The q24 band of chromosome 8 （8q24） is frequently amplified in human cancers including breast cancer, and several SNPs （single nucleotide polymorphisms） at 8q24, including rs13281615, have been identified for thei...The q24 band of chromosome 8 （8q24） is frequently amplified in human cancers including breast cancer, and several SNPs （single nucleotide polymorphisms） at 8q24, including rs13281615, have been identified for their association with cancer risks. These SNPs are in a ＂gene desert＂ region, and their functions in cancer development remain to be illustrated, although several of the SNPs appear to influence the genes in the ＂desert＂ in a long-range manner, including the v-myc avian myelocytomatosis viral oncogene homolog （MYC） and the non- protein coding plasmacytoma variant translocation 1 （PVT1）, both of which have been implicated in human cancers. In the current study, we examined rs13281615 for its potential role in breast cancer using normal and cancer tissues from 121 Chinese women with breast cancer. In addition to confirming the association of the GG genotype of rs 13281615 with breast cancer risk, we found that germline GG genotype was significantly associated with estrogen receptor （ER） positivity, higher tumor grade and higher proliferation index. We also found frequent somatic mutations （22/121 or 18.2%） of this SNP in breast cancer. Interestingly, the majority of the mutations （17/22 or 77%） involved a G→ A change, resulting in a decrease in the number of cancers with the GG risk genotype and subsequent loss of GG association with higher tumor grade and proliferation index in cancers. Furthermore, PVT1 expression was increased in cancers, and the increase was associated with the GG genotype of rs13281615. These results suggest that the GG genotype of SNP rs13281615 plays a role in breast cancer likely by influencing PVT1 expression, and that during oncogenesis, ＂protective＂ mutations could occur.展开更多
Peroxisome proliferator-activated receptorsγ(PPARγ)is a master regulator that controls energy metabolism and cell fate.PPARγ2,a PPARγisoform,is highly expressed in the normal prostate but expressed at lower levels...Peroxisome proliferator-activated receptorsγ(PPARγ)is a master regulator that controls energy metabolism and cell fate.PPARγ2,a PPARγisoform,is highly expressed in the normal prostate but expressed at lower levels in prostate cancer tissues.In the present study,PC3 and LNCaP cells were used to examine the benefits of restoring PPARγ2 activity.PPARγ2 was overexpressed in PC3 and LNCaP cells,and cell proliferation and migration were detected.Hematoxylin and eosin(H&E)staining was used to detect pathological changes.The genes regulated by PPARγ2 overexpression were detected by microarray analysis.The restoration of PPARγ2 in PC3 and LNCaP cells inhibited cell proliferation and migration.PC3-PPARγ2 tissue recombinants showed necrosis in cancerous regions and leukocyte infiltration in the surrounding stroma by H&E staining.We found higher mixed lineage kinase domain-like(MLKL)and lower microtubule-associated protein 1 light chain 3(LC3)expression in cancer tissues compared to controls by immunohistochemistry(IHC)staining.Microarray analysis showed that PPARγ2 gain of function in PC3 cells resulted in the reprogramming of lipid-and energy metabolism-associated signaling pathways.These data indicate that PPARγ2 exerts a crucial tumor-suppressive effect by triggering necrosis and an inflammatory reaction in human prostate cancer.展开更多
The androgen receptor （AR） plays an important role in the development and progression of prostate cancer （PCa）. Androgen deprivation therapy is initially effective in blocking tumor growth, but it eventually leads...The androgen receptor （AR） plays an important role in the development and progression of prostate cancer （PCa）. Androgen deprivation therapy is initially effective in blocking tumor growth, but it eventually leads to the hormonerefractory state. The detailed mechanisms of the conversion from androgen dependence to androgen independence remain unclear. Several PCa cell lines were established to study the role of AR in PCa, but the results were often inconsistent or contrasting in different cell lines, or in the same cell line grown under different conditions. The cellular and molecular alteration of epithelial cells and their microenvironments are complicated, and it is difficult to use a single cell line to address this important issue and also to study the pathophysiological effects of AR. In this paper, we summarize the different effects of AR on multiple cell lines and show the disadvantages of using a single human PCa cell line to study AR effects on PCa. We also discuss the advantages of widely used epithelium-stroma co-culture systems, xenograft mouse models, and genetically engineered PCa mouse models. The combination of in vitro cell line studies and in vivo mouse models might lead to more credible results and better strategies for the study of AR roles in PCa.展开更多
Three-dimensional （3D） quantitative structure-activity relationship （QSAR） studies of 44 curcumin-related compounds have been carried out based on our previously reported result for their anticancer activity again...Three-dimensional （3D） quantitative structure-activity relationship （QSAR） studies of 44 curcumin-related compounds have been carried out based on our previously reported result for their anticancer activity against pancreas cancer Panc-I cells and colon cancer HT-29 cells. The established 3D-QSAR models from the comparative molecular field analysis （CoMFA） in training set showed not only significant statistical quality, but also satisfying predictive ability, with high correlation coefficient values （R12= 0.911, R22= 0.985） and cross-validation coefficient values （q2= 0.580, q22= 0.722）. Based on the CoMFA contour maps, some key structural factors responsible for anticancer activity of these series of compounds were revealed. The results provide some useful theoretical references for understanding the mechanism of action, designing new curcumin-related compounds with anticancer activity and predicting their activities prior to synthesis.展开更多
AIM To investigate rates of distant metastases(DM)detected with[18]fluorodeoxyglucose-positron emissiontomography/computed tomography(^(18)FDG-PET/CT)in early stage invasive breast cancer.METHODS We searched the Engli...AIM To investigate rates of distant metastases(DM)detected with[18]fluorodeoxyglucose-positron emissiontomography/computed tomography(^(18)FDG-PET/CT)in early stage invasive breast cancer.METHODS We searched the English language literature databases of PubM ed,EMBASE,ISI Web of Knowledge,Web of Science and Google Scholar,for publications on DM detected in patients who had^(18)FDG-PET/CT scans as part of the staging for early stages of breast cancer(stageⅠ?andⅡ),prior to or immediately following surgery.Reports published between 2011 and 2017 were considered.The systematic review was conducted according to the PRISMA guidelines.RESULTS Among the 18 total studies included in the analysis,the risk of DM ranged from 0%to 8.3%and 0%to 12.9%for stageⅠ?andⅡinvasive breast cancer,respectively.Among the patients with clinical stageⅡ,the rate of occult metastases diagnosed by^(18)FDG-PET/CT was 7.2%(range,0%-19.6%)for stageⅡA and 15.8%(range,0%-40.8%)for stageⅡB.In young patients(<40-yearold),^(18)FDG-PET/CT demonstrated a higher prevalence of DM at the time of diagnosis for those with aggressive histology(i.e.,triple-negative receptors and poorly differentiated grade).CONCLUSION Young patients with poorly differentiated tumors and stageⅡB triple-negative breast cancer may benefit from^(18)FDG-PET/CT at initial staging to detect occult DM prior to surgery.展开更多
The explosion of new therapeutics in metastatic castrate-resistant prostatecancer （mCRPC） is unprecedented, but much more work needs to be done before we are satisfied. Six phase III trials with an overall survival ...The explosion of new therapeutics in metastatic castrate-resistant prostatecancer （mCRPC） is unprecedented, but much more work needs to be done before we are satisfied. Six phase III trials with an overall survival impact have now been reported （Table 1）.1-6 Four of these trials were exclusively or predominantly in the mCRPC post-docetaxel space （MDV3100, abiraterone, 223radium and cabazitaxel）. The 223radium trial also uniquely offered therapy to patients who were unsuitable for or refused docetaxel. The sipuleucel-T trial focused on mCRPC patients who were asymptomatic or minimally symptomatic; most of these patients were chemotherapy naive.展开更多
In many parts of the world hepatocellular carcinoma (HCC)is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood.There is increasing evidence t...In many parts of the world hepatocellular carcinoma (HCC)is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood.There is increasing evidence that activins,which are members of the transforming growth factorβ(TGFβ)superfamily of growth and differentiation factors,could play important roles in liver carcinogenesis.Activins are disulphide-linked homo- or heterodimers formed from four differentβsubunits termedβA,βB,βC,andβE,respectively.Activin A, the dimer of twoβA subunits,is critically involved in the regulation of cell growth,apoptosis,and tissue architecture in the liver,while the hepatic function of other activins is largely unexplored so far.Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG,and at the cell membrane antagonistic coreceptors like Cripto or BAMBI.Additionally,in the intracellular space inhibitory Smads can modulate and control activin activity.Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation,fibrosis and development of cancer.The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis.展开更多
This review summarizes and describes the use of curcumin in diagnosis,prevention,and treatment of Alzheimer＇s disease.For diagnosis of Alzheimer＇s disease,amyloid-β and highly phosphorylated tau protein are the maj...This review summarizes and describes the use of curcumin in diagnosis,prevention,and treatment of Alzheimer＇s disease.For diagnosis of Alzheimer＇s disease,amyloid-β and highly phosphorylated tau protein are the major biomarkers.Curcumin was developed as an early diagnostic probe based on its natural fluorescence and high binding affinity to amyloid-β.Because of its multi-target effects,curcumin has protective and preventive effects on many chronic diseases such as cerebrovascular disease,hypertension,and hyperlipidemia.For prevention and treatment of Alzheimer＇s disease,curcumin has been shown to effectively maintain the normal structure and function of cerebral vessels,mitochondria,and synapses,reduce risk factors for a variety of chronic diseases,and decrease the risk of Alzheimer＇s disease.The effect of curcumin on Alzheimer＇s disease involves multiple signaling pathways：anti-amyloid and metal iron chelating properties,antioxidation and anti-inflammatory activities.Indeed,there is a scientific basis for the rational application of curcumin in prevention and treatment of Alzheimer＇s disease.展开更多
Androgen and androgen receptor （AR） play important roles in male spermatogenesis and fertility, yet detailed androgen/AR signals in Sertoli cells remain unclear. To identify AR target genes in Sertoli cells, we anal...Androgen and androgen receptor （AR） play important roles in male spermatogenesis and fertility, yet detailed androgen/AR signals in Sertoli cells remain unclear. To identify AR target genes in Sertoli cells, we analyzed the gene expression profiles of testis between mice lacking AR in Sertoli cells （S-AR-/y） and their littermate wild-type （WT） mice. Digital gene expression analysis identified 2276 genes downregulated and 2865 genes upregulated in the S-AR-/y mice testis compared to WT ones. To further nail down the difference within Sertoli cells, we first constructed Sertoli cell line TM4 with stably transfected AR （named as TM4/AR） and found androgens failed to transactivate AR in Sertoli TM4 and TM4/AR cells. Interestingly, additional transient transfection of AR-cDNA resulted in significant androgen responsiveness with TM4/AR cells showing 10 times more androgen sensitivity than TM4 cells. In the condition where maximal androgen response was demonstrated, we then analyzed gene expression and found the expression levels of 2313 genes were changed more than twofold by transient transfection of AR-cDNA in the presence of testosterone. Among these genes, 603 androgen-/ AR-regulated genes, including 164 upregulated and 439 downregulated, were found in both S-AR-/y mice testis and TM4/AR cells. Using informatics analysis, the gene ontology was applied to analyze these androgen-/AR-regulated genes to predict the potential roles of androgen/AR in the process of spermatogenesis. Together, using gene analysis in both S-AR-/y mice testis and TM4/AR cells may help us to better understand the androeen/AR signals in Sertoli cells and their influences in spermatogenesis.展开更多
There is a continuing need for novel antivirals to treat hepatitis B virus (HBV) infection, as it remains a major health problem worldwide. Ideally new classes of antivirals would target multiple steps in the viral li...There is a continuing need for novel antivirals to treat hepatitis B virus (HBV) infection, as it remains a major health problem worldwide. Ideally new classes of antivirals would target multiple steps in the viral lifecycle. In this review, we consider the steps in which HBV RNAs are processed, exported from the nucleus and translated. These are often overlooked steps in the HBV life-cycle. HBV, like retroviruses, incorporates a number of unusual steps in these processes, which use a combination of viral and host cellular machinery. Some of these unusual steps deserve a closer scrutiny. They may provide alternative targets to existing antiviral therapies, which are associated with increasing drug resistance. The RNA post-transcriptional regulatory element identified 20 years ago promotes nucleocytoplasmic export of all unspliced HBV RNAs. There is evidence that inhibition of this step is part of the antiviral action of interferon. Similarly, the structured RNA epsilon element situated at the 5’ end of the polycistronic HBV pregenomic RNA also performs key roles during HBV replication. The pregenomic RNA, which is the template for translation of both the viral core and polymerase proteins, is also encapsidated and used in replication. This complex process, regulated at the epsilon element, also presents an attractive antiviral target. These RNA elements that mediate and regulate gene expression are highly conserved and could be targeted using novel strategies employing RNAi, miRNAs or aptamers. Such approaches targeting these functionally constrained genomic regions should avoid escape mutations. Therefore understanding these regulatory elements, along with providing potential targets, may also facilitate the development of other new classes of antiviral drugs.展开更多
Racemic[^(18)F]FBFP([^(18)F]1)proved to be a potentσ_(1) receptor radiotracer with superior imaging properties.The pure enantiomers of unlabeled compounds(S)-and(R)-1 and the corresponding iodonium ylide precursors w...Racemic[^(18)F]FBFP([^(18)F]1)proved to be a potentσ_(1) receptor radiotracer with superior imaging properties.The pure enantiomers of unlabeled compounds(S)-and(R)-1 and the corresponding iodonium ylide precursors were synthesized and characterized.The two enantiomers(S)-1 and(R)-1 exhibited comparable high affinity forσ_(1) receptors and selectivity overσ_(2) receptors.The Ca^(2+) fluorescence assay indicated that(R)-1 behaved as an antagonist and(S)-1 as an agonist forσ_(1) receptors.The ^(18)F-labeled enantiomers(S)-and(R)-[^(18)F]1 were obtained in>99%enantiomeric purity from the corresponding enantiopure iodonium ylide precursors with radiochemical yield of 24.4%±2.6%and molar activity of 86–214 GBq/μmol.In ICR mice both(S)-and(R)-[^(18)F]1displayed comparable high brain uptake,brain-to-blood ratio,in vivo stability and binding specificity in the brain and peripheral organs.In micro-positron emission tomography(PET)imaging studies in rats,(S)-[^(18)F]1 exhibited faster clearance from the brain than(R)-[^(18)F]1,indicating different brain kinetics of the two enantiomers.Both(S)-and(R)-[^(18)F]1 warrant further evaluation in primates to translate a single enantiomer with more suitable kinetics for imaging theσ_(1) receptors in humans.展开更多
Testicular nuclear receptor 4(TR4),also known as NR2C2(nuclear receptor subfamily 2,group C,member 2),is a transcriptional factor and a member of the nuclear receptor family.TR4 was initially cloned from human and rat...Testicular nuclear receptor 4(TR4),also known as NR2C2(nuclear receptor subfamily 2,group C,member 2),is a transcriptional factor and a member of the nuclear receptor family.TR4 was initially cloned from human and rat hypothalamus,prostate,and testes libraries.For almost two decades,its specific tissue distribution,genomic organization,and chromosomal assignment have been well investigated in humans and animals.However,it has been very difficult to study TR4's physiological functions due to a lack of specific ligands.Gene knock-out animal techniques provide an alternative approach for defining the biological functions of TR4.In vivo studies of TR4 gene knockout mice(TR4-/-) found that they display severe spinal curvature,subfertility,premature aging,and prostate prostatic intraepithelial neoplasia(PIN) development.Upstream modulators,downstream target gene regulation,feedback mechanisms,and differential modulation mediated by the recruitment of other nuclear receptors and coregulators have been identified in studies using the TR4-/-phenotype.With the establishment of a tissue-specific TR4-/-mouse model,research on TR4 will be more convenient in the future.展开更多
Background Within the follicular fluid,extracellular vesicles(EVs)guide oocyte growth through their cargo microRNAs(miRNAs).Here,we inv estigated the role of EVs and their cargo miRNAs by linking the miRNAs found in E...Background Within the follicular fluid,extracellular vesicles(EVs)guide oocyte growth through their cargo microRNAs(miRNAs).Here,we inv estigated the role of EVs and their cargo miRNAs by linking the miRNAs found in EVs,derived from the fluid of an individual follicle,to the ability of its oocyte to become a blastocyst(competent)or not(non-competent).Methods Bovine antral follicles were dissected,categorized as small(2-4 mm)or large(5-8 mm)and the corresponding oocytes were subjected to individual maturation,fertilization and embryo culture to the blastocyst stage.Follicular fluid was pooled in 4 groups(4 replicates)based on follicle size and competence of the corresponding oocyte to produce a blastocyst.Follicular fluid-derived EVs were isolated",characterized,and subjected to miRNAsequencing(Illumina Miseq)to assess differential expression(DE)in the 4 groups.Functional validation of the effect of miR-34c on embryo development was performed by supplementation of mimics and inhibitors during in vitro maturation(IVM).Results We identified 16 DE miRNAs linked to oocyte competence when follicular size was not considered.Within the large and small follicles,46 DE miRNAs were driving blastocyst formation in each group.Comparison of EVs from competent small and large follicles revealed 90 DE miRNAs.Cell regulation,cell differentiation,cell cycle,and metabolic process regulation were the most enriched pathways targeted by the DE miRNAs from competent oocytes.We identified bta-miR-34c as the most abundant in follicular fluid containing competent oocytes.Supplementation of miR-34c mimic and inhibitor during IVM did not affect embryo development.However,blastocyst quality,as evidenced by higher cell numbers,was significantly improved following oocyte IVM in the presence of miR-34c mimics,while miR-34c inhibitors resulted in the opposite effect.Conclusion This study demonstrates the regulatory effect of miRNAs from follicular fliived EVs on oocyte competence acquisitividing a further basis for understanding the significance of miRNAs in oocyte maturation and embryonic development Up-regulation of miR-34c in EVs from follicular fluid containing competent oocytes and the positive impact of miR-34c mimics added during IVM on the resulting blastocysts indicate its pivotal role in oocyte competence.展开更多
Androgen deprivation therapy （ADT）, which aims to reduce androgen-androgen receptor （AR） signaling, is the normal method of prostate cancer treatment. Despite its early success in suppressing prostate tumor growth...Androgen deprivation therapy （ADT）, which aims to reduce androgen-androgen receptor （AR） signaling, is the normal method of prostate cancer treatment. Despite its early success in suppressing prostate tumor growth, the therapy eventually fails, leading to recurrent hormone-refractory tumor growth. Recent studies have been carried out with stromal cell-specific or fibroblastspecific AR knockout mice or prostate stromal-specific and epithelial-specific AR knockout transgenic mice prostate cancer models and in vitro and in vivo studies of various human prostate cancer cells with knock-in and knock-out of the AR. These have indicated that the AR in prostatic stroma acts as a proliferation stimulator and survival factor, whereas epithelial AR acts as a survival factor for epithelial luminal cells and stromal smooth muscle cell differentiation, and as a suppressor for epithelial basal intermediate cell proliferation. These two opposite AR pose a major challenge for roles of the stromal and epithelial ADT and should be taken into account when developing new therapies targeting AR in selective cells.展开更多
Introduction: Squamous cell carcinoma (SCC) is the predominant neoplastic tumor that occurs in the oral cavity. SCC arising from the maxillary gingiva, hard palate and maxillary alveolus is relatively rare. Since soft...Introduction: Squamous cell carcinoma (SCC) is the predominant neoplastic tumor that occurs in the oral cavity. SCC arising from the maxillary gingiva, hard palate and maxillary alveolus is relatively rare. Since soft tissue barrier is thin, the diagnosis of cancer in these regions is usually ulcerative and invasive to the underlying bone already in the early stages of the disease. The aim of the present study was to retrospectively evaluate our data regarding the management of loco-regional lymph nodes and the efficacy of neck dissection in the clinically negative neck when maxillary squamous cell carcinoma is diagnosed. Furthermore, we wish to establish the role of prophylactic neck dissection and T stage from which it should be implemented. Methods: Archival records of oncological patients that were treated for SCC of the maxillary alveolus, hard palate and gingiva were collected. Overall 20 patients met the inclusion criteria, 11 men and 9 women. Average age of first diagnosis was 68 years. Results: At initial examination, 2 patients (10%) had clinically positive lymph nodes and undergone therapeutic neck dissection. The remaining 18 patients had clinically N0 necks. Five patients (28%) had occult positive lymph nodes following prophylactic neck dissection. One of the patients had a primary resection with no neck treatment. This patient eventually developed metastases in the neck two month post-surgery (occult disease). The overall positive lymph nodes in maxillary squamous cell carcinoma were 40% (8/20) with an occult metastasis rate of 33% (6/18). Disease specific mortality was 45% (9/20). Conclusion: In the present study, the majority of patients that were diagnosed with occult metastatic disease were either large tumors (T4, 60%) or with moderate to poor differentiation (mood-poor 80%). We conclude that patients who are present with a high grade (moderate-poor) large or invasive maxillary SCC (T2-T4), a prophylactic selective neck dissection (levels I-III) should be performed.展开更多
Neuroblastoma(NB),a frequently occurring pediatric disease,is derived from the neural crest cells in the sympathetic ganglia and adrenal medulla.Notably,it is a heterogeneous tumor consisting of many affection factors...Neuroblastoma(NB),a frequently occurring pediatric disease,is derived from the neural crest cells in the sympathetic ganglia and adrenal medulla.Notably,it is a heterogeneous tumor consisting of many affection factors,such as the diagnosis time within the first year and the diversity of the histology and genetic features.Despite improved outcomes in NB patients,it remains a difficult clinical problem and requires new therapeutic targets and methods.The somatic acquired activation point mutations in the receptor tyrosine kinase anaplastic lymphoma kinase(ALK)represent potential targets for treating NB.Herein,we review the underlying mechanisms of ALK in NB development,the latest available strategies to block ALK constitutive activity to treat NB,and discuss the current clinical challenges of resistance to these therapies and the strategies to overcome them.展开更多
Background:Chemotherapy resistance is a primary reason of ovarian cancer therapy failure;hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeuti...Background:Chemotherapy resistance is a primary reason of ovarian cancer therapy failure;hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeutic targets.Methods:RNA sequencing of cisplatin-resistant and sensitive(chemoresis-tant and chemosensitive,respectively)ovarian cancer organoids was performed,followed by detection of the expression level of fibrillin-1(FBN1)in organoids and clinical specimens of ovarian cancer.Subsequently,glucose metabolism,angiogenesis,and chemosensitivity were analyzed in structural glycoprotein FBNl-knockout cisplatin-resistant ovarian cancer organoids and cell lines.To gain insights into the specific functions and mechanisms of action of FBN1 in ovarian cancer,immunoprecipitation,silver nitrate staining,mass spectrometry,immunofluorescence,Western blotting,and Forister resonance energy transfer-fluorescence lifetime imaging analyses were performed,followed by in vivo assays using vertebrate model systems of nude mice and zebrafish.Results:FBN1 expression was significantly enhanced in cisplatin-resistant ovar-ian cancer organoids and tissues,indicating that FBNI might be a key factor in chemoresistance of ovarian cancer.We also discovered that FBN1 sustained the energy stress and induced angiogenesis in vitro and in vivo,which promoted the cisplatin-resistance of ovarian cancer.Knockout of FBN1 combined with treat-ment of the antiangiogenic drug apatinib improved the cisplatin-sensitivity of ovarian cancer cells.Mechanistically,FBN1 mediated the phosphorylation of vascular endothelial growth factor receptor 2(VEGFR2)at the Tyrl054 residue,which activated its downstream focal adhesion kinase(FAK)/protein kinase B(PKB or AKT)pathway,induced the phosphorylation of signal transducer and activator of transcription 2(STAT2)at the tyrosine residue 690(Tyr690),pro-moted the nuclear translocation of STAT2,and ultimately altered the expression of genes associated with STAT2-mediated angiogenesis and glycolysis.Conclusions:The FBN1/VEGFR2/STAT2 signaling axis may induce chemore-sistance of ovarian cancer cells by participating in the process of glycolysis and angiogenesis.The present study suggested a novel FBNl-targeted therapy and/or combination of FBN1 inhibition and antiangiogenic drug for treating ovarian cancer.展开更多
Invariant natural killer T(iNKT)cells are part of the family of unconventional T cells,and they recognize glycolipid antigens presented on the MHC class I like molecule CD1^([1]).In humans there are five CD1 molecules...Invariant natural killer T(iNKT)cells are part of the family of unconventional T cells,and they recognize glycolipid antigens presented on the MHC class I like molecule CD1^([1]).In humans there are five CD1 molecules named CD1a to CD1e,whereas mice use only CD1d for lipid presentation.Functionally,iNKT cells can elicit both cytotoxicity similarly to conventional CD8 T cells and secrete cytokines that influence the adaptive immune response including providing direct T cell help to B cells^([2]).In the context of tumors,they can use both release of granzyme B and use Fas-mediated mechanisms for killing of tumor cells.As iNKT cells use a restricted TCR repertoire and CD1 molecules are non-heterogenous the risk of graft vs host disease is limited and thus these T cells have been an attractive option for off the shelf immunotherapy to treat cancer^([3]).展开更多
Mammalian cells have the ability to respond to a myriad of diverse extracellular stimuli that modulate cell function.This often involves ligands binding to cell surface receptors and subsequent activation of intracell...Mammalian cells have the ability to respond to a myriad of diverse extracellular stimuli that modulate cell function.This often involves ligands binding to cell surface receptors and subsequent activation of intracellular signaling pathways.These pathways can lead to changes in gene expression patterns that in turn regulate cell growth,differentiation,migration,and function.One important type of cell surface receptor is the receptor tyrosine kinase(RTK).In response to in response to ligand binding,RTKs dimerize,then trans-phosphorylate each other,leading to activation of downstream pathways.While the signaling proteins in these pathways are important for normal cell growth control,when improperly regulated they can lead to uncontrolled growth and sometimes cancer.For this reason,they are often considered to be good candidates for drug targets for chemotherapeutic drugs.RTKs can activate multiple different signaling pathways.Some of the signaling proteins in these pathways can have crosstalk with other RTK activated pathways,and some of them can be activated by multiple mechanisms in addition to activation by RTKs.While there is a wide array of different signaling proteins and pathways activated by RTKs,in this review we will discuss components of several key pathways including the MAPK pathway,the Her2/Neu pathway,mTOR,and Pak kinases.We provide an overview of the roles for these pathways in cell signaling and discuss how different components of these pathways are being considered as targets for cancer treatment.展开更多
The control of cell proliferation is an essential feature in development and tissue homeostasis and is prominently deregulated in tumors.Three publications in Nature now uncover the mechanism underlying the degradatio...The control of cell proliferation is an essential feature in development and tissue homeostasis and is prominently deregulated in tumors.Three publications in Nature now uncover the mechanism underlying the degradation of cyclin D1-3 and provide important insights for the targeted therapy of the cancer cell cycle.展开更多
基金supported by the National Nature Science Foundation of China (Nos.30870980,31171250,and 30625032)the National Basic Research Program of China (No.2007CB914802)
文摘The q24 band of chromosome 8 （8q24） is frequently amplified in human cancers including breast cancer, and several SNPs （single nucleotide polymorphisms） at 8q24, including rs13281615, have been identified for their association with cancer risks. These SNPs are in a ＂gene desert＂ region, and their functions in cancer development remain to be illustrated, although several of the SNPs appear to influence the genes in the ＂desert＂ in a long-range manner, including the v-myc avian myelocytomatosis viral oncogene homolog （MYC） and the non- protein coding plasmacytoma variant translocation 1 （PVT1）, both of which have been implicated in human cancers. In the current study, we examined rs13281615 for its potential role in breast cancer using normal and cancer tissues from 121 Chinese women with breast cancer. In addition to confirming the association of the GG genotype of rs 13281615 with breast cancer risk, we found that germline GG genotype was significantly associated with estrogen receptor （ER） positivity, higher tumor grade and higher proliferation index. We also found frequent somatic mutations （22/121 or 18.2%） of this SNP in breast cancer. Interestingly, the majority of the mutations （17/22 or 77%） involved a G→ A change, resulting in a decrease in the number of cancers with the GG risk genotype and subsequent loss of GG association with higher tumor grade and proliferation index in cancers. Furthermore, PVT1 expression was increased in cancers, and the increase was associated with the GG genotype of rs13281615. These results suggest that the GG genotype of SNP rs13281615 plays a role in breast cancer likely by influencing PVT1 expression, and that during oncogenesis, ＂protective＂ mutations could occur.
基金The work was supported by the National Natural Science Foundation of China(NSFCNo.81874171 and 81703259).
文摘Peroxisome proliferator-activated receptorsγ(PPARγ)is a master regulator that controls energy metabolism and cell fate.PPARγ2,a PPARγisoform,is highly expressed in the normal prostate but expressed at lower levels in prostate cancer tissues.In the present study,PC3 and LNCaP cells were used to examine the benefits of restoring PPARγ2 activity.PPARγ2 was overexpressed in PC3 and LNCaP cells,and cell proliferation and migration were detected.Hematoxylin and eosin(H&E)staining was used to detect pathological changes.The genes regulated by PPARγ2 overexpression were detected by microarray analysis.The restoration of PPARγ2 in PC3 and LNCaP cells inhibited cell proliferation and migration.PC3-PPARγ2 tissue recombinants showed necrosis in cancerous regions and leukocyte infiltration in the surrounding stroma by H&E staining.We found higher mixed lineage kinase domain-like(MLKL)and lower microtubule-associated protein 1 light chain 3(LC3)expression in cancer tissues compared to controls by immunohistochemistry(IHC)staining.Microarray analysis showed that PPARγ2 gain of function in PC3 cells resulted in the reprogramming of lipid-and energy metabolism-associated signaling pathways.These data indicate that PPARγ2 exerts a crucial tumor-suppressive effect by triggering necrosis and an inflammatory reaction in human prostate cancer.
文摘The androgen receptor （AR） plays an important role in the development and progression of prostate cancer （PCa）. Androgen deprivation therapy is initially effective in blocking tumor growth, but it eventually leads to the hormonerefractory state. The detailed mechanisms of the conversion from androgen dependence to androgen independence remain unclear. Several PCa cell lines were established to study the role of AR in PCa, but the results were often inconsistent or contrasting in different cell lines, or in the same cell line grown under different conditions. The cellular and molecular alteration of epithelial cells and their microenvironments are complicated, and it is difficult to use a single cell line to address this important issue and also to study the pathophysiological effects of AR. In this paper, we summarize the different effects of AR on multiple cell lines and show the disadvantages of using a single human PCa cell line to study AR effects on PCa. We also discuss the advantages of widely used epithelium-stroma co-culture systems, xenograft mouse models, and genetically engineered PCa mouse models. The combination of in vitro cell line studies and in vivo mouse models might lead to more credible results and better strategies for the study of AR roles in PCa.
基金Supported by the National Natural Science Foundation of China(21272043,8127452)Science and Technology Planning Project of Guangdong Province(2011B090400573,2012B091000170)Guangdong Natural Science Foundation(S2011010004967)
文摘Three-dimensional （3D） quantitative structure-activity relationship （QSAR） studies of 44 curcumin-related compounds have been carried out based on our previously reported result for their anticancer activity against pancreas cancer Panc-I cells and colon cancer HT-29 cells. The established 3D-QSAR models from the comparative molecular field analysis （CoMFA） in training set showed not only significant statistical quality, but also satisfying predictive ability, with high correlation coefficient values （R12= 0.911, R22= 0.985） and cross-validation coefficient values （q2= 0.580, q22= 0.722）. Based on the CoMFA contour maps, some key structural factors responsible for anticancer activity of these series of compounds were revealed. The results provide some useful theoretical references for understanding the mechanism of action, designing new curcumin-related compounds with anticancer activity and predicting their activities prior to synthesis.
文摘AIM To investigate rates of distant metastases(DM)detected with[18]fluorodeoxyglucose-positron emissiontomography/computed tomography(^(18)FDG-PET/CT)in early stage invasive breast cancer.METHODS We searched the English language literature databases of PubM ed,EMBASE,ISI Web of Knowledge,Web of Science and Google Scholar,for publications on DM detected in patients who had^(18)FDG-PET/CT scans as part of the staging for early stages of breast cancer(stageⅠ?andⅡ),prior to or immediately following surgery.Reports published between 2011 and 2017 were considered.The systematic review was conducted according to the PRISMA guidelines.RESULTS Among the 18 total studies included in the analysis,the risk of DM ranged from 0%to 8.3%and 0%to 12.9%for stageⅠ?andⅡinvasive breast cancer,respectively.Among the patients with clinical stageⅡ,the rate of occult metastases diagnosed by^(18)FDG-PET/CT was 7.2%(range,0%-19.6%)for stageⅡA and 15.8%(range,0%-40.8%)for stageⅡB.In young patients(<40-yearold),^(18)FDG-PET/CT demonstrated a higher prevalence of DM at the time of diagnosis for those with aggressive histology(i.e.,triple-negative receptors and poorly differentiated grade).CONCLUSION Young patients with poorly differentiated tumors and stageⅡB triple-negative breast cancer may benefit from^(18)FDG-PET/CT at initial staging to detect occult DM prior to surgery.
文摘The explosion of new therapeutics in metastatic castrate-resistant prostatecancer （mCRPC） is unprecedented, but much more work needs to be done before we are satisfied. Six phase III trials with an overall survival impact have now been reported （Table 1）.1-6 Four of these trials were exclusively or predominantly in the mCRPC post-docetaxel space （MDV3100, abiraterone, 223radium and cabazitaxel）. The 223radium trial also uniquely offered therapy to patients who were unsuitable for or refused docetaxel. The sipuleucel-T trial focused on mCRPC patients who were asymptomatic or minimally symptomatic; most of these patients were chemotherapy naive.
文摘In many parts of the world hepatocellular carcinoma (HCC)is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood.There is increasing evidence that activins,which are members of the transforming growth factorβ(TGFβ)superfamily of growth and differentiation factors,could play important roles in liver carcinogenesis.Activins are disulphide-linked homo- or heterodimers formed from four differentβsubunits termedβA,βB,βC,andβE,respectively.Activin A, the dimer of twoβA subunits,is critically involved in the regulation of cell growth,apoptosis,and tissue architecture in the liver,while the hepatic function of other activins is largely unexplored so far.Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG,and at the cell membrane antagonistic coreceptors like Cripto or BAMBI.Additionally,in the intracellular space inhibitory Smads can modulate and control activin activity.Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation,fibrosis and development of cancer.The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis.
基金supported by a grant from the Department of Education of Guangdong Province of China,No.2016KCXTD005
文摘This review summarizes and describes the use of curcumin in diagnosis,prevention,and treatment of Alzheimer＇s disease.For diagnosis of Alzheimer＇s disease,amyloid-β and highly phosphorylated tau protein are the major biomarkers.Curcumin was developed as an early diagnostic probe based on its natural fluorescence and high binding affinity to amyloid-β.Because of its multi-target effects,curcumin has protective and preventive effects on many chronic diseases such as cerebrovascular disease,hypertension,and hyperlipidemia.For prevention and treatment of Alzheimer＇s disease,curcumin has been shown to effectively maintain the normal structure and function of cerebral vessels,mitochondria,and synapses,reduce risk factors for a variety of chronic diseases,and decrease the risk of Alzheimer＇s disease.The effect of curcumin on Alzheimer＇s disease involves multiple signaling pathways：anti-amyloid and metal iron chelating properties,antioxidation and anti-inflammatory activities.Indeed,there is a scientific basis for the rational application of curcumin in prevention and treatment of Alzheimer＇s disease.
基金This work was supported by the National Natural Science Foundation of China （no. 30971636）, and the George H. Whipple Professorship Endowment, and National Science Council, Talwan, China （96-2314-B-182A-023-MY2 and 97- 2314-B-182A-077-MY3）. Supplementary Information accompanies the paper on Asian lournal of Andrology website （http：Hwww.nature.com/aja）.
文摘Androgen and androgen receptor （AR） play important roles in male spermatogenesis and fertility, yet detailed androgen/AR signals in Sertoli cells remain unclear. To identify AR target genes in Sertoli cells, we analyzed the gene expression profiles of testis between mice lacking AR in Sertoli cells （S-AR-/y） and their littermate wild-type （WT） mice. Digital gene expression analysis identified 2276 genes downregulated and 2865 genes upregulated in the S-AR-/y mice testis compared to WT ones. To further nail down the difference within Sertoli cells, we first constructed Sertoli cell line TM4 with stably transfected AR （named as TM4/AR） and found androgens failed to transactivate AR in Sertoli TM4 and TM4/AR cells. Interestingly, additional transient transfection of AR-cDNA resulted in significant androgen responsiveness with TM4/AR cells showing 10 times more androgen sensitivity than TM4 cells. In the condition where maximal androgen response was demonstrated, we then analyzed gene expression and found the expression levels of 2313 genes were changed more than twofold by transient transfection of AR-cDNA in the presence of testosterone. Among these genes, 603 androgen-/ AR-regulated genes, including 164 upregulated and 439 downregulated, were found in both S-AR-/y mice testis and TM4/AR cells. Using informatics analysis, the gene ontology was applied to analyze these androgen-/AR-regulated genes to predict the potential roles of androgen/AR in the process of spermatogenesis. Together, using gene analysis in both S-AR-/y mice testis and TM4/AR cells may help us to better understand the androeen/AR signals in Sertoli cells and their influences in spermatogenesis.
基金Supported by Thailand Research Fundthe Commission on Higher Education Fund grant(to Nattanan Panjaworayan T-Thienprasert),No.MRG5680051and NZ Health Research Council Grant 05/195(to Augustine Chen and Chris M Brown)
文摘There is a continuing need for novel antivirals to treat hepatitis B virus (HBV) infection, as it remains a major health problem worldwide. Ideally new classes of antivirals would target multiple steps in the viral lifecycle. In this review, we consider the steps in which HBV RNAs are processed, exported from the nucleus and translated. These are often overlooked steps in the HBV life-cycle. HBV, like retroviruses, incorporates a number of unusual steps in these processes, which use a combination of viral and host cellular machinery. Some of these unusual steps deserve a closer scrutiny. They may provide alternative targets to existing antiviral therapies, which are associated with increasing drug resistance. The RNA post-transcriptional regulatory element identified 20 years ago promotes nucleocytoplasmic export of all unspliced HBV RNAs. There is evidence that inhibition of this step is part of the antiviral action of interferon. Similarly, the structured RNA epsilon element situated at the 5’ end of the polycistronic HBV pregenomic RNA also performs key roles during HBV replication. The pregenomic RNA, which is the template for translation of both the viral core and polymerase proteins, is also encapsidated and used in replication. This complex process, regulated at the epsilon element, also presents an attractive antiviral target. These RNA elements that mediate and regulate gene expression are highly conserved and could be targeted using novel strategies employing RNAi, miRNAs or aptamers. Such approaches targeting these functionally constrained genomic regions should avoid escape mutations. Therefore understanding these regulatory elements, along with providing potential targets, may also facilitate the development of other new classes of antiviral drugs.
基金the financial support from Beijing Natural Science Foundation(No.7212203)National Natural Science Foundation of China(No.21876013)。
文摘Racemic[^(18)F]FBFP([^(18)F]1)proved to be a potentσ_(1) receptor radiotracer with superior imaging properties.The pure enantiomers of unlabeled compounds(S)-and(R)-1 and the corresponding iodonium ylide precursors were synthesized and characterized.The two enantiomers(S)-1 and(R)-1 exhibited comparable high affinity forσ_(1) receptors and selectivity overσ_(2) receptors.The Ca^(2+) fluorescence assay indicated that(R)-1 behaved as an antagonist and(S)-1 as an agonist forσ_(1) receptors.The ^(18)F-labeled enantiomers(S)-and(R)-[^(18)F]1 were obtained in>99%enantiomeric purity from the corresponding enantiopure iodonium ylide precursors with radiochemical yield of 24.4%±2.6%and molar activity of 86–214 GBq/μmol.In ICR mice both(S)-and(R)-[^(18)F]1displayed comparable high brain uptake,brain-to-blood ratio,in vivo stability and binding specificity in the brain and peripheral organs.In micro-positron emission tomography(PET)imaging studies in rats,(S)-[^(18)F]1 exhibited faster clearance from the brain than(R)-[^(18)F]1,indicating different brain kinetics of the two enantiomers.Both(S)-and(R)-[^(18)F]1 warrant further evaluation in primates to translate a single enantiomer with more suitable kinetics for imaging theσ_(1) receptors in humans.
基金supported by the National Natural Science Foundation of China (No.30973001)the National Basic Research Program (973) of China (No.2012CB518304)+2 种基金the Zhejiang Provincial Natural Science Foundation of China (No.Y2110446)the Qianjiang Talents Project of Zhejiang Province (No.2011R10039)the PAO Yu-kong International Foundation for Scholars and Scientists,China
文摘Testicular nuclear receptor 4(TR4),also known as NR2C2(nuclear receptor subfamily 2,group C,member 2),is a transcriptional factor and a member of the nuclear receptor family.TR4 was initially cloned from human and rat hypothalamus,prostate,and testes libraries.For almost two decades,its specific tissue distribution,genomic organization,and chromosomal assignment have been well investigated in humans and animals.However,it has been very difficult to study TR4's physiological functions due to a lack of specific ligands.Gene knock-out animal techniques provide an alternative approach for defining the biological functions of TR4.In vivo studies of TR4 gene knockout mice(TR4-/-) found that they display severe spinal curvature,subfertility,premature aging,and prostate prostatic intraepithelial neoplasia(PIN) development.Upstream modulators,downstream target gene regulation,feedback mechanisms,and differential modulation mediated by the recruitment of other nuclear receptors and coregulators have been identified in studies using the TR4-/-phenotype.With the establishment of a tissue-specific TR4-/-mouse model,research on TR4 will be more convenient in the future.
基金supported by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 860960by Bijzonder Onderzoeksfonds GOA(Geconcerteerde onderzoeksacties)2018000504(GOA030-18 BOF)supported by the Research Foundation Flanders(FWO)(grant numbers:1228821N and 12A2H24N)。
文摘Background Within the follicular fluid,extracellular vesicles(EVs)guide oocyte growth through their cargo microRNAs(miRNAs).Here,we inv estigated the role of EVs and their cargo miRNAs by linking the miRNAs found in EVs,derived from the fluid of an individual follicle,to the ability of its oocyte to become a blastocyst(competent)or not(non-competent).Methods Bovine antral follicles were dissected,categorized as small(2-4 mm)or large(5-8 mm)and the corresponding oocytes were subjected to individual maturation,fertilization and embryo culture to the blastocyst stage.Follicular fluid was pooled in 4 groups(4 replicates)based on follicle size and competence of the corresponding oocyte to produce a blastocyst.Follicular fluid-derived EVs were isolated",characterized,and subjected to miRNAsequencing(Illumina Miseq)to assess differential expression(DE)in the 4 groups.Functional validation of the effect of miR-34c on embryo development was performed by supplementation of mimics and inhibitors during in vitro maturation(IVM).Results We identified 16 DE miRNAs linked to oocyte competence when follicular size was not considered.Within the large and small follicles,46 DE miRNAs were driving blastocyst formation in each group.Comparison of EVs from competent small and large follicles revealed 90 DE miRNAs.Cell regulation,cell differentiation,cell cycle,and metabolic process regulation were the most enriched pathways targeted by the DE miRNAs from competent oocytes.We identified bta-miR-34c as the most abundant in follicular fluid containing competent oocytes.Supplementation of miR-34c mimic and inhibitor during IVM did not affect embryo development.However,blastocyst quality,as evidenced by higher cell numbers,was significantly improved following oocyte IVM in the presence of miR-34c mimics,while miR-34c inhibitors resulted in the opposite effect.Conclusion This study demonstrates the regulatory effect of miRNAs from follicular fliived EVs on oocyte competence acquisitividing a further basis for understanding the significance of miRNAs in oocyte maturation and embryonic development Up-regulation of miR-34c in EVs from follicular fluid containing competent oocytes and the positive impact of miR-34c mimics added during IVM on the resulting blastocysts indicate its pivotal role in oocyte competence.
文摘Androgen deprivation therapy （ADT）, which aims to reduce androgen-androgen receptor （AR） signaling, is the normal method of prostate cancer treatment. Despite its early success in suppressing prostate tumor growth, the therapy eventually fails, leading to recurrent hormone-refractory tumor growth. Recent studies have been carried out with stromal cell-specific or fibroblastspecific AR knockout mice or prostate stromal-specific and epithelial-specific AR knockout transgenic mice prostate cancer models and in vitro and in vivo studies of various human prostate cancer cells with knock-in and knock-out of the AR. These have indicated that the AR in prostatic stroma acts as a proliferation stimulator and survival factor, whereas epithelial AR acts as a survival factor for epithelial luminal cells and stromal smooth muscle cell differentiation, and as a suppressor for epithelial basal intermediate cell proliferation. These two opposite AR pose a major challenge for roles of the stromal and epithelial ADT and should be taken into account when developing new therapies targeting AR in selective cells.
文摘Introduction: Squamous cell carcinoma (SCC) is the predominant neoplastic tumor that occurs in the oral cavity. SCC arising from the maxillary gingiva, hard palate and maxillary alveolus is relatively rare. Since soft tissue barrier is thin, the diagnosis of cancer in these regions is usually ulcerative and invasive to the underlying bone already in the early stages of the disease. The aim of the present study was to retrospectively evaluate our data regarding the management of loco-regional lymph nodes and the efficacy of neck dissection in the clinically negative neck when maxillary squamous cell carcinoma is diagnosed. Furthermore, we wish to establish the role of prophylactic neck dissection and T stage from which it should be implemented. Methods: Archival records of oncological patients that were treated for SCC of the maxillary alveolus, hard palate and gingiva were collected. Overall 20 patients met the inclusion criteria, 11 men and 9 women. Average age of first diagnosis was 68 years. Results: At initial examination, 2 patients (10%) had clinically positive lymph nodes and undergone therapeutic neck dissection. The remaining 18 patients had clinically N0 necks. Five patients (28%) had occult positive lymph nodes following prophylactic neck dissection. One of the patients had a primary resection with no neck treatment. This patient eventually developed metastases in the neck two month post-surgery (occult disease). The overall positive lymph nodes in maxillary squamous cell carcinoma were 40% (8/20) with an occult metastasis rate of 33% (6/18). Disease specific mortality was 45% (9/20). Conclusion: In the present study, the majority of patients that were diagnosed with occult metastatic disease were either large tumors (T4, 60%) or with moderate to poor differentiation (mood-poor 80%). We conclude that patients who are present with a high grade (moderate-poor) large or invasive maxillary SCC (T2-T4), a prophylactic selective neck dissection (levels I-III) should be performed.
基金This work is supported by grants from the National Natural Science Foundation of China(82002633)Medical Scientific Research Foundation of Guangdong Province of China(A2019433)+1 种基金Shenzhen Health Family Planning System Research Project(SZBC2018012)to Tianfeng LiThe Science,Technology and Innovation Commission of Shenzhen(JCYJ20220531093213030)to Zhenjian Zhuo.
文摘Neuroblastoma(NB),a frequently occurring pediatric disease,is derived from the neural crest cells in the sympathetic ganglia and adrenal medulla.Notably,it is a heterogeneous tumor consisting of many affection factors,such as the diagnosis time within the first year and the diversity of the histology and genetic features.Despite improved outcomes in NB patients,it remains a difficult clinical problem and requires new therapeutic targets and methods.The somatic acquired activation point mutations in the receptor tyrosine kinase anaplastic lymphoma kinase(ALK)represent potential targets for treating NB.Herein,we review the underlying mechanisms of ALK in NB development,the latest available strategies to block ALK constitutive activity to treat NB,and discuss the current clinical challenges of resistance to these therapies and the strategies to overcome them.
基金Shanghai Municipal Health Commission,Grant/Award Number:20194Y0039Natural Science Foundation of China,Grant/Award Numbers:81872117,81502235funded by Project of the Shanghai Municipal Health Com-mission(No.20194Y0039 to HZ.S)and Natural Science Foundation of China(No.81872117 and 81502235 to ZL.W).
文摘Background:Chemotherapy resistance is a primary reason of ovarian cancer therapy failure;hence it is important to investigate the underlying mechanisms of chemotherapy resistance and develop novel potential therapeutic targets.Methods:RNA sequencing of cisplatin-resistant and sensitive(chemoresis-tant and chemosensitive,respectively)ovarian cancer organoids was performed,followed by detection of the expression level of fibrillin-1(FBN1)in organoids and clinical specimens of ovarian cancer.Subsequently,glucose metabolism,angiogenesis,and chemosensitivity were analyzed in structural glycoprotein FBNl-knockout cisplatin-resistant ovarian cancer organoids and cell lines.To gain insights into the specific functions and mechanisms of action of FBN1 in ovarian cancer,immunoprecipitation,silver nitrate staining,mass spectrometry,immunofluorescence,Western blotting,and Forister resonance energy transfer-fluorescence lifetime imaging analyses were performed,followed by in vivo assays using vertebrate model systems of nude mice and zebrafish.Results:FBN1 expression was significantly enhanced in cisplatin-resistant ovar-ian cancer organoids and tissues,indicating that FBNI might be a key factor in chemoresistance of ovarian cancer.We also discovered that FBN1 sustained the energy stress and induced angiogenesis in vitro and in vivo,which promoted the cisplatin-resistance of ovarian cancer.Knockout of FBN1 combined with treat-ment of the antiangiogenic drug apatinib improved the cisplatin-sensitivity of ovarian cancer cells.Mechanistically,FBN1 mediated the phosphorylation of vascular endothelial growth factor receptor 2(VEGFR2)at the Tyrl054 residue,which activated its downstream focal adhesion kinase(FAK)/protein kinase B(PKB or AKT)pathway,induced the phosphorylation of signal transducer and activator of transcription 2(STAT2)at the tyrosine residue 690(Tyr690),pro-moted the nuclear translocation of STAT2,and ultimately altered the expression of genes associated with STAT2-mediated angiogenesis and glycolysis.Conclusions:The FBN1/VEGFR2/STAT2 signaling axis may induce chemore-sistance of ovarian cancer cells by participating in the process of glycolysis and angiogenesis.The present study suggested a novel FBNl-targeted therapy and/or combination of FBN1 inhibition and antiangiogenic drug for treating ovarian cancer.
基金supported by the Swedish Research council and the Swedish cancer foundation.
文摘Invariant natural killer T(iNKT)cells are part of the family of unconventional T cells,and they recognize glycolipid antigens presented on the MHC class I like molecule CD1^([1]).In humans there are five CD1 molecules named CD1a to CD1e,whereas mice use only CD1d for lipid presentation.Functionally,iNKT cells can elicit both cytotoxicity similarly to conventional CD8 T cells and secrete cytokines that influence the adaptive immune response including providing direct T cell help to B cells^([2]).In the context of tumors,they can use both release of granzyme B and use Fas-mediated mechanisms for killing of tumor cells.As iNKT cells use a restricted TCR repertoire and CD1 molecules are non-heterogenous the risk of graft vs host disease is limited and thus these T cells have been an attractive option for off the shelf immunotherapy to treat cancer^([3]).
基金the lab and for Emma Cordover’s work was from the Busch Biomedical Grantthe New Jersey Health Foundation Grantthe Aresty Research Center.
文摘Mammalian cells have the ability to respond to a myriad of diverse extracellular stimuli that modulate cell function.This often involves ligands binding to cell surface receptors and subsequent activation of intracellular signaling pathways.These pathways can lead to changes in gene expression patterns that in turn regulate cell growth,differentiation,migration,and function.One important type of cell surface receptor is the receptor tyrosine kinase(RTK).In response to in response to ligand binding,RTKs dimerize,then trans-phosphorylate each other,leading to activation of downstream pathways.While the signaling proteins in these pathways are important for normal cell growth control,when improperly regulated they can lead to uncontrolled growth and sometimes cancer.For this reason,they are often considered to be good candidates for drug targets for chemotherapeutic drugs.RTKs can activate multiple different signaling pathways.Some of the signaling proteins in these pathways can have crosstalk with other RTK activated pathways,and some of them can be activated by multiple mechanisms in addition to activation by RTKs.While there is a wide array of different signaling proteins and pathways activated by RTKs,in this review we will discuss components of several key pathways including the MAPK pathway,the Her2/Neu pathway,mTOR,and Pak kinases.We provide an overview of the roles for these pathways in cell signaling and discuss how different components of these pathways are being considered as targets for cancer treatment.
基金Research on cell cycle in our lab is funded by the Baden-Wurttemberg Foundation(BWSTJSF2019-027,to M.C.-H.)the German Cancer Aid(70113919 to S.D.)the German Cancer Consortium DKTK(FR04 to S.D.).
文摘The control of cell proliferation is an essential feature in development and tissue homeostasis and is prominently deregulated in tumors.Three publications in Nature now uncover the mechanism underlying the degradation of cyclin D1-3 and provide important insights for the targeted therapy of the cancer cell cycle.
