Esophageal squamous cell carcinoma(ESCC)is among the most prevalent causes of cancer-related death in patients worldwide.Resistance to immunotherapy and chemotherapy results in worse survival outcomes in ESCC.It is ur...Esophageal squamous cell carcinoma(ESCC)is among the most prevalent causes of cancer-related death in patients worldwide.Resistance to immunotherapy and chemotherapy results in worse survival outcomes in ESCC.It is urgent to explore the underlying molecular mechanism of immune evasion and chemoresistance in ESCC.Here,we conducted RNA-sequencing analysis in ten ESCC tissues from cisplatin-based neoadjuvant chemotherapy patients.We found that DMRTA1 was extremely upregulated in the non-pathologic complete response(non-pCR)group.The proliferation rate of esophageal squamous carcinoma cells was markedly decreased after knockdown of DMRTA1 expression,which could increase cisplatin sensitivity in ESCC.Additionally,suppression of DMRTA1 could decrease the immune escape of esophageal squamous carcinoma cells.Further mechanistic studies suggest that DMRTA1 can promote its expression by binding to the promoter of SOX2,which plays important roles in the progression and chemoresistance of ESCC in the form of positive feedback.Therefore,DMRTA1 could be a potential target to suppress immune escape and overcome chemoresistance in ESCC.展开更多
Here,we used reverse transcription-PCR(RT-PCR) and western blot to detect protease-activated receptor(PAR) 1,PAR 2 and PAR 4 expression in cancer tissues and cell lines of esophageal squamous cell carcinoma,and invest...Here,we used reverse transcription-PCR(RT-PCR) and western blot to detect protease-activated receptor(PAR) 1,PAR 2 and PAR 4 expression in cancer tissues and cell lines of esophageal squamous cell carcinoma,and investigated the co-relationship between PAR expression and clinic-pathological data for esophageal cancer.The methylation of PAR4 gene promoter involved in esophageal carcinoma was also analyzed.By comparing the mRNA expressions of normal esophageal tissue and human esophageal epithelial cells(HEEpiC),we found that among the 28 cases of esophageal squamous cell carcinoma,PAR1(60%) and PAR2(71%) were elevated in 17 and 20 cases,respectively,and PAR4(68%) expression was lowered in 19 cases.Whereas,in human esophageal squamous cells(TE-1 and TE-10),PAR1 and PAR2 expression was increased but PAR4 was decreased.Combined with clinical data,the expression of PAR1 in poorly differentiated(P=0.016) and middle and lower parts of the esophagus(P=0.016) was higher; expression of PAR4 in poorly differentiated carcinoma was lower(P=0.049).Regarding TE-1 and TE-10 protein expression,we found that in randomized esophageal carcinoma,PAR1(P=0.027) and PAR2(P=0.039) expressions were increased,but lowered for PAR4(P=0.0001).In HEEpiC,TE-1,TE-10,esophageal and normal esophagus tissue samples(case No.7),the frequency of methylation at the 19 CpG loci of PAR4 was 35.4%,95.2%,83.8%,62.6% and 48.2%,respectively.Our results indicate that the expression of PAR1 and PAR2 in esophageal squamous cell carcinoma is increased but PAR4 is decreased.Hypermethylation of the promoter of the PAR4 gene may contribute to reduced expression of PAR4 in esophageal squamous cell carcinoma.展开更多
AIM To investigate the underlying molecularmechanisms of miR-451 to inhibit proliferation ofesophageal carcinoma cell line EC9706.METHODS： Assays for cell growth, apoptosis andinvasion were used to evaluate the effec...AIM To investigate the underlying molecularmechanisms of miR-451 to inhibit proliferation ofesophageal carcinoma cell line EC9706.METHODS： Assays for cell growth, apoptosis andinvasion were used to evaluate the effects of miR-451expression on EC cells. Luciferase reporter and Westernblot assays were used to test whether cyclin-dependentkinase inhibitor 2D （CDKN2D） and MAP3K1 act as majortargets of miR-451.RESULTS： The results showed that CDKN2D andMAP3K1 are direct targets of miR-451. CDKN2D andMAP3K1 overexpression reversed the effect of miR-451.MiR-451 inhibited the proliferation of EC9706 bytargeting CDKN2D and MAP3K1.CONCLUSION： These findings suggest that miR-451might be a novel prognostic biomarker and a potentialtarget for the treatment of esophageal squamous cellcarcinoma in the future.展开更多
Background:Long non-codingRNAs(lncRNAs)have been found to be involved in the development of many cancers.In this study,we aimed to identify the molecular mechanisms of lncRNA BAALC antisense RNA 1(BAALC-AS1)in regulat...Background:Long non-codingRNAs(lncRNAs)have been found to be involved in the development of many cancers.In this study,we aimed to identify the molecular mechanisms of lncRNA BAALC antisense RNA 1(BAALC-AS1)in regulating the malignancy of esophageal squamous cell carcinoma(ESCC).Methods:The expression of BAALC-AS1 in cancer patients was analyzed using a tissue microarray.The protein and RNA levels of BAALC-AS1 were determined by Western blotting analysis and quantitative reverse transcription-PCR(RT-qPCR),respectively.The cell proliferation was determined by cell viability assays,bromodeoxyuridine incorporation,and flow cytometry.The relationships among BAALC-AS1,RasGAPSH3 domain-binding protein 2(G3BP2),and c-Myc were determined using RNA immunoprecipitation,RNA pull-down assays,and luciferase assays.Results:The expression of BAALC-AS1 was highly up-regulated and associated with malignant phenotypes in ESCC tissues and cell lines.In vivo and in vitro assays showed that BAALC-AS1 promoted ESCC cell proliferation,migration,and invasion.BAALC-AS1 directly interacted with G3BP2,and thereby inhibited the degradation of c-Myc RNA 3’-UTR by G3BP2,thus leading to the accumulation of c-Myc expression.Additionally,c-Myc acted as a transcription factor that can induce the expression of BAALC-AS1 by directly binding to its promoter region.Conclusions:BAALC-AS1/G3BP2/c-Myc feedback loop plays a critical role in the development of ESCC,which might provide a novel therapeutic target and facilitate the development of new therapeutic strategies for the treatment of ESCC.展开更多
BACKGROUND It is well known that an alcohol consumption habit together with inactive heterozygous aldehyde dehydrogenase-2(ALDH2)is an important risk factor for the development of esophageal squamous cell carcinoma(ES...BACKGROUND It is well known that an alcohol consumption habit together with inactive heterozygous aldehyde dehydrogenase-2(ALDH2)is an important risk factor for the development of esophageal squamous cell carcinoma(ESCC).It remains controversial whether human papillomavirus(HPV)infection contributes to the occurrence/development of ESCC.There has been no study in which the relationship between ESCC and HPV in addition to alcohol dehydrogenase-1B(ADH1B)and ALDH2 genotypes was evaluated.AIM To evaluate relationships between HPV infection and development of esophageal cancer,particularly early esophageal cancer,based on ADH1B/ALDH2 polymorphisms.METHODS We conducted an exploratory retrospective study using new specimens,and we enrolled 145 patients who underwent endoscopic resection for superficial ESCC and had been observed for more than two years by both physical examination and endoscopic examination in Hokkaido University Hospital.Saliva was collected to analyze genetic polymorphisms of ADH1B/ALDH2.We performed in situ hybridization for resected specimens to detect HPV by using an HPV type 16/18 probe.RESULTS HPV was detected in 15(10.3%)of the 145 patients with ESCC.HPV-positive rates in inactive ALDH2*1/*2 and ALDH2*1/*1+*2/*2 were 10.8%and 9.8%,respectively(P=1.00).HPV-positive rates in slow-metabolizing ADH1B*1/*1 and ADH1B*1/*2+*2/*2 were 12.0%and 10.0%,respectively(P=0.72).HPV-positive rates in the heavy or moderate alcohol consumption group and the light or rare consumption group were 11.1%and 8.7%,respectively(P=0.68).HPV-positive rates in the heavy smoking group and the light or no smoking group were 11.8%and 8.3%,respectively(P=0.59).The 3-year incidence rates of secondary ESCC or head and neck cancer after initial treatment in the HPV-positive and HPVnegative groups were 14.4%and 21.4%(P=0.22),respectively.CONCLUSION In the present situation,HPV status is considered to be less important than other risk factors,such as alcohol consumption,smoking habit,ADH1B/ALDH2 polymorphisms,and HPV status would therefore have no effect on ESCC risk management.展开更多
基金funded by the Department of Education of Yunnan Province(No.2021J0244).
文摘Esophageal squamous cell carcinoma(ESCC)is among the most prevalent causes of cancer-related death in patients worldwide.Resistance to immunotherapy and chemotherapy results in worse survival outcomes in ESCC.It is urgent to explore the underlying molecular mechanism of immune evasion and chemoresistance in ESCC.Here,we conducted RNA-sequencing analysis in ten ESCC tissues from cisplatin-based neoadjuvant chemotherapy patients.We found that DMRTA1 was extremely upregulated in the non-pathologic complete response(non-pCR)group.The proliferation rate of esophageal squamous carcinoma cells was markedly decreased after knockdown of DMRTA1 expression,which could increase cisplatin sensitivity in ESCC.Additionally,suppression of DMRTA1 could decrease the immune escape of esophageal squamous carcinoma cells.Further mechanistic studies suggest that DMRTA1 can promote its expression by binding to the promoter of SOX2,which plays important roles in the progression and chemoresistance of ESCC in the form of positive feedback.Therefore,DMRTA1 could be a potential target to suppress immune escape and overcome chemoresistance in ESCC.
基金supported by the National Natural Foundation of China(81160302)the Major Research Project of Yunnan Province(2011FZ109)Research project of Yunnan Education Bureau(2014Y153)
文摘Here,we used reverse transcription-PCR(RT-PCR) and western blot to detect protease-activated receptor(PAR) 1,PAR 2 and PAR 4 expression in cancer tissues and cell lines of esophageal squamous cell carcinoma,and investigated the co-relationship between PAR expression and clinic-pathological data for esophageal cancer.The methylation of PAR4 gene promoter involved in esophageal carcinoma was also analyzed.By comparing the mRNA expressions of normal esophageal tissue and human esophageal epithelial cells(HEEpiC),we found that among the 28 cases of esophageal squamous cell carcinoma,PAR1(60%) and PAR2(71%) were elevated in 17 and 20 cases,respectively,and PAR4(68%) expression was lowered in 19 cases.Whereas,in human esophageal squamous cells(TE-1 and TE-10),PAR1 and PAR2 expression was increased but PAR4 was decreased.Combined with clinical data,the expression of PAR1 in poorly differentiated(P=0.016) and middle and lower parts of the esophagus(P=0.016) was higher; expression of PAR4 in poorly differentiated carcinoma was lower(P=0.049).Regarding TE-1 and TE-10 protein expression,we found that in randomized esophageal carcinoma,PAR1(P=0.027) and PAR2(P=0.039) expressions were increased,but lowered for PAR4(P=0.0001).In HEEpiC,TE-1,TE-10,esophageal and normal esophagus tissue samples(case No.7),the frequency of methylation at the 19 CpG loci of PAR4 was 35.4%,95.2%,83.8%,62.6% and 48.2%,respectively.Our results indicate that the expression of PAR1 and PAR2 in esophageal squamous cell carcinoma is increased but PAR4 is decreased.Hypermethylation of the promoter of the PAR4 gene may contribute to reduced expression of PAR4 in esophageal squamous cell carcinoma.
基金Supported by National Natural Science Foundation of China,No.81301726
文摘AIM To investigate the underlying molecularmechanisms of miR-451 to inhibit proliferation ofesophageal carcinoma cell line EC9706.METHODS： Assays for cell growth, apoptosis andinvasion were used to evaluate the effects of miR-451expression on EC cells. Luciferase reporter and Westernblot assays were used to test whether cyclin-dependentkinase inhibitor 2D （CDKN2D） and MAP3K1 act as majortargets of miR-451.RESULTS： The results showed that CDKN2D andMAP3K1 are direct targets of miR-451. CDKN2D andMAP3K1 overexpression reversed the effect of miR-451.MiR-451 inhibited the proliferation of EC9706 bytargeting CDKN2D and MAP3K1.CONCLUSION： These findings suggest that miR-451might be a novel prognostic biomarker and a potentialtarget for the treatment of esophageal squamous cellcarcinoma in the future.
基金supported by the National Natural Science Foundation of China(81830086,81988101,81702748,and 81902835)China Postdoctoral Science Foundation(2020M670067)+1 种基金Beijing Municipal Commission of Health and Family Planning Project(PXM2018_026279_000005)Guangdong Basic and Applied Basic Research Foundation(2019B030302012).
文摘Background:Long non-codingRNAs(lncRNAs)have been found to be involved in the development of many cancers.In this study,we aimed to identify the molecular mechanisms of lncRNA BAALC antisense RNA 1(BAALC-AS1)in regulating the malignancy of esophageal squamous cell carcinoma(ESCC).Methods:The expression of BAALC-AS1 in cancer patients was analyzed using a tissue microarray.The protein and RNA levels of BAALC-AS1 were determined by Western blotting analysis and quantitative reverse transcription-PCR(RT-qPCR),respectively.The cell proliferation was determined by cell viability assays,bromodeoxyuridine incorporation,and flow cytometry.The relationships among BAALC-AS1,RasGAPSH3 domain-binding protein 2(G3BP2),and c-Myc were determined using RNA immunoprecipitation,RNA pull-down assays,and luciferase assays.Results:The expression of BAALC-AS1 was highly up-regulated and associated with malignant phenotypes in ESCC tissues and cell lines.In vivo and in vitro assays showed that BAALC-AS1 promoted ESCC cell proliferation,migration,and invasion.BAALC-AS1 directly interacted with G3BP2,and thereby inhibited the degradation of c-Myc RNA 3’-UTR by G3BP2,thus leading to the accumulation of c-Myc expression.Additionally,c-Myc acted as a transcription factor that can induce the expression of BAALC-AS1 by directly binding to its promoter region.Conclusions:BAALC-AS1/G3BP2/c-Myc feedback loop plays a critical role in the development of ESCC,which might provide a novel therapeutic target and facilitate the development of new therapeutic strategies for the treatment of ESCC.
文摘BACKGROUND It is well known that an alcohol consumption habit together with inactive heterozygous aldehyde dehydrogenase-2(ALDH2)is an important risk factor for the development of esophageal squamous cell carcinoma(ESCC).It remains controversial whether human papillomavirus(HPV)infection contributes to the occurrence/development of ESCC.There has been no study in which the relationship between ESCC and HPV in addition to alcohol dehydrogenase-1B(ADH1B)and ALDH2 genotypes was evaluated.AIM To evaluate relationships between HPV infection and development of esophageal cancer,particularly early esophageal cancer,based on ADH1B/ALDH2 polymorphisms.METHODS We conducted an exploratory retrospective study using new specimens,and we enrolled 145 patients who underwent endoscopic resection for superficial ESCC and had been observed for more than two years by both physical examination and endoscopic examination in Hokkaido University Hospital.Saliva was collected to analyze genetic polymorphisms of ADH1B/ALDH2.We performed in situ hybridization for resected specimens to detect HPV by using an HPV type 16/18 probe.RESULTS HPV was detected in 15(10.3%)of the 145 patients with ESCC.HPV-positive rates in inactive ALDH2*1/*2 and ALDH2*1/*1+*2/*2 were 10.8%and 9.8%,respectively(P=1.00).HPV-positive rates in slow-metabolizing ADH1B*1/*1 and ADH1B*1/*2+*2/*2 were 12.0%and 10.0%,respectively(P=0.72).HPV-positive rates in the heavy or moderate alcohol consumption group and the light or rare consumption group were 11.1%and 8.7%,respectively(P=0.68).HPV-positive rates in the heavy smoking group and the light or no smoking group were 11.8%and 8.3%,respectively(P=0.59).The 3-year incidence rates of secondary ESCC or head and neck cancer after initial treatment in the HPV-positive and HPVnegative groups were 14.4%and 21.4%(P=0.22),respectively.CONCLUSION In the present situation,HPV status is considered to be less important than other risk factors,such as alcohol consumption,smoking habit,ADH1B/ALDH2 polymorphisms,and HPV status would therefore have no effect on ESCC risk management.
