=0.000),96 h(F=51.407,P=0.000),120 h(F=35.125,P=0.000)post-transfection,was significantly lower than that of shRNANC cells and CON cells.The apoptosis ratio of shRNA-iASPP cells was 9.42%±0.39%(F=299.490,P=0.000),which was significantly higher than that of CON cells(2.80%±0.42%)and shRNA-NC cells(3.18%±0.28%).The percentage of shRNA-iASPP cells in G0/G1 phase was 74.65%±1.09%(F=388.901,P=0.000),which was strikingly increased,compared with that of CON cells(55.19%±1.02%)and shRNA-NC cells(54.62%±0.88%).The number of invading cells was 56±4 in the shRNA-iASPP group(F=84.965,P=0.000),which decreased significantly,compared with the CON group(111±3)and the shRNA-NC group(105±8).The survival rate of shRNA-iASPP cells administrated with paclitaxel was highly decreased,compared with CON cells and shRNA-NC cells(F=634.841,P=0.000).Conclusion These results suggest iASPP may play an important role in progression and aggressive behavior of HNSCC and may be an efficient chemotherapeutic target for the treatment of HNSCC.
文摘AIM:To investigate the predictive clinical value of in vitro 3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay for directing chemosensitivity in patients with gastric cancer. METHODS:Results of a total of 353 consecutive patients with gastric cancer treated with MTT-directed chemotherapy or physician’s empirical chemotherapy from July 1997 to April 2003 were reviewed and analyzed retrospectively. RESULTS:The overall 5-year survival rate of MTT- sensitive group (MSG) and control group (CG) was 47.5% and 45.1%, respectively. The results of subgroup analysis with Cox proportional-hazards model were favorable for the MSG-sensitive group. However, no statistically significant difference in survival rate was observed between the two groups. CONCLUSION:Individualized chemotherapy based on in vitro MTT assay is beneficial, but needs to be confirmed by further randomized controlled trials.
基金Supported by Research Council of Norway,NO.70174300
文摘Metabolomics is a field of study in systems biology that involves the identification and quantification of metabolites present in a biological system. Analyzing metabolic differences between unperturbed and perturbed networks, such as cancerous and noncancerous samples, can provide insight into underlying disease pathology, disease prognosis and diagnosis. Despite the large number of review articles concerning metabolomics and its application in cancer research, biomarker and drug discovery, these reviews do not focus on a specific type of cancer. Metabolomics may provide biomarkers useful for identification of early stage gastric cancer, potentially addressing an important clinical need. Here, we present a short review on metabolomics as a tool for biomarker discovery in human gastric cancer, with a primary focus on its use as a predictor of anticancer drug chemosensitivity, diagnosis, prognosis, and metastasis.
文摘Although gastric cancer(GC)is one of the leading causes of cancer-related death,major therapeutic advances have not been made,and patients with GC still face poor outcomes.The prognosis of GC also remains poor because the molecular mechanisms of GC progression are incompletely understood.MicroRNAs(miRNAs)are noncoding RNAs that are associated with gastric carcinogenesis.Studies investigating the regulation of gene expression by miRNAs have made considerable progress in recent years,and abnormalities in miRNA expression have been shown to be associated with the occurrence and progression of GC.miRNAs contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors,affecting cell proliferation,apoptosis,motility,and invasion.Moreover,a number of miRNAs have been shown to be associated with tumor type,tumor stage,and patient survival and therefore may be developed as novel diagnostic or prognostic markers.In this review,we discuss the involvement of miRNAs in GC and the mechanisms through which they regulate gene expression and biological functions.Then,we review recent research on the involvement of miRNAs in GC prognosis,their potential use in chemotherapy,and their effects on Helicobacter pylori infections in GC.A greater understanding of the roles of miRNAs in gastric carcinogenesis could provide insights into the mechanisms of tumor development and could help to identify novel therapeutic targets.
文摘AIM： To examine the effects of cyclin D1 antisense oligodexoyneucleotides （ASODN） on growth and chemosensitivity of gastric carcinoma cell lines SGC7901 and its mechanism. METHODS： Phosphorothioate modified cyclin D1 ASODN was encapsulated by LipofectAMINE2000 （LF2000） and transfected into cells, the dose-effect curves and growth curves were observed. 5-FU, MTX, CDDP of different concentrations were given after transfecting cells with cyclin D1 ASODN for 24 h, the dose-effect responses were observed and IC50s were calculated. The mRNA expression of cyclin D1, thymidylate synthase （TS）, thymidine phosphorylase （TP） and dihydrofolate reductase （DHFR） was detected by reverse transcription-PCR （RTPCR） at 24 h and 48 h after transfection. RESULTS： Dose-dependent inhibitory effect was caused by cyclin D1 ASODN in SGC7901 cells. Transfecting gastric carcinoma cells with 0.2 μmol/L cyclin D1 ASODN for 24 h could inhibit growth significantly and reduce expression of cyclin D1 mRNA. Cyclin D1 ASODN could increase the chemosensitivity to 5-FU, MTX, CDDP in cells, The IC50s of different chemotherapeutic agents in ASODN plus chemotherapy groups were significantly lower than those in controls. Transfection with cyclin D1 ASODN leaded to an increase in TS and DHFR mRNA and a decrease in TP mRNA as determined by RT-PCR at 24 h, the alterations were more significant at 48 h. CONCLUSIONS： Cyclin D1 ASODN can decrease mRNA expression of cyclin D1, inhibit growth and enhance the chemosensitivity by changing the expression of enzymes related to metabolism of chemotherapeutic agents in SGC7901 gastric carcinoma cells.
基金Grants-in-Aid and the 21st Century COE Program Special Research Grant from the Ministry of Education, Culture, Sports, Science and Technology of Japana Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan
文摘AIM: To evaluate the significance of BNIP3 in the pathogenesis of pancreatic cancer, we analyzed the relationship between the expression of BNIP3 and survival rate of the patients with pancreatic cancer, or chemosensitivities in pancreatic cancer cell lines, particularly for gemcitabine, the first-line anti-tumor drug for pancreatic cancer. METHODS: To compare the expression level of BNIP3 with the resistance to gemcitabine, eight pancreatic cancer cell lines were subjected to gemcitabine treatment and the quantitative real-time RT-PCR method was used to evaluate BNIP3 expression. Immunohistochemical analysis was also performed using 22 pancreatic cancer specimens to study relationship between BNIP3 expression and survival rate. RESULTS: Although no significantly positive association between BNIP3 mRNA level and gemcitabine chemosensitivity was observed, pancreatic cancer cell lines that were sensitive to gemcitabine treatment tended to show high levels of BNIP3 expression. The converse, an absence of BNIP3 expression, was not correlated with gemcitabine resistance. We further compared the BNIP3 expression profiles of resected primary pancreaticcancer specimens with the prognosis of the patients, and found a tendency of favorable prognosis and low BNIP3 expression. CONCLUSION: High levels of BNIP3 expression cannot be used as one of the predicting factors for gemcitabine chemosensitivity, and some yet to be known factors will have to fill the gap for the accurate prediction of pancreatic cancer chemosensitivity to gemcitabine. However, BNIP3 expression may have an impact on prediction of prognosis of patients with pancreatic cancer.
文摘Objective To investigate and compare the biological characteristics and sensitivity to chemotherapy and radiotherapy of intrahepatic and extrahepatic cholangiocarcinoma cells in vitro.Methods The intrahepatic and extrahepatic cholangiocarcinoma cell lines were established,and cells with steady passage were chosen to study the biological characteristics including morphology,growth dynamics,chromosome,and levels of cancer antigen(CA)125,CA19-9,alpha-fetoprotein(AFP),and carcino-embryonic antigen(CEA).Meanwhile,MTT assay was used to determine the sensitivity of both kinds of cells to 6 chemotherapeutic drugs,including cisplatin,paclitaxel,harringtonine,5-fluorouracil,vincristine,and aclacimomycin,and the inhibitory rate of cells under the irradiation of 10 Gy ray was also measured.Results The intrahepatic cholangiocarcinoma cells were mostly fusiform in shape,and extrahepatic cholangiocarcinoma cells were mostly round or polygon in shape.Their doubling time was 26.3 hours and 23.1 hours,respectively.Their average number of chromosomes was 59(range,38-84)and 67(range,49-103),respectively.The chromosome karyotypes of most intrahepatic cholangiocarcinoma cells were hyperdiploid and hypotriploid,while hypertriploid was predominant in extrahepatic cholangiocarcinoma cells.The level of CA 125 in supernatant of extrahepatic cholangiocarcinoma cells increased obviously,while levels of other determined tumor markers in both kinds of cells were all within normal range.The intrahepatic cholangiocarcinoma cells were low sensitive to cisplatin and paclitaxel,but not sensitive to the other 4 chemotherapeutic drugs.The extrahepatic cholangiocarcinoma cells were high sensitive to cisplatin,but not sensitive to the other 5 drugs.Both kinds of cells had poor sensitivity to radiotherapy.Conclusions Intrahepatic and extrahepatic cholangiocarcinoma cells show differences in shape,doubling time,chromosome karyotype,tumor marker level,and chemosensitivity,whereas they both have poor radiosensitivity.Though they are similar in histopathology,they have different growth characteristics and have discrepancy in treatment and prognosis.
基金supported by grants from the National Key Research and Development Project(Grant No.2019YFA0905600)the Major State Basic Research Development Program of the Natural Science Foundation of Shandong Province in China(Grant No.ZR2020ZD11)+2 种基金the National Natural Science Foundation of China(Grant Nos.81772633 and 31470967)the Science and Technology Program of Tianjin,China(Grant No.19YFSLQY00110)the Taishan Scholars Program of Shandong Province。
文摘Objective:We aimed to develop a novel anti-HIF-1αintrabody to decrease gemcitabine resistance in pancreatic cancer patients.Methods:Surface plasmon resonance and glutathione S-transferase pull-down assays were conducted to identify the binding affinity and specificity of anti-HIF-1αVHH212[a single-domain antibody(nanobody)].Molecular dynamics simulation was used to determine the protein-protein interactions between hypoxia-inducible factor-1α(HIF-1α)and VHH212.The real-time polymerase chain reaction(PCR)and Western blot analyses were performed to identify the expressions of HIF-1αand VEGF-A in pancreatic ductal adenocarcinoma cell lines.The efficiency of the VHH212 nanobody in inhibiting the HIF-1 signaling pathway was measured using a dual-luciferase reporter assay.Finally,a PANC-1 xenograft model was developed to evaluate the anti-tumor efficiency of combined treatment.Immunohistochemistry analysis was conducted to detect the expressions of HIF-1αand VEGF-A in tumor tissues.Results:VHH212 was stably expressed in tumor cells with low cytotoxicity,high affinity,specific subcellular localization,and neutralization of HIF-1αin the cytoplasm or nucleus.The binding affinity between VHH212 and the HIF-1αPAS-B domain was 42.7 n M.Intrabody competitive inhibition of the HIF-1αheterodimer with an aryl hydrocarbon receptor nuclear translocator was used to inhibit the HIF-1/VEGF pathway in vitro.Compared with single agent gemcitabine,co-treatment with gemcitabine and a VHH212-encoding adenovirus significantly suppressed tumor growth in the xenograft model with 80.44%tumor inhibition.Conclusions:We developed an anti-HIF-1αnanobody and showed the function of VHH212 in a preclinical murine model of PANC-1 pancreatic cancer.The combination of VHH212 and gemcitabine significantly inhibited tumor development.These results suggested that combined use of anti-HIF-1αnanobodies with first-line treatment may in the future be an effective treatment for pancreatic cancer.
文摘The molecular basis for enhanced chemosensitivity of testicular germ cell tumors （GCT） has been an area of great interest, as it could potentially give us therapeutic leads in other resistant malignancies. Thus far, however, the increased sensitivity of C＆T has been variously attributed to multiple factors -- an inability to detoxify cisplatin, a lack of export pumps, an inability to repair the DNA damage, an intact apoptotic cascade and lack of p53 mutation; but a unifying underlying etiology leading to the aforementioned processes and having a translational implication has so far been elusive. Herein, we offer evidence to support a potential significant role for the previously demonstrated low hypoxia inducible factor-la （HIF-la） expression in mediating the general exquisite chemosensitivity of testicular GCT, through the aforementioned processes. This molecular mechanism based hypothesis could have a significant translational implication in platinum refractory GCT as well as other platinum resistant malignancies.
基金Supported by Department of Science and Technology,Government of India
文摘AIM： To determine the functional significance of TC21 in esophageal squamous cell carcinoma （ESCC）. METHODS： TC21 siRNA transfection was carried out using Hyperfectamine to knock down TC21, and tran- scripts were analyzed by reverse transcription-poly- merase chain reaction and protein by Western blotting.We demonstrated the effect of TC21 downregulation of cell signaling in esophageal cancer cells by assess- ing the phosphorylation status of its downstream tar- gets, phosphoinositide 3-kinase （PI3K）, phosphatase and tensin homolog （PTEN）, protein kinase B （pAl〈t）, nuclear factor-KB （NF-~B） and cyclinD1 using specific antibodies. Cell survival analysis after cisplatin treat- ment was carried out by cell viability assay and cell cycle analysis using flow cytometry. RESULTS： TC21 knockdown in human ESCC cell line TEl3 cells, showed only a marginal increase （14.2%） in cell death compared with control cells. The expres- sions of the signaling proteins PI3K and pAkt, transcrip- tion factor NF-KB, and cell cycle protein cyclin D1 were markedly decreased in response to TC21 downregula- tion, whereas the level of pPTEN, an antagonist of PI3K, was increased. In addition, we evaluated the potential of TC21 as a putative target for sensitizing ESCC cells to the chemotherapeutic agent cisplatin. Increased cell death （38.4%） was observed in cells treated with cis- platin after TC21 knockdown compared with cells which were treated with cisplatin alone （20% cell death）. CONCLUSION： Results suggest that TC21 mediates its effects via the PI3K-Akt pathway, NF-KB and cyclin D1, and enhances chemoresistance in esophageal cancer cells.
文摘Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However, a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, even in the absence of a response to modern targeted therapies and immunotherapies; accordingly, determining predictive biomarkers of the response to chemotherapies for metastatic melanoma remains a priority to guide treatment in these patients. We report a case study of a patient with B-Raf proto-oncogene serine/threonine kinase-mutated metastatic melanoma harbouring many genetic mutations. The patient did not respond to prior targeted therapies or immunotherapies but experienced a dramatic objective radiological and clinical response to subsequent dacarbazine-based chemotherapy. In the era of targeted therapies and immunotherapies for metastatic melanoma, cytotoxic chemotherapies may still represent an interesting therapeutic weapon in a well-deined subgroup of patients presenting with speciic genetic and molecular features.
基金Supported by National Natural Science Foundation of China,No.81272480/H1609
文摘AIM: To investigate the effect of Girdin knockdown on the chemosensitivity of colorectal cancer cells to oxaliplatin and the possible mechanisms involved.
基金supported by the National Natural Science Foundation of China(Grant No.81502309)。
文摘Objective:The aim of the study was to identify specific chemosensitivity drugs for various molecular subtypes of breast tumors in Chinese women,by detecting the expression of drug resistance genes and by using the drug sensitivity test on different molecular subtypes of breast cancers.Methods:The expression of drug resistance genes including Topo Ⅱ,GST-π,P-gp,LRP,and CD133 were detected with immunohistochemistry in a tissue microarray.Drug sensitivity tests included those for paclitaxel,epirubicin,carboplatin,vinorelbine,and fluorouracil and were conducted on primary cancer tissue cells and cell lines,including the T47 D,BT-474,and MDA-MB-231 cells and human breast cancer xenografts in nude mice.Results:The different drug resistant genes Topo Ⅱ,GST-π,P-gp,and LRP were differentially expressed among different molecular subtypes of breast cancers(P<0.05).Positive expression of CD133 was highest in basal-like breast cancer(P<0.05).Kaplan-Meier survival analysis showed that positive expressions of Topo Ⅱ and CD133 both correlated with shorter disease-free survival(DFS)(P<0.05)and overall survival(P<0.05),and positive expression of LRP correlated only with shorter DFS(P<0.05).BT-474 showed chemosensitivity to paclitaxel and epirubicin,while MDA-MB-231 showed chemosensitivities to paclitaxel,epirubicin,carboplatin,and fluorouracil(T/C≤50%).The basal-like and HER2+breast cancer primary cells showed chemosensitivities to paclitaxel and epirubicin with significant differences compared with luminal breast cancer primary cells(P<0.05).Conclusions:The differential expression of drug resistance genes and the differential chemosensitivities of drugs in different molecular subtype of breast cancers suggested that individual treatment should be given for each type of breast cancer.
基金the major science and technology project of health and family planning commission of Changzhou City(Nos.ZD201502,ZD201709).
文摘Pancreatic cancer is one of the most aggressive malignancies with poor prognosis and high mortality.Recent studies showed that microRNAs are dysregulated and involved in the initiation and progression of pancreatic cancer.In this study,we found that miR-708 was significantly downregulated in pancreatic cancer tissues and cell lines.Lentivirus-mediated overexpression of miR-708 could significantly inhibit the proliferation and invasion,while enhanced chemosensitivity to gemcitabine in both Panc-1 and SW1990 cells.Luciferase reporter assay showed that miR-708 bound the 3’-untranslated region of survivin and suppressed the expression of survivin in pancreatic cancer cells.In pancreatic cancer tissues,survivin protein was highly expressed and negatively correlated with miR-708 expression.Furthermore,the restoration of survivin expression could partially antagonize proliferation inhibition and apoptosis induction by miR-708 in pancreatic cancer cells.The Panc-1 cells with overexpression of miR-708 also showed decreased proliferation capability in nude mouse model compared with parental cells.In conclusion,our results suggest that miR-708 inhibits pancreatic cancer and could be a novel potential candidate to treat pancreatic cancer.
