Ovarian cancer(OC),a highly lethal gynaecological malignancy,is often diagnosed at advanced stages,resulting in a poor prognosis.Sialylation,an important form of glycosylation,significantly contributes to the progress...Ovarian cancer(OC),a highly lethal gynaecological malignancy,is often diagnosed at advanced stages,resulting in a poor prognosis.Sialylation,an important form of glycosylation,significantly contributes to the progression of various solid tumours,including OC.Aberrant sialylation promotes tumour progression and metastasis by altering the structure and function of glycoproteins.Although its role in several solid tumours is well documented,the role of abnormal sialylation in OC and its potential as a therapeutic target remain poorly understood.This review highlights sialylation as a key regulator of the progression,metastasis,and drug resistance of OC.A deeper understanding of altered sialylation can contribute to the identification of novel therapeutic strategies for OC.展开更多
Objective: To study the effects of basil polysaccharide (BP) in inhibiting tumor growth and metastasis in vivo. Methods: One hundred and fifty mice were randomly divided into five groups to observe the effect on tumor...Objective: To study the effects of basil polysaccharide (BP) in inhibiting tumor growth and metastasis in vivo. Methods: One hundred and fifty mice were randomly divided into five groups to observe the effect on tumor growth after H22 cancer cells had been transplanted subcutaneously into their right armpit region and treated with different dosages (5 mg/kg, 2. 5 mg/kg and 1. 25 mg/kg) of BP for 14 days, with Mi-tomycin (Mit-C) used as control. Another 150 mice were randomly divided into three groups, models of tumor metastasis in the lung by various paths (lymphatic, blood circulatory and spontaneous) were established respectively. They were treated with BP or Mit-C to observe the influence of treatments on tumor metastasis by various paths. Results: BP of various dosages showed no effect on tumor growth, but in high and middle dosage, it could significantly reduce the number or metastasis nodules ( P<0. 05). Conclusion: BP has a tumor metastasis inhibitory effect, which might be one of the candidates for new anti-tumor metastasis agents. Its mechanism may be blocking the function of platelets in the tumor metastasis progress.展开更多
In order to establish an animal model with hepatic metastasis intrasplenic inoculation of carcinoma cells from murine uterine cervical carcinoma (U14) was employed. Results showed a high incidence of hepatic metastasi...In order to establish an animal model with hepatic metastasis intrasplenic inoculation of carcinoma cells from murine uterine cervical carcinoma (U14) was employed. Results showed a high incidence of hepatic metastasis could be obtained through the intrasplenic inoculation of 1 × 106 carcinoma cells. Removal of the primary carcinoma through splenec-tomy at different intervals after intrasplenic inoculation proved that the hepatic metastatic mechanism was not due to mechanical pressure but occurred spontaneously. This experimental model provides a useful means for studying the mechanism and prevention of hepatic metastasis.展开更多
Background and Objective Lymph node, peripheral blood and bone marrow from NSCLC patients have undetectable micro-metastasis by general method, and the tumor micrometastasis
Background and Objective Our previous studies have proved that nm23-H1 gene was a tumor metastatic suppressive gene, tumor metastasis phenotype of human lung cancer could
Background and Objective The disease incidence and mortality of lung cancer has been increased dramatically for recent 50 years in many countries in the world. In2002, the new cases
Background and Objective Lung cancer is the most lethal malignangy that threatens human health and lives nowadays in the world, The overall cure rate of lung cancer is only 13% -15%,
Background: Our previous studies have proved that nm23-H1 gene was a tumor metastatic suppressive gene, tumor metastasis phenotype of human lung cancer could be reversed by transfection of nm23-H1 cDNA, but
Cancer metastasis is the major cause of cancer-related deaths and accounts for poor therapeutic outcomes.A metastatic cas-cade is a series of complicated biological processes.N6-methyladenosine(m^(6)A)is the most abun...Cancer metastasis is the major cause of cancer-related deaths and accounts for poor therapeutic outcomes.A metastatic cas-cade is a series of complicated biological processes.N6-methyladenosine(m^(6)A)is the most abundant and conserved epi-transcriptomic modification in eukaryotic cells,which has great impacts on RNA production and metabolism,including RNA splicing,processing,degradation and translation.Accumulating evidence demonstrates that m^(6)A plays a critical role in regulating cancer metastasis.However,there is a lack of studies that review the recent advances of m^(6)A in cancer metastasis.Here,we systematically retrieved the functions and mechanisms of how the m^(6)A axis regulates metastasis,and especially summarized the organ-specific liver,lung and brain metastasis mediated by m^(6)A in various cancers.Moreover,we discussed the potential application of m^(6)A modification in cancer diagnosis and therapy,as well as the present limitations and future perspectives of m^(6)A in cancer metastasis.This review provides a comprehensive knowledge on the m^(6)A-mediated regulation of gene expression,which is helpful to extensively understand the complexity of cancer metastasis from a new epitranscriptomic point of view and shed light on the developing novel strategies to anti-metastasis based on m^(6)A alteration.展开更多
Intercellular cross-talk plays important roles in cancer progression and metastasis.Yet how these cancer cells interact with each other is still largely unknown.Exosomes released by tumor cells have been proved to be ...Intercellular cross-talk plays important roles in cancer progression and metastasis.Yet how these cancer cells interact with each other is still largely unknown.Exosomes released by tumor cells have been proved to be effective cell-to-cell signal mediators.We explored the functional roles of exosomes in metastasis and the potential prognostic values for hepatocellular carcinoma(HCC).Exosomes were extracted from HCC cells of different metastatic potentials.The metastatic effects of exosomes derived from highly metastatic HCC cells(HMH)were evaluated both in vitro and in vivo.Exosomal proteins were identified with iTRAQ mass spectrum and verified in cell lines,xenograft tumor samples,and functional analyses.Exosomes released by HMH significantly enhanced the in vitro invasion and in vivo metastasis of low metastatic HCC cells(LMH).S100 calcium-binding protein A4(S100A4)was identified as a functional factor in exosomes derived from HMH.S100A4r,ch exosomes significantly promoted tumor metastasis both in vitro and in vivo compared with S100A4^(rich) exosomes or controls.Moreover,exosomal S100A4 could induce expression of osteopontin(OPN),along with other tumor metastasis/stemness-related genes.Exosomal S100A4 activated OPN transcription via STAT3 phosphorylation.HCC patients with high exosomal S100A4 in plasma also had a poorer prognosis.In conclusion,exosomes from HMH could promote the metastatic potential of LMH,and exosomal S100A4 is a key enhancer for HCC metastasis,activating STAT3 phosphorylation and up-regulating OPN expression.This suggested exosomal S100A4 to be a novel prognostic marker and therapeutic target for HCC metastasis.展开更多
Dear Editor,Cancer metastasis,dissemination of cancer cells from primary tumors to distant sites,attributes to 90%cancer-related death.1 Although the targeted therapies,bio-nanomaterial-based target delivery,and the c...Dear Editor,Cancer metastasis,dissemination of cancer cells from primary tumors to distant sites,attributes to 90%cancer-related death.1 Although the targeted therapies,bio-nanomaterial-based target delivery,and the consequent adoption of the so-called personalized medicine have obtained notable achievements in some cancers,significant problems still exist with these approaches.2 There are hardly any cancer therapeutic agents that can interfere with metastasized cancer.In recent times,we proposed a novel concept,namely cancer metastasis chemoprevention,which is different from the existing cancer chemotherapy and cancer chemoprevention.Cancer metastasis chemoprevention aims at safely preventing circulating tumor cells(CTCs)and related molecules from gemmating into the metastatic tissues.The strategy does not intend to kill cancer cells as cancer chemotherapy does,nor to aimlessly prevent cancers from carcinogenesis as cancer chemoprevention does.展开更多
Enolase 2(ENO2)is a key glycolytic enzyme in the metabolic process of glycolysis,but its potential function in pancreatic ductal adenocarcinoma(PDAC)is unclear.In this study,we observed a significant overexpression of...Enolase 2(ENO2)is a key glycolytic enzyme in the metabolic process of glycolysis,but its potential function in pancreatic ductal adenocarcinoma(PDAC)is unclear.In this study,we observed a significant overexpression of ENO2 in PDAC tissues,and its expression was correlated with metastasis and poor prognosis in PDAC patients.K394 was identified as a major acetylation site in ENO2 that regulates its enzymatic activity,cell metabolism and PDAC progression.Knockdown of ENO2 suppressed tumor growth and liver metastasis in PDAC.Re-expression of wild-type(WT)ENO2,but not the K394 acetylation mimetic mutant,could reverse the decreased tumor malignancy.We further characterized histone deacetylase 3(HDAC3)and P300/CBP-associated factor(PCAF)as the potential deacetylase and acetyltransferase for ENO2,respectively.HDAC3-mediated deacetylation was shown to lead to ENO2 activation and enhancement of glycolysis.Importantly,insulin-like growth factor-1(IGF-1)was found to decrease K394 acetylation and stimulate ENO2 activity in a dose-and time-dependent manner.The PI3K/AKT/mTOR pathway facilitated the phosphorylation of HDAC3 on S424,which promoted K394 deacetylation and activation of ENO2.Linsitinib,an oral small-molecule inhibitor of IGF-1R,could inhibit IGF-1-induced ENO2 deacetylation by HDAC3 and the PI3K/AKT/mTOR pathway.Furthermore,linsitinib showed a different effect on the growth and metastasis of PDAC depending on the overexpression of WT versus K394-mutant ENO2.Our results reveal a novel mechanism by which acetylation negatively regulates ENO2 activity in the metastasis of PDAC by modulating glycolysis.Blockade of IGF-1-induced ENO2 deacetylation represents a promising strategy to prevent the development of PDAC.展开更多
Metastasis and metabolism reprogramming are two major hallmarks of cancer.In the initiation and progression of cancer,tumor cells are known to undergo fundamental metabolic changes to sustain their development and pro...Metastasis and metabolism reprogramming are two major hallmarks of cancer.In the initiation and progression of cancer,tumor cells are known to undergo fundamental metabolic changes to sustain their development and progression.In recent years,much more attentions have been drawn to their important roles in facilitating cancer metastasis through regulating the biological properties.In this review,we summarized the recent progresses in the studies of metabolism reprogramming of cancer metastasis,particularly of primary liver cancer,and highlight their potential applications.展开更多
The war against cancer traces back to the signature event half-a-century ago when the US National Cancer Act was signed into law.The cancer crusade costs trillions with disappointing returns,teasing the possibility of...The war against cancer traces back to the signature event half-a-century ago when the US National Cancer Act was signed into law.The cancer crusade costs trillions with disappointing returns,teasing the possibility of a new breakthrough.Cure for cancer post-metastases still seems tantalisingly out of reach.Once metastasized,cancer-related death is extremely difficult,if not impossible,to be reversed.Here we present cancer pre-metastasis chemoprevention strategy that can prevent circulating tumour cells(CTCs)from initiating metastases safely and effectively,and is disparate from the traditional cancer chemotherapy and cancer chemoprevention.Deep learning of the biology of CTCs and their disseminating organotropism,complexity of their adhesion to endothelial niche reveals that if the adhesion of CTCs to their metastasis niche(the first and the most important part in cancer metastatic cascade)can be pharmaceutically interrupted,the lethal metastatic cascade could be prevented from getting initiated.We analyse the key inflammatory and adhesive factors contributing to CTC adhesion/germination,provide pharmacological fundamentals for abortifacients to intervene CTC adhesion to the distant metastasis sites.The adhesion/inhibition ratio(AIR)is defined for selecting the best cancer metastasis chemopreventive candidates.The successful development of such new therapeutic modalities for cancer metastasis chemoprevention has great potential to revolutionise the current ineffective post-metastasis treatments.展开更多
Dear Editor,Metastasis is the cause of most fatalities in cancer patients and remains the phenomenon poorly understood mechanistically. Deciphering of the regulatory networks underlying the cancer cell metastasis is u...Dear Editor,Metastasis is the cause of most fatalities in cancer patients and remains the phenomenon poorly understood mechanistically. Deciphering of the regulatory networks underlying the cancer cell metastasis is urgently needed. Nucleolar protein 7 (NOL7) has been reported to function as a tumor suppressor in cervical cancer.1 Our current study reveals a novel tumor-promoting capacity of NOL7 in melanoma. We first detected that NOL7 expression is upregulated in metastatic melanoma as compared with its expression at the primary site through isobaric tag for relative and absolute quantitation proteomic screening, further confirming this finding with the analysis of NOL7 protein and messenger RNA (mRNA) levels (Supplementary Fig. S1). Importantly, NOL7 expression increased with the disease progression from benign nevus to primary melanoma and further to metastatic melanoma (Fig. 1a and Supplementary Fig. S1d). Previous studies have shown that melanoma is commonly associated with the amplification of the chromosome region 6p, particularly 6p21–23, where the NOL7 gene resides, and that this region frequently undergoes heterozygous loss in cervical cancer.2 It might therefore be predicted that NOL7 exhibits a different expression pattern and plays different roles in melanoma and cervical cancer.展开更多
Background:Metastasis is the major cause of treatment failure in patients with nasopharyngeal carcinoma(NPC).We previously reported that TEL2,a negative regulator of SERPINE1,could inhibit NPC metastasis to lymph node...Background:Metastasis is the major cause of treatment failure in patients with nasopharyngeal carcinoma(NPC).We previously reported that TEL2,a negative regulator of SERPINE1,could inhibit NPC metastasis to lymph nodes.Method:A series of in vivo and in vitro assays were performed to elucidate the regulation between Snail and TEL2.TEL2 expression was analyzed in three representative NPC cell lines expressing low levels of Snail(S26,6-10B,HK1)and two cell lines expressing high levels of Snail(S18,5-8F).Luciferase and chromatin immunoprecipitation assays were used to analyze the interaction between Snail and TEL2.The roles of the Snail/TEL2 pathway in cell migration and invasion of NPC cells were examined using transwell assays.Metastasis to the lungs was examined using nude mouse receiving NPC cells injection through the tail vein.Results:Ectopic Snail expression down-regulated TEL2 at the mRNA and protein levels,whereas knockdown of Snail using short hairpin RNA up-regulated TEL2.Luciferase and chromatin immunoprecipitation assays indicated that Snail binds directly to the TEL2 promoter.Ectopic Snail expression enhanced migration and invasion of NPC cells,and such effects were mitigated by TEL2 overexpression.TEL2 overexpression also attenuated hypoxia-induced cell migration and invasion,and increased the number of metastatic pulmonary nodules.Snail overexpression reduced the number of metastatic pulmonary nodules.Conclusions:TEL2 is a novel target of Snail and suppresses Snail-induced migration,invasion and metastasis in NPC.展开更多
Dear Editor,Aberrant DNA methylation gets involved in cancer initiation,progression,and recurrence,which in turn makes it an ideal cancer biomarker.Various methylation markers or their panels have been developed in di...Dear Editor,Aberrant DNA methylation gets involved in cancer initiation,progression,and recurrence,which in turn makes it an ideal cancer biomarker.Various methylation markers or their panels have been developed in diverse cancer types.However,the model-constructing based marker mining strategy and incompatibility of application have greatly impeded their ways to clinic.Thus,single methylation marker applicable to all/most cancer types and multiple clinical scenarios is desperately needed.The hope came from the unexpected observation that HIST1H4F was universally hypermethylated in all 17 cancer types;thus,we raised the concept of“Universal Cancer Only Marker(UCOM)”and established a paradigm for discovery and clinical application of UCOM.1 Recently,a novel UCOM,hypermethylated PCDHGB7,was identified and found to advance cervical cancer(CC)screening to the precancerous stage.2 During the screening of UCOM,we discerned a bunch of cancer cell-differentially methylated regions.1 Among them,sine oculis(SIX)homeobox family of transcription factors,which were found to function as tumorigenesis regulator by promoting epithelial-to-mesenchymal transition and metastasis recently in addition to their traditional roles in tissue formation and organogenesis,3 sparked our special attention.Herein,we interrogate whether SIX6 methylation could serve as a novel UCOM and its potential applications.展开更多
Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour metastasis.SIRT6 can promote the migration of pancreatic cancer and could be ...Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour metastasis.SIRT6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic cancer.However,highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be discovered.Here,we developed a noveSIRT6 allosteric inhibitor,compound 11e,with maximal inhibitory potency and an IC_(50) value of 0.98±0.13μmol/L.Moreover,compound 11e exhibited significant selectivity against other histone deacetylases(HADC1-11 and SIRT1-3)at concentrations up to 100μmol/L.The allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural analyses.Importantly,we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver metastasis.To our knowledge,this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic cancer.It not only provides a promising lead compound for subsequent inhibitor developmentargeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.展开更多
Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells.Cancer cells could exhibit a"neural addiction"property and build up l...Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells.Cancer cells could exhibit a"neural addiction"property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated axonogenesis.Targeting the dysregulated nervous systems might represent a novel strategy for cancer treatment.However,whether intrahepatic cholangiocarcinoma(ICC)could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely unknown.Immunofluorescence staining and Enzyme-linked immunosorbent assay suggested that IcC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes IcC metastasis by inducing epithelial-mesenchymal transition(EMT).Acetylcholine promoted iCC metastasis through interacting with its receptor,alpha 5 nicotine acetylcholine receptor subunits(CHRNA5).Furthermore,acetylcholine/CHRNA5 axis activated GSK3β/β-catenin signaling pathway partially through the influx of Ca^(2+)-mediated activation of Ca/calmodulin-dependent protein kinases(CAMKll).In addition,acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor(BDNF),which formed a feedforward acetylcholine-BDNF axis to promote ICC progression.KN93,a small-molecule inhibitor of CAMKIll,significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC cells.Above all,Acetylcholine/CHRNA5 axis increased the expression ofβ-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKIl/GSK3βsignaling,and the CAMKIl inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.展开更多
The editors of the Journal of Cancer Metastasis and Treatment(JCMT)would like to take this opportunity to express their sincere gratitude to the reviewers and vip editors for assessing manuscripts in 2019[Table 1].
基金supported by Hubei Provincial Natural Science Foundation of China(No.2023AFB670).
文摘Ovarian cancer(OC),a highly lethal gynaecological malignancy,is often diagnosed at advanced stages,resulting in a poor prognosis.Sialylation,an important form of glycosylation,significantly contributes to the progression of various solid tumours,including OC.Aberrant sialylation promotes tumour progression and metastasis by altering the structure and function of glycoproteins.Although its role in several solid tumours is well documented,the role of abnormal sialylation in OC and its potential as a therapeutic target remain poorly understood.This review highlights sialylation as a key regulator of the progression,metastasis,and drug resistance of OC.A deeper understanding of altered sialylation can contribute to the identification of novel therapeutic strategies for OC.
基金This program was funded by Health Office of Shandong Province (No. 2001CA1CDA1) Chinese Medicine Bureau of Shandong Province (No. 99 - 46)
文摘Objective: To study the effects of basil polysaccharide (BP) in inhibiting tumor growth and metastasis in vivo. Methods: One hundred and fifty mice were randomly divided into five groups to observe the effect on tumor growth after H22 cancer cells had been transplanted subcutaneously into their right armpit region and treated with different dosages (5 mg/kg, 2. 5 mg/kg and 1. 25 mg/kg) of BP for 14 days, with Mi-tomycin (Mit-C) used as control. Another 150 mice were randomly divided into three groups, models of tumor metastasis in the lung by various paths (lymphatic, blood circulatory and spontaneous) were established respectively. They were treated with BP or Mit-C to observe the influence of treatments on tumor metastasis by various paths. Results: BP of various dosages showed no effect on tumor growth, but in high and middle dosage, it could significantly reduce the number or metastasis nodules ( P<0. 05). Conclusion: BP has a tumor metastasis inhibitory effect, which might be one of the candidates for new anti-tumor metastasis agents. Its mechanism may be blocking the function of platelets in the tumor metastasis progress.
文摘In order to establish an animal model with hepatic metastasis intrasplenic inoculation of carcinoma cells from murine uterine cervical carcinoma (U14) was employed. Results showed a high incidence of hepatic metastasis could be obtained through the intrasplenic inoculation of 1 × 106 carcinoma cells. Removal of the primary carcinoma through splenec-tomy at different intervals after intrasplenic inoculation proved that the hepatic metastatic mechanism was not due to mechanical pressure but occurred spontaneously. This experimental model provides a useful means for studying the mechanism and prevention of hepatic metastasis.
基金supported by the grants from the Key Project of National Natural Science Foundation of China (No.30430300 , to Qinghua ZHOU)Key Projects of Tianjin Sci-Tech Support Program (No. 07SYSYSF05000 and No. 06YF-SZSF05300, to Qinghua ZHOU)
文摘Background and Objective Lymph node, peripheral blood and bone marrow from NSCLC patients have undetectable micro-metastasis by general method, and the tumor micrometastasis
基金supported by the grants from the Key Project of National Natural Science Foundation of China (No.30430300 , to Qinghua ZHOU)Key Projects of Tian-jin Sci-Tech Support Program (No. 07SYSYSF05000 and No. 06YFSZSF05300, to Qinghua ZHOU)
文摘Background and Objective Our previous studies have proved that nm23-H1 gene was a tumor metastatic suppressive gene, tumor metastasis phenotype of human lung cancer could
基金supported by a grant from the key project of the National Natural Science Foundation of China (to Qinghua ZHOU)(No. 30430300)National Natural Science Foundation of China (to Qinghua ZHOU)(No. 30670922)INTERNATION Scienc and Techniquie COOPRATION PROGRAM OF CHINA (ISCP) (to Qinghua ZHOU)(No.2006DFB32330)
文摘Background and Objective The disease incidence and mortality of lung cancer has been increased dramatically for recent 50 years in many countries in the world. In2002, the new cases
基金supported by a grant from the key project of the National Natural Science Foundation of China (to Qinghua ZHOU)(No. 30430300)National Natural Science Foundation of China (to Qinghua ZHOU)(No. 30670922)INTERNATION Scienc and Techniquie COOPRATION PROGRAM OF CHINA (ISCP) (to Qinghua ZHOU)(No.2006DFB32330)
文摘Background and Objective Lung cancer is the most lethal malignangy that threatens human health and lives nowadays in the world, The overall cure rate of lung cancer is only 13% -15%,
基金supported by the grants from the Key Project of National Natural Science Foundation of China (No.30430300 , to Qinghua ZHOU)Key Projects of Tianjin Sci-Tech Support Program (No. 07SY-SYSF05000 and No. 06YFSZSF05300, to Qinghua ZHOU)
文摘Background: Our previous studies have proved that nm23-H1 gene was a tumor metastatic suppressive gene, tumor metastasis phenotype of human lung cancer could be reversed by transfection of nm23-H1 cDNA, but
基金supported by the Key Program of the National Natural Science Foundation of China(81930074,2020-2024)the Major Program of National Natural Science Foundation of China(91959203,2020-2023)the Natural Science Foundation of China(81672820,2017-2020,81672378,2017-2020,82173093)。
文摘Cancer metastasis is the major cause of cancer-related deaths and accounts for poor therapeutic outcomes.A metastatic cas-cade is a series of complicated biological processes.N6-methyladenosine(m^(6)A)is the most abundant and conserved epi-transcriptomic modification in eukaryotic cells,which has great impacts on RNA production and metabolism,including RNA splicing,processing,degradation and translation.Accumulating evidence demonstrates that m^(6)A plays a critical role in regulating cancer metastasis.However,there is a lack of studies that review the recent advances of m^(6)A in cancer metastasis.Here,we systematically retrieved the functions and mechanisms of how the m^(6)A axis regulates metastasis,and especially summarized the organ-specific liver,lung and brain metastasis mediated by m^(6)A in various cancers.Moreover,we discussed the potential application of m^(6)A modification in cancer diagnosis and therapy,as well as the present limitations and future perspectives of m^(6)A in cancer metastasis.This review provides a comprehensive knowledge on the m^(6)A-mediated regulation of gene expression,which is helpful to extensively understand the complexity of cancer metastasis from a new epitranscriptomic point of view and shed light on the developing novel strategies to anti-metastasis based on m^(6)A alteration.
基金supported by the Program of Shanghai Academic Research Leader(20XD1400900)the National Key Research and Development Program of China(2017YFC1308604)the National Natural Science Foundation of China(81702857,81672820,81930074,91959203 and 81372647).
文摘Intercellular cross-talk plays important roles in cancer progression and metastasis.Yet how these cancer cells interact with each other is still largely unknown.Exosomes released by tumor cells have been proved to be effective cell-to-cell signal mediators.We explored the functional roles of exosomes in metastasis and the potential prognostic values for hepatocellular carcinoma(HCC).Exosomes were extracted from HCC cells of different metastatic potentials.The metastatic effects of exosomes derived from highly metastatic HCC cells(HMH)were evaluated both in vitro and in vivo.Exosomal proteins were identified with iTRAQ mass spectrum and verified in cell lines,xenograft tumor samples,and functional analyses.Exosomes released by HMH significantly enhanced the in vitro invasion and in vivo metastasis of low metastatic HCC cells(LMH).S100 calcium-binding protein A4(S100A4)was identified as a functional factor in exosomes derived from HMH.S100A4r,ch exosomes significantly promoted tumor metastasis both in vitro and in vivo compared with S100A4^(rich) exosomes or controls.Moreover,exosomal S100A4 could induce expression of osteopontin(OPN),along with other tumor metastasis/stemness-related genes.Exosomal S100A4 activated OPN transcription via STAT3 phosphorylation.HCC patients with high exosomal S100A4 in plasma also had a poorer prognosis.In conclusion,exosomes from HMH could promote the metastatic potential of LMH,and exosomal S100A4 is a key enhancer for HCC metastasis,activating STAT3 phosphorylation and up-regulating OPN expression.This suggested exosomal S100A4 to be a novel prognostic marker and therapeutic target for HCC metastasis.
基金supported by the Natural Science Foundation of China(81961138017,81773063,U1505225,81703555,and 81801849).
文摘Dear Editor,Cancer metastasis,dissemination of cancer cells from primary tumors to distant sites,attributes to 90%cancer-related death.1 Although the targeted therapies,bio-nanomaterial-based target delivery,and the consequent adoption of the so-called personalized medicine have obtained notable achievements in some cancers,significant problems still exist with these approaches.2 There are hardly any cancer therapeutic agents that can interfere with metastasized cancer.In recent times,we proposed a novel concept,namely cancer metastasis chemoprevention,which is different from the existing cancer chemotherapy and cancer chemoprevention.Cancer metastasis chemoprevention aims at safely preventing circulating tumor cells(CTCs)and related molecules from gemmating into the metastatic tissues.The strategy does not intend to kill cancer cells as cancer chemotherapy does,nor to aimlessly prevent cancers from carcinogenesis as cancer chemoprevention does.
基金supported by the National Key Research and Development Program of China(No.2017YFC1308604)the Shanghai Program for Innovative Research Team in Universities,the National Natural Science Foundation of China(No.81802903,81672820,81772563,81930074 and 81872356)+2 种基金the NSFC Program of International Cooperation and Exchanges(No.81120108016)the National Key Basic Research Program of China(No.2013CB910500 and 2014CB542101)China National Key Projects for Infectious Disease(No.2012ZX10002-012).
文摘Enolase 2(ENO2)is a key glycolytic enzyme in the metabolic process of glycolysis,but its potential function in pancreatic ductal adenocarcinoma(PDAC)is unclear.In this study,we observed a significant overexpression of ENO2 in PDAC tissues,and its expression was correlated with metastasis and poor prognosis in PDAC patients.K394 was identified as a major acetylation site in ENO2 that regulates its enzymatic activity,cell metabolism and PDAC progression.Knockdown of ENO2 suppressed tumor growth and liver metastasis in PDAC.Re-expression of wild-type(WT)ENO2,but not the K394 acetylation mimetic mutant,could reverse the decreased tumor malignancy.We further characterized histone deacetylase 3(HDAC3)and P300/CBP-associated factor(PCAF)as the potential deacetylase and acetyltransferase for ENO2,respectively.HDAC3-mediated deacetylation was shown to lead to ENO2 activation and enhancement of glycolysis.Importantly,insulin-like growth factor-1(IGF-1)was found to decrease K394 acetylation and stimulate ENO2 activity in a dose-and time-dependent manner.The PI3K/AKT/mTOR pathway facilitated the phosphorylation of HDAC3 on S424,which promoted K394 deacetylation and activation of ENO2.Linsitinib,an oral small-molecule inhibitor of IGF-1R,could inhibit IGF-1-induced ENO2 deacetylation by HDAC3 and the PI3K/AKT/mTOR pathway.Furthermore,linsitinib showed a different effect on the growth and metastasis of PDAC depending on the overexpression of WT versus K394-mutant ENO2.Our results reveal a novel mechanism by which acetylation negatively regulates ENO2 activity in the metastasis of PDAC by modulating glycolysis.Blockade of IGF-1-induced ENO2 deacetylation represents a promising strategy to prevent the development of PDAC.
基金This study was supported by National Major Science and Technology Projects of China(No.2017ZX10203207)National Natural Science Foundation of China(No.81472677).
文摘Metastasis and metabolism reprogramming are two major hallmarks of cancer.In the initiation and progression of cancer,tumor cells are known to undergo fundamental metabolic changes to sustain their development and progression.In recent years,much more attentions have been drawn to their important roles in facilitating cancer metastasis through regulating the biological properties.In this review,we summarized the recent progresses in the studies of metabolism reprogramming of cancer metastasis,particularly of primary liver cancer,and highlight their potential applications.
基金NSFC 81961138017,81773063,82202355 and 3220422101Belt&Road Program,CAST and (2021FZR0101)Natural Science Foundation of Fujian Province(2021J05210,2021J011046).
文摘The war against cancer traces back to the signature event half-a-century ago when the US National Cancer Act was signed into law.The cancer crusade costs trillions with disappointing returns,teasing the possibility of a new breakthrough.Cure for cancer post-metastases still seems tantalisingly out of reach.Once metastasized,cancer-related death is extremely difficult,if not impossible,to be reversed.Here we present cancer pre-metastasis chemoprevention strategy that can prevent circulating tumour cells(CTCs)from initiating metastases safely and effectively,and is disparate from the traditional cancer chemotherapy and cancer chemoprevention.Deep learning of the biology of CTCs and their disseminating organotropism,complexity of their adhesion to endothelial niche reveals that if the adhesion of CTCs to their metastasis niche(the first and the most important part in cancer metastatic cascade)can be pharmaceutically interrupted,the lethal metastatic cascade could be prevented from getting initiated.We analyse the key inflammatory and adhesive factors contributing to CTC adhesion/germination,provide pharmacological fundamentals for abortifacients to intervene CTC adhesion to the distant metastasis sites.The adhesion/inhibition ratio(AIR)is defined for selecting the best cancer metastasis chemopreventive candidates.The successful development of such new therapeutic modalities for cancer metastasis chemoprevention has great potential to revolutionise the current ineffective post-metastasis treatments.
基金This work was supported by the grants from the National Natural Science Foundation of China(81961138017,81773063,and U1505225)Ministry of Science and Technology of China(2015CB931804)Young and Middle-aged Teacher Education Research Project of Fujian Province,JAT190623。
文摘Dear Editor,Metastasis is the cause of most fatalities in cancer patients and remains the phenomenon poorly understood mechanistically. Deciphering of the regulatory networks underlying the cancer cell metastasis is urgently needed. Nucleolar protein 7 (NOL7) has been reported to function as a tumor suppressor in cervical cancer.1 Our current study reveals a novel tumor-promoting capacity of NOL7 in melanoma. We first detected that NOL7 expression is upregulated in metastatic melanoma as compared with its expression at the primary site through isobaric tag for relative and absolute quantitation proteomic screening, further confirming this finding with the analysis of NOL7 protein and messenger RNA (mRNA) levels (Supplementary Fig. S1). Importantly, NOL7 expression increased with the disease progression from benign nevus to primary melanoma and further to metastatic melanoma (Fig. 1a and Supplementary Fig. S1d). Previous studies have shown that melanoma is commonly associated with the amplification of the chromosome region 6p, particularly 6p21–23, where the NOL7 gene resides, and that this region frequently undergoes heterozygous loss in cervical cancer.2 It might therefore be predicted that NOL7 exhibits a different expression pattern and plays different roles in melanoma and cervical cancer.
基金supported by grants to YS from the National Science Founda-tion of China(81660449)the Jiangxi Provincial Natural Science Foundation of China(20161ACB21001,20171BCD40026)+1 种基金the Jiangxi Provincial Health and Family Planning Commission Foundation(20164005,2015A077)as well as by a grant to TK from the Science and Technology Program of Guangzhou,China(201508020102).
文摘Background:Metastasis is the major cause of treatment failure in patients with nasopharyngeal carcinoma(NPC).We previously reported that TEL2,a negative regulator of SERPINE1,could inhibit NPC metastasis to lymph nodes.Method:A series of in vivo and in vitro assays were performed to elucidate the regulation between Snail and TEL2.TEL2 expression was analyzed in three representative NPC cell lines expressing low levels of Snail(S26,6-10B,HK1)and two cell lines expressing high levels of Snail(S18,5-8F).Luciferase and chromatin immunoprecipitation assays were used to analyze the interaction between Snail and TEL2.The roles of the Snail/TEL2 pathway in cell migration and invasion of NPC cells were examined using transwell assays.Metastasis to the lungs was examined using nude mouse receiving NPC cells injection through the tail vein.Results:Ectopic Snail expression down-regulated TEL2 at the mRNA and protein levels,whereas knockdown of Snail using short hairpin RNA up-regulated TEL2.Luciferase and chromatin immunoprecipitation assays indicated that Snail binds directly to the TEL2 promoter.Ectopic Snail expression enhanced migration and invasion of NPC cells,and such effects were mitigated by TEL2 overexpression.TEL2 overexpression also attenuated hypoxia-induced cell migration and invasion,and increased the number of metastatic pulmonary nodules.Snail overexpression reduced the number of metastatic pulmonary nodules.Conclusions:TEL2 is a novel target of Snail and suppresses Snail-induced migration,invasion and metastasis in NPC.
基金supported by National Key R&D Program of China(Grant No.2018YFC1005004)the National Natural Science Foundation of China(Grant No.31872814,32000505)the Major Special Projects of Basic Research of Shanghai Science and Technology Commission(Grant No.18JC1411101)。
文摘Dear Editor,Aberrant DNA methylation gets involved in cancer initiation,progression,and recurrence,which in turn makes it an ideal cancer biomarker.Various methylation markers or their panels have been developed in diverse cancer types.However,the model-constructing based marker mining strategy and incompatibility of application have greatly impeded their ways to clinic.Thus,single methylation marker applicable to all/most cancer types and multiple clinical scenarios is desperately needed.The hope came from the unexpected observation that HIST1H4F was universally hypermethylated in all 17 cancer types;thus,we raised the concept of“Universal Cancer Only Marker(UCOM)”and established a paradigm for discovery and clinical application of UCOM.1 Recently,a novel UCOM,hypermethylated PCDHGB7,was identified and found to advance cervical cancer(CC)screening to the precancerous stage.2 During the screening of UCOM,we discerned a bunch of cancer cell-differentially methylated regions.1 Among them,sine oculis(SIX)homeobox family of transcription factors,which were found to function as tumorigenesis regulator by promoting epithelial-to-mesenchymal transition and metastasis recently in addition to their traditional roles in tissue formation and organogenesis,3 sparked our special attention.Herein,we interrogate whether SIX6 methylation could serve as a novel UCOM and its potential applications.
基金supported by the National Key R&D Program of China(grant no.2022YFF1203005)the National Natural Science Foundation of China(22237005,81903458,82273425)+1 种基金Innovative research team of high-level local universities in Shanghai(SHSMU-ZDCX20212700,China)China Postdoctoral Science Foundation(2019M660090)。
文摘Pancreatic cancer,one of the most aggressive malignancies,has no effective treatment due to the lack of targets and drugs related to tumour metastasis.SIRT6 can promote the migration of pancreatic cancer and could be a potential target for antimetastasis of pancreatic cancer.However,highly selective and potency SIRT6 inhibitor that can be used in vivo is yet to be discovered.Here,we developed a noveSIRT6 allosteric inhibitor,compound 11e,with maximal inhibitory potency and an IC_(50) value of 0.98±0.13μmol/L.Moreover,compound 11e exhibited significant selectivity against other histone deacetylases(HADC1-11 and SIRT1-3)at concentrations up to 100μmol/L.The allosteric site and the molecular mechanism of inhibition were extensively elucidated by cocrystal complex structure and dynamic structural analyses.Importantly,we confirmed the antimetastatic function of such inhibitors in four pancreatic cancer cell lines as well as in two mouse models of pancreatic cancer liver metastasis.To our knowledge,this is the first study to reveal the in vivo effects of SIRT6 inhibitors on liver metastatic pancreatic cancer.It not only provides a promising lead compound for subsequent inhibitor developmentargeting SIRT6 but also provides a potential approach to address the challenge of metastasis in pancreatic cancer.
基金supported by National Key Research and Development Program of China (2023YFC2413200/2023YFC2413201)National Nature Science Foundation of China (NSFC) (No.91959203 and No.81930074)the grant provided by National Research Center for Translational Medicine at Shanghai,Rujin Hospital,Shanghai Jiao Tong University School of Medicine (Shanghai,China) (NRCTM (SH)-2023-03).
文摘Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells.Cancer cells could exhibit a"neural addiction"property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated axonogenesis.Targeting the dysregulated nervous systems might represent a novel strategy for cancer treatment.However,whether intrahepatic cholangiocarcinoma(ICC)could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely unknown.Immunofluorescence staining and Enzyme-linked immunosorbent assay suggested that IcC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes IcC metastasis by inducing epithelial-mesenchymal transition(EMT).Acetylcholine promoted iCC metastasis through interacting with its receptor,alpha 5 nicotine acetylcholine receptor subunits(CHRNA5).Furthermore,acetylcholine/CHRNA5 axis activated GSK3β/β-catenin signaling pathway partially through the influx of Ca^(2+)-mediated activation of Ca/calmodulin-dependent protein kinases(CAMKll).In addition,acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor(BDNF),which formed a feedforward acetylcholine-BDNF axis to promote ICC progression.KN93,a small-molecule inhibitor of CAMKIll,significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC cells.Above all,Acetylcholine/CHRNA5 axis increased the expression ofβ-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKIl/GSK3βsignaling,and the CAMKIl inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.
文摘The editors of the Journal of Cancer Metastasis and Treatment(JCMT)would like to take this opportunity to express their sincere gratitude to the reviewers and vip editors for assessing manuscripts in 2019[Table 1].
