AIM: To comprehensively understand the underlying molecular events accounting for aberrant Wnt signaling activation in hepatocellular carcinoma(HCC).METHODS: This study was retrospective. The HCC tissue specimens used...AIM: To comprehensively understand the underlying molecular events accounting for aberrant Wnt signaling activation in hepatocellular carcinoma(HCC).METHODS: This study was retrospective. The HCC tissue specimens used in this research were obtained from patients who underwent liver surgery. The Catalogue of Somatic Mutations in Cancer(COSMIC) database was searched for the mutation statuses of CTNNB1, TP53, and protein degradation regulator genes of CTNNB1. Dual-luciferase reporter assay was performed with TOP/FOP reporters to detect whether TP53 gain-of-function(GOF) mutations could enhance the transcriptional activity of Wnt signaling. Methylation sensitive restriction enzyme-quantitative PCR was used to explore the methylation status of Cp G islands located in the promoters of APC, SFRP1, and SFRP5 in HCCs with different risk factors. Finally, nestedreverse transcription PCR was performed to examine the integration of HBx in front of LINE1 element and the existence of HBx-LINE1 chimeric transcript in Hepatitis B virus-related HCC. All results in this article were analyzed with the software SPSS version 19.0 for Windows, and different groups were compared by χ2 test as appropriate.RESULTS: Based on the data from COSMIC database, compared with other solid tumors, mutation frequency of CTNNB1 was significantly higher in HCC(P < 0.01). The rate of CTNNB1 mutation was significantly less frequent in Hepatitis B virus-related HCC than in other etiologies(P < 0.01). Dual-luciferase reporter system and TOP/FOP reporter assays confirmed that TP53 GOF mutants were able to enhance the transcriptional ability of Wnt signaling. An exclusive relationship between the status of TP53 and CTNNB1 mutations was observed. However, according to the COSMIC database, TP53 GOF mutation is rare in HCC, which indicates that TP53 GOF mutation is not a reason for the aberrant activation of Wnt signaling in HCC. APC and AXIN1 were mutated in HCC. By using methylation sensitive restriction enzyme-quantitative PCR, hypermethylation of APC was展开更多
The debate exists whether or not gonadotropin-releasing hormone（GnRH） analogs used in controlled ovarian hyperstimulation（COH） impair endometrial receptivity.Homeobox A11（Hoxa11）,Meis homeobox 1（Meis1）,cadheri...The debate exists whether or not gonadotropin-releasing hormone（GnRH） analogs used in controlled ovarian hyperstimulation（COH） impair endometrial receptivity.Homeobox A11（Hoxa11）,Meis homeobox 1（Meis1）,cadherin 1（Cdh1）,and catenin beta 1（Ctnnb1） are well known to be involved in successful implantation.In this study,the endometrial expression of Hoxa11,Meis1,Cdh1,and Ctnnb1 during the peri-implantation period was investigated in an in vitro fertilization（IVF） mouse model by real-time RT-PCR and Western blot to evaluate the relationship between Hoxa11,Meis1,Cdh1,and Ctnnb1 expression and the impact of the COH on endometrial receptivity.The mimic COH protocols included GnRH agonist plus human menopausal gonadotropin（HMG）（GnRH agonist group）,GnRH antagonist plus HMG（GnRH antagonist group）,and HMG alone（HMG group）.The expression levels of Hoxa11,Meis1,Cdh1,and Ctnnb1 mRNA and protein were decreased in all of the COH groups.The expression levels of Hoxa11 and Ctnnb1 were the lowest in the GnRH agonist group,and those of Meis1 and Cdh1 were lower in the GnRH analog groups than the HMG group.There were positive correlations between the expression of Hoxa11 and Ctnnb1,as well as the expression of Meis1 and Cdh1 among all the groups.In conclusion,the COH protocols,particularly with GnRH analogs,suppressed Hoxa11,Meis1,Ctnnb1 and Cdh1 expression,in mouse endometrium during the peri-implantation period.Our data reveal a novel molecular mechanism by which the COH protocols might impair endometrial receptivity.展开更多
Hepatocellular carcinoma(HCC)is a liver cancer,highly heterogeneous both at the histopathological and molecular levels.It arises from hepatocytes as the result of the accumulation of numerous genomic alterations in va...Hepatocellular carcinoma(HCC)is a liver cancer,highly heterogeneous both at the histopathological and molecular levels.It arises from hepatocytes as the result of the accumulation of numerous genomic alterations in various signaling pathways,including canonical WNT/β-catenin,AKT/mTOR,MAPK pathways as well as signaling associated with telomere maintenance,p53/cell cycle regulation,epigenetic modifiers,and oxidative stress.The role of WNT/β-catenin signaling in liver homeostasis and regeneration is well established,whereas in development and progression of HCC is extensively studied.Herein,we review recent advances in our understanding of how WNT/β-catenin signaling facilitates the HCC development,acquisition of stemness features,metastasis,and resistance to treatment.We outline genetic and epigenetic alterations that lead to activated WNT/β-catenin signaling in HCC.We discuss the pivotal roles of CTNNB1 mutations,aberrantly expressed non-coding RNAs and complexity of crosstalk between WNT/β-catenin signaling and other signaling pathways as challenging or advantageous aspects of therapy development and molecular stratification of HCC patients for treatment.展开更多
AIM： To examine the expression of beta-catenin in colorectal cancer and look for association with other dinico-pathological parameters. METHODS;： Tumor samples from 163 cases of colorectal cancer （CRC） who had und...AIM： To examine the expression of beta-catenin in colorectal cancer and look for association with other dinico-pathological parameters. METHODS;： Tumor samples from 163 cases of colorectal cancer （CRC） who had undergone primary colectomy between May, 1998 and November, 2002 with complete follow-up data for either 5 years or until death were recruited for a beta-catenin immunohistochemical study. The percentage of immunoreacted tumor cells was defined as overall staining density （OSD） and percentage of cells having nuclear localization was counted as nuclear staining density （NSD）. Univariate exploration used log-rank test and multivariate survival analysis used Cox＇s hazard regression model. RESULTS： Beta-catenin immunoreactivity was detected in 161 samples （98.8%）, of which 131 cases had nuclear staining. High OSD （≥ 75%）, detected in 123 cases （75.5%）, was significantly associated with earlier clinical staging （P 〈 0.01）, lower nodal status （P = 0.02）, non-metastatic status （P 〈 0.01） and better differentiation （P = 0.02）. Multivariate analysis found that high OSD was independently associated with better survival [Cox＇s hazard ratio 0.51, 95% confidence interval （CI） 0.31-0.83]. Although high NSD （≥ 75%） was correlated with high pre-operative serum CEA （P = 0.03）, well differentiation （P 〈 0.01）, and increased staining intensity（P 〈 0.01）, the parameter was not significantly associated with survival. CONCLI3SIOM： Unlike previous reports, the study did not find a predictive value of nuclear beta-catenin in CRC. Instead, the overall expression of beta-catenin in CRC showed an association with better differentiation and earlier staging. Moreover, the parameter also independently predicted superior survival.展开更多
Studies that compare tumor genotype with phenotype have provided the basis of a new histological/molecular classification of hepatocellular adenomas. Based on two molecular criteria （presence of a TCFI/HNF1α or β-c...Studies that compare tumor genotype with phenotype have provided the basis of a new histological/molecular classification of hepatocellular adenomas. Based on two molecular criteria （presence of a TCFI/HNF1α or β-catenin mutation）, and an additional histological criterion （presence or absence of an inflammatory infiltrate）, subgroups of hepatocellular adenoma can be defined and distinguished from focal nodular hyperplasia. Analysis of 96 hepatocellular adenomas performed by a French collaborative network showed that they can be divided into four broad subgroups： the first one is defined by the presence of mutations in TCF1 gene inactivating the hepatocyte nuclear factor 1 （HNF1α）, the second by the presence of β-catenin activating mutations; the category without mutations of HNF1α or β-catenin is further divided into 2 subgroups depending on the presence or absence of inflammation. Therefore, the approach to the diagnosis of problematic benign hepatocytic nodules may be entering a new era directed by new molecular information. It is hoped that immunohistological tools will improve significantly diagnosis of liver biopsy in our ability to distinguish hepatocellular adenoma from focal nodular hyperplasia （FNH）, and to delineate clinically meaningful entities within each group to define the best clinical management. The optimal care of patients with a liver nodule will benefit from the recent knowledge coming from molecular biology and the combined expertise of hepatologists, pathologists, radiologists, and surgeons.展开更多
Background and Objective: Radioresistant cells in esophageal cancer is one of the important reasons for the local failure of radiotherapy. In recent years, some researchers used gene chip technology to screen the diff...Background and Objective: Radioresistant cells in esophageal cancer is one of the important reasons for the local failure of radiotherapy. In recent years, some researchers used gene chip technology to screen the differentially expressed genes between parental and radioresistant human esophageal cancer cells. But there were some problems in these studies, for example comparing cells at only one time interval, and genetic background not matching. In this study, we selected 3 different pairs of parental and radioresistant human esophageal cancer cells, and compared the gene expression profiles by cDNA microarray at 3 time intervals to identify and analyze the differentially expressed genes between parental and radioresistant human esophageal cancer cells. Methods: We compared the gene expression profiles between parental cells (TE13, Seg-1, Kyse170) and radioresistant cells (TE13R, Seg-1R, Kyse170R) before, and at 8 h and 24 h after irradiation with a cDNA microarray consisting of 48 000 genes (Human Genome). We identified differentially expressed genes by Pathway and GO analyses, and verified the differentially expressed genes LEF1 and CTNNB1 by RT-PCR. Results: A total of 460, 451, and 397 differentially expressed genes were found before, and at 8 h and 24 h after irradiation. After Pathway and GO analyses, 14 differentially expressed genes, participating in cell growth, apoptosis, cell cycle regulation, gene repair and signal transmission, were selected to further research. LEF1 and CTNNB1 were verified by RT-PCR, and the results were consistent with those of cDNA microarray. Conclusions: The WNT signal pathway may be an important pathway participating in the formation of radioresistance of esophageal cancer cells. LEF1 and CTNNB1 may be the important genes causing the esophageal cancer cell radioresistance.展开更多
Recent research has shown that the alteration of combinations in gene expression contributes to cellular phenotypic changes. Previously, it has been demonstrated that the combination of cadherin 1 and cadherin 2 expre...Recent research has shown that the alteration of combinations in gene expression contributes to cellular phenotypic changes. Previously, it has been demonstrated that the combination of cadherin 1 and cadherin 2 expression can identify the diffuse-type and intestinal-type gastric cancers. Although the diffuse-type gastric cancer has been resistant to treatment, the precise mechanism and phenotypic involvement has not been revealed. It may be possible that stem cells transform into gastric cancer cells, possibly through the involvement of a molecule alteration and signaling mechanism. In this review article, we focus on the role of catenin beta 1 (CTNNB1 or β-catenin) and describe the regulation of CTNNB1 signaling in gastric cancer and stem cells.展开更多
Idiopathic pulmonary fibrosis(IPF)is a progressive disease with unknown etiology and limited therapeutic options.Activation of fibroblasts is a prominent feature of pulmonary fibrosis.Here we report that lncRNA DACH1(...Idiopathic pulmonary fibrosis(IPF)is a progressive disease with unknown etiology and limited therapeutic options.Activation of fibroblasts is a prominent feature of pulmonary fibrosis.Here we report that lncRNA DACH1(dachshund homolog 1)is downregulated in the lungs of IPF patients and in an experimental mouse model of lung fibrosis.LncDACH1 knockout mice develop spontaneous pulmonary fibrosis,whereas overexpression of LncDACH1 attenuated TGF-β1-induced aberrant activation,collagen deposition and differentiation of mouse lung fibroblasts.Similarly,forced expression of LncDACH1 not only prevented bleomycin(BLM)-induced lung fibrosis,but also reversed established lung fibrosis in a BLM model.Mechanistically,LncDACH1 binding to the serine/arginine-rich splicing factor 1(SRSF1)protein decreases its activity and inhibits the accumulation of Ctnnb1.Enhanced expression of SRSF1 blocked the anti-fibrotic effect of LncDACH1 in lung fibroblasts.Furthermore,loss of LncDACH1 promoted proliferation,differentiation,and extracellular matrix(ECM)deposition in mouse lung fibroblasts,whereas such effects were abolished by silencing of Ctnnb1.In addition,a conserved fragment of LncDACH1 alleviated hyperproliferation,ECM deposition and differentiation of MRC-5 cells driven by TGF-β1.Collectively,LncDACH1 inhibits lung fibrosis by interacting with SRSF1 to suppress CTNNB1 accumulation,suggesting that LncDACH1 might be a potential therapeutic target for pulmonary fibrosis.展开更多
基金Supported by National Natural Science Foundation of China,No.81372603973 Program,No.2015CB554000+1 种基金National S T Major Project for Infectious Diseases,No.2012ZX10004-904The 111 Project,No.B07001
文摘AIM: To comprehensively understand the underlying molecular events accounting for aberrant Wnt signaling activation in hepatocellular carcinoma(HCC).METHODS: This study was retrospective. The HCC tissue specimens used in this research were obtained from patients who underwent liver surgery. The Catalogue of Somatic Mutations in Cancer(COSMIC) database was searched for the mutation statuses of CTNNB1, TP53, and protein degradation regulator genes of CTNNB1. Dual-luciferase reporter assay was performed with TOP/FOP reporters to detect whether TP53 gain-of-function(GOF) mutations could enhance the transcriptional activity of Wnt signaling. Methylation sensitive restriction enzyme-quantitative PCR was used to explore the methylation status of Cp G islands located in the promoters of APC, SFRP1, and SFRP5 in HCCs with different risk factors. Finally, nestedreverse transcription PCR was performed to examine the integration of HBx in front of LINE1 element and the existence of HBx-LINE1 chimeric transcript in Hepatitis B virus-related HCC. All results in this article were analyzed with the software SPSS version 19.0 for Windows, and different groups were compared by χ2 test as appropriate.RESULTS: Based on the data from COSMIC database, compared with other solid tumors, mutation frequency of CTNNB1 was significantly higher in HCC(P < 0.01). The rate of CTNNB1 mutation was significantly less frequent in Hepatitis B virus-related HCC than in other etiologies(P < 0.01). Dual-luciferase reporter system and TOP/FOP reporter assays confirmed that TP53 GOF mutants were able to enhance the transcriptional ability of Wnt signaling. An exclusive relationship between the status of TP53 and CTNNB1 mutations was observed. However, according to the COSMIC database, TP53 GOF mutation is rare in HCC, which indicates that TP53 GOF mutation is not a reason for the aberrant activation of Wnt signaling in HCC. APC and AXIN1 were mutated in HCC. By using methylation sensitive restriction enzyme-quantitative PCR, hypermethylation of APC was
基金supported by a grant from the Major State Basic Research Development Program of China (973 Program)(No. 2007-CB948100)
文摘The debate exists whether or not gonadotropin-releasing hormone（GnRH） analogs used in controlled ovarian hyperstimulation（COH） impair endometrial receptivity.Homeobox A11（Hoxa11）,Meis homeobox 1（Meis1）,cadherin 1（Cdh1）,and catenin beta 1（Ctnnb1） are well known to be involved in successful implantation.In this study,the endometrial expression of Hoxa11,Meis1,Cdh1,and Ctnnb1 during the peri-implantation period was investigated in an in vitro fertilization（IVF） mouse model by real-time RT-PCR and Western blot to evaluate the relationship between Hoxa11,Meis1,Cdh1,and Ctnnb1 expression and the impact of the COH on endometrial receptivity.The mimic COH protocols included GnRH agonist plus human menopausal gonadotropin（HMG）（GnRH agonist group）,GnRH antagonist plus HMG（GnRH antagonist group）,and HMG alone（HMG group）.The expression levels of Hoxa11,Meis1,Cdh1,and Ctnnb1 mRNA and protein were decreased in all of the COH groups.The expression levels of Hoxa11 and Ctnnb1 were the lowest in the GnRH agonist group,and those of Meis1 and Cdh1 were lower in the GnRH analog groups than the HMG group.There were positive correlations between the expression of Hoxa11 and Ctnnb1,as well as the expression of Meis1 and Cdh1 among all the groups.In conclusion,the COH protocols,particularly with GnRH analogs,suppressed Hoxa11,Meis1,Ctnnb1 and Cdh1 expression,in mouse endometrium during the peri-implantation period.Our data reveal a novel molecular mechanism by which the COH protocols might impair endometrial receptivity.
基金supported by the research funding of the Medical University of Lodz(No.503/1-156-01/503-11-001).
文摘Hepatocellular carcinoma(HCC)is a liver cancer,highly heterogeneous both at the histopathological and molecular levels.It arises from hepatocytes as the result of the accumulation of numerous genomic alterations in various signaling pathways,including canonical WNT/β-catenin,AKT/mTOR,MAPK pathways as well as signaling associated with telomere maintenance,p53/cell cycle regulation,epigenetic modifiers,and oxidative stress.The role of WNT/β-catenin signaling in liver homeostasis and regeneration is well established,whereas in development and progression of HCC is extensively studied.Herein,we review recent advances in our understanding of how WNT/β-catenin signaling facilitates the HCC development,acquisition of stemness features,metastasis,and resistance to treatment.We outline genetic and epigenetic alterations that lead to activated WNT/β-catenin signaling in HCC.We discuss the pivotal roles of CTNNB1 mutations,aberrantly expressed non-coding RNAs and complexity of crosstalk between WNT/β-catenin signaling and other signaling pathways as challenging or advantageous aspects of therapy development and molecular stratification of HCC patients for treatment.
基金The Faculty of Medicine,Prince of Songkla University
文摘AIM： To examine the expression of beta-catenin in colorectal cancer and look for association with other dinico-pathological parameters. METHODS;： Tumor samples from 163 cases of colorectal cancer （CRC） who had undergone primary colectomy between May, 1998 and November, 2002 with complete follow-up data for either 5 years or until death were recruited for a beta-catenin immunohistochemical study. The percentage of immunoreacted tumor cells was defined as overall staining density （OSD） and percentage of cells having nuclear localization was counted as nuclear staining density （NSD）. Univariate exploration used log-rank test and multivariate survival analysis used Cox＇s hazard regression model. RESULTS： Beta-catenin immunoreactivity was detected in 161 samples （98.8%）, of which 131 cases had nuclear staining. High OSD （≥ 75%）, detected in 123 cases （75.5%）, was significantly associated with earlier clinical staging （P 〈 0.01）, lower nodal status （P = 0.02）, non-metastatic status （P 〈 0.01） and better differentiation （P = 0.02）. Multivariate analysis found that high OSD was independently associated with better survival [Cox＇s hazard ratio 0.51, 95% confidence interval （CI） 0.31-0.83]. Although high NSD （≥ 75%） was correlated with high pre-operative serum CEA （P = 0.03）, well differentiation （P 〈 0.01）, and increased staining intensity（P 〈 0.01）, the parameter was not significantly associated with survival. CONCLI3SIOM： Unlike previous reports, the study did not find a predictive value of nuclear beta-catenin in CRC. Instead, the overall expression of beta-catenin in CRC showed an association with better differentiation and earlier staging. Moreover, the parameter also independently predicted superior survival.
文摘Studies that compare tumor genotype with phenotype have provided the basis of a new histological/molecular classification of hepatocellular adenomas. Based on two molecular criteria （presence of a TCFI/HNF1α or β-catenin mutation）, and an additional histological criterion （presence or absence of an inflammatory infiltrate）, subgroups of hepatocellular adenoma can be defined and distinguished from focal nodular hyperplasia. Analysis of 96 hepatocellular adenomas performed by a French collaborative network showed that they can be divided into four broad subgroups： the first one is defined by the presence of mutations in TCF1 gene inactivating the hepatocyte nuclear factor 1 （HNF1α）, the second by the presence of β-catenin activating mutations; the category without mutations of HNF1α or β-catenin is further divided into 2 subgroups depending on the presence or absence of inflammation. Therefore, the approach to the diagnosis of problematic benign hepatocytic nodules may be entering a new era directed by new molecular information. It is hoped that immunohistological tools will improve significantly diagnosis of liver biopsy in our ability to distinguish hepatocellular adenoma from focal nodular hyperplasia （FNH）, and to delineate clinically meaningful entities within each group to define the best clinical management. The optimal care of patients with a liver nodule will benefit from the recent knowledge coming from molecular biology and the combined expertise of hepatologists, pathologists, radiologists, and surgeons.
基金National Natural Science Foundation of China (No.30670619)
文摘Background and Objective: Radioresistant cells in esophageal cancer is one of the important reasons for the local failure of radiotherapy. In recent years, some researchers used gene chip technology to screen the differentially expressed genes between parental and radioresistant human esophageal cancer cells. But there were some problems in these studies, for example comparing cells at only one time interval, and genetic background not matching. In this study, we selected 3 different pairs of parental and radioresistant human esophageal cancer cells, and compared the gene expression profiles by cDNA microarray at 3 time intervals to identify and analyze the differentially expressed genes between parental and radioresistant human esophageal cancer cells. Methods: We compared the gene expression profiles between parental cells (TE13, Seg-1, Kyse170) and radioresistant cells (TE13R, Seg-1R, Kyse170R) before, and at 8 h and 24 h after irradiation with a cDNA microarray consisting of 48 000 genes (Human Genome). We identified differentially expressed genes by Pathway and GO analyses, and verified the differentially expressed genes LEF1 and CTNNB1 by RT-PCR. Results: A total of 460, 451, and 397 differentially expressed genes were found before, and at 8 h and 24 h after irradiation. After Pathway and GO analyses, 14 differentially expressed genes, participating in cell growth, apoptosis, cell cycle regulation, gene repair and signal transmission, were selected to further research. LEF1 and CTNNB1 were verified by RT-PCR, and the results were consistent with those of cDNA microarray. Conclusions: The WNT signal pathway may be an important pathway participating in the formation of radioresistance of esophageal cancer cells. LEF1 and CTNNB1 may be the important genes causing the esophageal cancer cell radioresistance.
文摘Recent research has shown that the alteration of combinations in gene expression contributes to cellular phenotypic changes. Previously, it has been demonstrated that the combination of cadherin 1 and cadherin 2 expression can identify the diffuse-type and intestinal-type gastric cancers. Although the diffuse-type gastric cancer has been resistant to treatment, the precise mechanism and phenotypic involvement has not been revealed. It may be possible that stem cells transform into gastric cancer cells, possibly through the involvement of a molecule alteration and signaling mechanism. In this review article, we focus on the role of catenin beta 1 (CTNNB1 or β-catenin) and describe the regulation of CTNNB1 signaling in gastric cancer and stem cells.
基金supported by the National Natural Science Foundation of China (32171127 and 91949109)the HMU Marshal Initiative Funding (HMUMIF-21023, China)+3 种基金the Major Scientific Fund Project of Heilongjiang Province (ZD2019H001, China)the CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M5-078, China)the Guangdong Province Basic and Applied Basic Research Fund (2021A1515111049, China)Postgraduate Research and Practice Innovation Program of HMU (YJSCX202015HYD, China)
文摘Idiopathic pulmonary fibrosis(IPF)is a progressive disease with unknown etiology and limited therapeutic options.Activation of fibroblasts is a prominent feature of pulmonary fibrosis.Here we report that lncRNA DACH1(dachshund homolog 1)is downregulated in the lungs of IPF patients and in an experimental mouse model of lung fibrosis.LncDACH1 knockout mice develop spontaneous pulmonary fibrosis,whereas overexpression of LncDACH1 attenuated TGF-β1-induced aberrant activation,collagen deposition and differentiation of mouse lung fibroblasts.Similarly,forced expression of LncDACH1 not only prevented bleomycin(BLM)-induced lung fibrosis,but also reversed established lung fibrosis in a BLM model.Mechanistically,LncDACH1 binding to the serine/arginine-rich splicing factor 1(SRSF1)protein decreases its activity and inhibits the accumulation of Ctnnb1.Enhanced expression of SRSF1 blocked the anti-fibrotic effect of LncDACH1 in lung fibroblasts.Furthermore,loss of LncDACH1 promoted proliferation,differentiation,and extracellular matrix(ECM)deposition in mouse lung fibroblasts,whereas such effects were abolished by silencing of Ctnnb1.In addition,a conserved fragment of LncDACH1 alleviated hyperproliferation,ECM deposition and differentiation of MRC-5 cells driven by TGF-β1.Collectively,LncDACH1 inhibits lung fibrosis by interacting with SRSF1 to suppress CTNNB1 accumulation,suggesting that LncDACH1 might be a potential therapeutic target for pulmonary fibrosis.
