EZH2-mediated epigenetic silencing of tumor-suppressive let-7c/miR-99a cluster by hepatitis B virus X antigen enhances hepatocellular carcinoma progression and metastasis
Abstract Background Hepatitis B virus (HBV)-encoded X antigen, HBx, assists in the development of hepatocellular carcinoma (HCC) through complex mechanisms. Our results provide new insights into the EZH2 epigenetic repression of let-7c that promotes HCC migration induced by HBx. Thus, let-7c and HMG...
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| Format: | Article |
| Language: | English |
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BMC
2023-09-01
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| Series: | Cancer Cell International |
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| Online Access: | https://doi.org/10.1186/s12935-023-03002-9 |
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| author | Chen-Shiou Wu Yi-Chung Chien Chia‐Jui Yen Jia-Yan Wu Li-Yuan Bai Yung-Luen Yu |
| author_facet | Chen-Shiou Wu Yi-Chung Chien Chia‐Jui Yen Jia-Yan Wu Li-Yuan Bai Yung-Luen Yu |
| author_sort | Chen-Shiou Wu |
| collection | DOAJ |
| description | Abstract Background Hepatitis B virus (HBV)-encoded X antigen, HBx, assists in the development of hepatocellular carcinoma (HCC) through complex mechanisms. Our results provide new insights into the EZH2 epigenetic repression of let-7c that promotes HCC migration induced by HBx. Thus, let-7c and HMGA2 represent key diagnostic markers and potential therapeutic targets for the treatment of HBV-related HCC. Results We investigated the epigenetic regulation of let-7c, an important representative miRNA in liver tumor metastasis, in human HCC cells to verify the effect of HBx. Based on quantitative PCR (qPCR) of mRNA isolated from tumor and adjacent non-tumor liver tissues of 24 patients with HBV-related HCC, EZH2 expression was significantly overexpressed in most HCC tissues (87.5%). We executed a miRNA microarray analysis in paired HBV-related HCC tumor and adjacent non-tumorous liver tissue from six of these patients and identified let-7c, miR-199a-3p, and miR-99a as being downregulated in the tumor tissue. Real-time PCR analysis verified significant downregulation of let-7c and miR-99a in both HepG2X and Hep3BX cells, which stably overexpress HBx, relative to parental cells. HBX enhanced EZH2 expression and attenuated let-7c expression to induce HMGA2 expression in the HCC cells. Knockdown of HMGA2 significantly downregulated the metastatic potential of HCC cells induced by HBx. Conclusions The deregulation of let-7c expression by HBx may indicate a potential novel pathway through deregulating cell metastasis and imply that HMGA2 might be used as a new prognostic marker and/or as an effective therapeutic target for HCC. |
| first_indexed | 2024-03-09T14:54:42Z |
| format | Article |
| id | doaj.art-f04c244483694cb8ac2dbbc76756ab8c |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-03-09T14:54:42Z |
| publishDate | 2023-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-f04c244483694cb8ac2dbbc76756ab8c2023-11-26T14:18:12ZengBMCCancer Cell International1475-28672023-09-0123111110.1186/s12935-023-03002-9EZH2-mediated epigenetic silencing of tumor-suppressive let-7c/miR-99a cluster by hepatitis B virus X antigen enhances hepatocellular carcinoma progression and metastasisChen-Shiou Wu0Yi-Chung Chien1Chia‐Jui Yen2Jia-Yan Wu3Li-Yuan Bai4Yung-Luen Yu5Institute of Translational Medicine and New Drug DevelopmentInstitute of Translational Medicine and New Drug DevelopmentDivision of Hematology and Oncology, Department of Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung UniversityInstitute of Translational Medicine and New Drug DevelopmentDivision of Hematology and Oncology, China Medical University HospitalInstitute of Translational Medicine and New Drug DevelopmentAbstract Background Hepatitis B virus (HBV)-encoded X antigen, HBx, assists in the development of hepatocellular carcinoma (HCC) through complex mechanisms. Our results provide new insights into the EZH2 epigenetic repression of let-7c that promotes HCC migration induced by HBx. Thus, let-7c and HMGA2 represent key diagnostic markers and potential therapeutic targets for the treatment of HBV-related HCC. Results We investigated the epigenetic regulation of let-7c, an important representative miRNA in liver tumor metastasis, in human HCC cells to verify the effect of HBx. Based on quantitative PCR (qPCR) of mRNA isolated from tumor and adjacent non-tumor liver tissues of 24 patients with HBV-related HCC, EZH2 expression was significantly overexpressed in most HCC tissues (87.5%). We executed a miRNA microarray analysis in paired HBV-related HCC tumor and adjacent non-tumorous liver tissue from six of these patients and identified let-7c, miR-199a-3p, and miR-99a as being downregulated in the tumor tissue. Real-time PCR analysis verified significant downregulation of let-7c and miR-99a in both HepG2X and Hep3BX cells, which stably overexpress HBx, relative to parental cells. HBX enhanced EZH2 expression and attenuated let-7c expression to induce HMGA2 expression in the HCC cells. Knockdown of HMGA2 significantly downregulated the metastatic potential of HCC cells induced by HBx. Conclusions The deregulation of let-7c expression by HBx may indicate a potential novel pathway through deregulating cell metastasis and imply that HMGA2 might be used as a new prognostic marker and/or as an effective therapeutic target for HCC.https://doi.org/10.1186/s12935-023-03002-9EZH2let-7cmiR-99aHepatitis B Virus X AntigenHepatocellular Carcinoma |
| spellingShingle | Chen-Shiou Wu Yi-Chung Chien Chia‐Jui Yen Jia-Yan Wu Li-Yuan Bai Yung-Luen Yu EZH2-mediated epigenetic silencing of tumor-suppressive let-7c/miR-99a cluster by hepatitis B virus X antigen enhances hepatocellular carcinoma progression and metastasis Cancer Cell International EZH2 let-7c miR-99a Hepatitis B Virus X Antigen Hepatocellular Carcinoma |
| title | EZH2-mediated epigenetic silencing of tumor-suppressive let-7c/miR-99a cluster by hepatitis B virus X antigen enhances hepatocellular carcinoma progression and metastasis |
| title_full | EZH2-mediated epigenetic silencing of tumor-suppressive let-7c/miR-99a cluster by hepatitis B virus X antigen enhances hepatocellular carcinoma progression and metastasis |
| title_fullStr | EZH2-mediated epigenetic silencing of tumor-suppressive let-7c/miR-99a cluster by hepatitis B virus X antigen enhances hepatocellular carcinoma progression and metastasis |
| title_full_unstemmed | EZH2-mediated epigenetic silencing of tumor-suppressive let-7c/miR-99a cluster by hepatitis B virus X antigen enhances hepatocellular carcinoma progression and metastasis |
| title_short | EZH2-mediated epigenetic silencing of tumor-suppressive let-7c/miR-99a cluster by hepatitis B virus X antigen enhances hepatocellular carcinoma progression and metastasis |
| title_sort | ezh2 mediated epigenetic silencing of tumor suppressive let 7c mir 99a cluster by hepatitis b virus x antigen enhances hepatocellular carcinoma progression and metastasis |
| topic | EZH2 let-7c miR-99a Hepatitis B Virus X Antigen Hepatocellular Carcinoma |
| url | https://doi.org/10.1186/s12935-023-03002-9 |
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