Hepatitis B Virus-KMT2B Integration Drives Hepatic Oncogenic Processes in a Human Gene-edited Induced Pluripotent Stem Cells-derived ModelSummary
Background & Aims: Hepatitis B virus (HBV)-DNA integration into the host genome contributes to hepatocellular carcinoma (HCC) development. KMT2B is the second most frequent locus of HBV-DNA integration in HCC; however, its role and function remain unclear. We aimed to clarify the impact of H...
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Elsevier
2025-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X24001772 |
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| author | Jun Tsuchiya Masato Miyoshi Sei Kakinuma Fukiko Kawai-Kitahata Akihide Kamiya Taro Shimizu Ayako Sato Keiya Watakabe Tomohiro Mochida Kento Inada Rion Kamimae Shun Kaneko Miyako Murakawa Sayuri Nitta Mina Nakagawa Mamoru Watanabe Yasuhiro Asahina Ryuichi Okamoto |
| author_facet | Jun Tsuchiya Masato Miyoshi Sei Kakinuma Fukiko Kawai-Kitahata Akihide Kamiya Taro Shimizu Ayako Sato Keiya Watakabe Tomohiro Mochida Kento Inada Rion Kamimae Shun Kaneko Miyako Murakawa Sayuri Nitta Mina Nakagawa Mamoru Watanabe Yasuhiro Asahina Ryuichi Okamoto |
| author_sort | Jun Tsuchiya |
| collection | DOAJ |
| description | Background & Aims: Hepatitis B virus (HBV)-DNA integration into the host genome contributes to hepatocellular carcinoma (HCC) development. KMT2B is the second most frequent locus of HBV-DNA integration in HCC; however, its role and function remain unclear. We aimed to clarify the impact of HBV-KMT2B integration in HCC development using a human genome-edited induced pluripotent stem cell (iPSCs) model. Methods: Based on the genetic information on HBV-KMT2B integration in HCC, we determined its complete DNA sequence and transcript variants. To exclude the effect of other oncogenic mutations, we reproduced HBV integration in healthy donor iPSCs with an intact genome and analyzed its effects using iPSC-derived hepatic progenitor cells (HPCs) and hepatocytes (iPS-Heps). Results: The reproduced HBV-KMT2B integration significantly upregulated the proliferation of hepatic cells. Comprehensive transcriptional and epigenetic analyses revealed enhanced expression of cell cycle-related genes in hepatic cells with HBV-KMT2B integration based on perturbation of histone 3 lysine 4 tri-methylation (H3K4me3), mimicking that in the original HCC sample. Long-read RNA-sequence detected the common KMT2B transcript variants in the HCC sample and HPCs. Overexpression of the truncated variant significantly enhanced proliferation of hepatic cells, whereas HBV-KMT2B fusion transcripts did not enhance proliferation. HBV-KMT2B-integrated HPCs exhibited replication stress and DNA damage, indicating that our model initiated the process of hepatocarcinogenesis due to abnormally promoted KMT2B function. Conclusions: Our disease model using genetically engineered iPSCs provides the first insight into both the KMT2B function in HCC development and the oncogenic processes by HBV-KMT2B integration. We clarified the novel oncogenic mechanism in HBV-related HCC due to aberrant KMT2B function. |
| format | Article |
| id | doaj-art-a471b682b3ab4b5b919e70619ee207fe |
| institution | Kabale University |
| issn | 2352-345X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj-art-a471b682b3ab4b5b919e70619ee207fe2025-01-17T04:49:35ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2025-01-01192101422Hepatitis B Virus-KMT2B Integration Drives Hepatic Oncogenic Processes in a Human Gene-edited Induced Pluripotent Stem Cells-derived ModelSummaryJun Tsuchiya0Masato Miyoshi1Sei Kakinuma2Fukiko Kawai-Kitahata3Akihide Kamiya4Taro Shimizu5Ayako Sato6Keiya Watakabe7Tomohiro Mochida8Kento Inada9Rion Kamimae10Shun Kaneko11Miyako Murakawa12Sayuri Nitta13Mina Nakagawa14Mamoru Watanabe15Yasuhiro Asahina16Ryuichi Okamoto17Department of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, JapanDepartment of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, JapanDepartment of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, Japan; Department of Clinical and Diagnostic Laboratory Science, Institute of Science Tokyo (Science Tokyo), Tokyo, Japan; Correspondence Address correspondence to: Sei Kakinuma, MD, PhD, Institute of Science Tokyo, Department of Clinical and Diagnostic Laboratory Science, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 1138519 Japan.Department of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, JapanDepartment of Molecular Life Sciences, School of Medicine, Tokai University, Kanagawa, JapanDepartment of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, JapanDepartment of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, JapanDepartment of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, JapanDepartment of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, JapanDepartment of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, JapanDepartment of Clinical and Diagnostic Laboratory Science, Institute of Science Tokyo (Science Tokyo), Tokyo, JapanDepartment of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, JapanDepartment of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, JapanDepartment of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, JapanDepartment of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, JapanDepartment of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, Japan; Faculty of Medicine, Juntendo University, Tokyo, JapanDepartment of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, Japan; Division of Hepatic Medical Science, Institute of Science Tokyo (Science Tokyo), Tokyo, Japan; Yasuhiro Asahina, MD, PhD, Institute of Science Tokyo, Department of Gastroenterology and Hepatology, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 1138519 Japan.Department of Gastroenterology and Hepatology, Institute of Science Tokyo (Science Tokyo), Tokyo, Japan; Ryuichi Okamoto, MD, PhD, Institute of Science Tokyo, Department of Gastroenterology and Hepatology, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 1138519 Japan.Background & Aims: Hepatitis B virus (HBV)-DNA integration into the host genome contributes to hepatocellular carcinoma (HCC) development. KMT2B is the second most frequent locus of HBV-DNA integration in HCC; however, its role and function remain unclear. We aimed to clarify the impact of HBV-KMT2B integration in HCC development using a human genome-edited induced pluripotent stem cell (iPSCs) model. Methods: Based on the genetic information on HBV-KMT2B integration in HCC, we determined its complete DNA sequence and transcript variants. To exclude the effect of other oncogenic mutations, we reproduced HBV integration in healthy donor iPSCs with an intact genome and analyzed its effects using iPSC-derived hepatic progenitor cells (HPCs) and hepatocytes (iPS-Heps). Results: The reproduced HBV-KMT2B integration significantly upregulated the proliferation of hepatic cells. Comprehensive transcriptional and epigenetic analyses revealed enhanced expression of cell cycle-related genes in hepatic cells with HBV-KMT2B integration based on perturbation of histone 3 lysine 4 tri-methylation (H3K4me3), mimicking that in the original HCC sample. Long-read RNA-sequence detected the common KMT2B transcript variants in the HCC sample and HPCs. Overexpression of the truncated variant significantly enhanced proliferation of hepatic cells, whereas HBV-KMT2B fusion transcripts did not enhance proliferation. HBV-KMT2B-integrated HPCs exhibited replication stress and DNA damage, indicating that our model initiated the process of hepatocarcinogenesis due to abnormally promoted KMT2B function. Conclusions: Our disease model using genetically engineered iPSCs provides the first insight into both the KMT2B function in HCC development and the oncogenic processes by HBV-KMT2B integration. We clarified the novel oncogenic mechanism in HBV-related HCC due to aberrant KMT2B function.http://www.sciencedirect.com/science/article/pii/S2352345X24001772H3K4me3Hepatitis B Virus (HBV) Genome IntegrationHepatocellular Carcinomainduced Pluripotent Stem Cells (iPSCs)Replication Stress |
| spellingShingle | Jun Tsuchiya Masato Miyoshi Sei Kakinuma Fukiko Kawai-Kitahata Akihide Kamiya Taro Shimizu Ayako Sato Keiya Watakabe Tomohiro Mochida Kento Inada Rion Kamimae Shun Kaneko Miyako Murakawa Sayuri Nitta Mina Nakagawa Mamoru Watanabe Yasuhiro Asahina Ryuichi Okamoto Hepatitis B Virus-KMT2B Integration Drives Hepatic Oncogenic Processes in a Human Gene-edited Induced Pluripotent Stem Cells-derived ModelSummary Cellular and Molecular Gastroenterology and Hepatology H3K4me3 Hepatitis B Virus (HBV) Genome Integration Hepatocellular Carcinoma induced Pluripotent Stem Cells (iPSCs) Replication Stress |
| title | Hepatitis B Virus-KMT2B Integration Drives Hepatic Oncogenic Processes in a Human Gene-edited Induced Pluripotent Stem Cells-derived ModelSummary |
| title_full | Hepatitis B Virus-KMT2B Integration Drives Hepatic Oncogenic Processes in a Human Gene-edited Induced Pluripotent Stem Cells-derived ModelSummary |
| title_fullStr | Hepatitis B Virus-KMT2B Integration Drives Hepatic Oncogenic Processes in a Human Gene-edited Induced Pluripotent Stem Cells-derived ModelSummary |
| title_full_unstemmed | Hepatitis B Virus-KMT2B Integration Drives Hepatic Oncogenic Processes in a Human Gene-edited Induced Pluripotent Stem Cells-derived ModelSummary |
| title_short | Hepatitis B Virus-KMT2B Integration Drives Hepatic Oncogenic Processes in a Human Gene-edited Induced Pluripotent Stem Cells-derived ModelSummary |
| title_sort | hepatitis b virus kmt2b integration drives hepatic oncogenic processes in a human gene edited induced pluripotent stem cells derived modelsummary |
| topic | H3K4me3 Hepatitis B Virus (HBV) Genome Integration Hepatocellular Carcinoma induced Pluripotent Stem Cells (iPSCs) Replication Stress |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X24001772 |
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