HBx mutant-regulated RPL13AP25 mediates suboptimal virological response to entecavir and HCC progression
Abstract Background A number of effective antiviral agents for chronic hepatitis B are available worldwide, and these agents have exhibited satisfactory virologic suppression, but suboptimal responses still occur in some patients. We aimed to explore the contribution of long non-coding RNAs (lncRNAs...
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BMC
2025-06-01
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| Series: | Cancer Cell International |
| Online Access: | https://doi.org/10.1186/s12935-025-03873-0 |
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| author | Yang-Hsiang Lin Ming-Wei Lai Yu-De Chu Kwang-Huei Lin Chao-Wei Hsu Rong-Nan Chien Po-Heng Chuang Chih-Lang Lin Chau-Ting Yeh |
| author_facet | Yang-Hsiang Lin Ming-Wei Lai Yu-De Chu Kwang-Huei Lin Chao-Wei Hsu Rong-Nan Chien Po-Heng Chuang Chih-Lang Lin Chau-Ting Yeh |
| author_sort | Yang-Hsiang Lin |
| collection | DOAJ |
| description | Abstract Background A number of effective antiviral agents for chronic hepatitis B are available worldwide, and these agents have exhibited satisfactory virologic suppression, but suboptimal responses still occur in some patients. We aimed to explore the contribution of long non-coding RNAs (lncRNAs) in mediating suboptimal responses in chronic hepatitis B patients, which remains to be fully elucidated. Methods Cox regression models were used to analyze associations between suboptimal response and clinical factors. Hepatitis B virus X (HBx) gene was sequenced from entecavir-treated patients who developed hepatocellular carcinoma (HCC). Functional assays were conducted using Transwell assays, MTT assays, and xenograft model. Results Suboptimal response was found to be a significant independent predictor of HCC development. Five of the six patients who developed HCC in the suboptimal response period were found to have HBx mutations (HBx-L100 insertion, HBx-G32R/K130M, HBx-Q87G/k130M/C143R, HBx-L123S, and HBx-H94Y/K130M). Overexpression of the HBx-H94Y/K130M mutation in HepG2.2.15 cells showed significantly increased cccDNA accumulation and enhanced cell migration compared to controls and other HBx mutants. RNA-seq analysis identified RPL13AP25 as a direct target of HBx-H94Y/K130M. RPL13AP25 was highly expressed in HCC tissues, and its elevated expression was associated with poor overall survival and enhanced cell motility and cccDNA accumulation both in vitro and in vivo. Mechanistically, both HBx-H94Y/K130M and RPL13AP25 enhanced the hyperphosphorylation of eIF4EBP1, leading to its dissociation from eIF4E, which subsequently enhances protein synthesis and ultimately contributes to HCC. Conclusions The HBx-H94Y/K130M mutant, selected during the period of suboptimal virological response, appears to promote cccDNA accumulation, likely through the upregulation of RPL13AP25, which contributed to HCC progression. |
| format | Article |
| id | doaj-art-57fe3c82aadb43c981bdb5a1f4050ee7 |
| institution | DOAJ |
| issn | 1475-2867 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
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| series | Cancer Cell International |
| spelling | doaj-art-57fe3c82aadb43c981bdb5a1f4050ee72025-08-20T03:22:57ZengBMCCancer Cell International1475-28672025-06-0125111510.1186/s12935-025-03873-0HBx mutant-regulated RPL13AP25 mediates suboptimal virological response to entecavir and HCC progressionYang-Hsiang Lin0Ming-Wei Lai1Yu-De Chu2Kwang-Huei Lin3Chao-Wei Hsu4Rong-Nan Chien5Po-Heng Chuang6Chih-Lang Lin7Chau-Ting Yeh8Liver Research Center, Chang Gung Memorial HospitalLiver Research Center, Chang Gung Memorial HospitalLiver Research Center, Chang Gung Memorial HospitalLiver Research Center, Chang Gung Memorial HospitalLiver Research Center, Chang Gung Memorial HospitalLiver Research Center, Chang Gung Memorial HospitalDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Jen-Ai HospitalLiver Research Unit, Department of Gastroenterology and Hepatology, Keelung Branch, Chang Gung Memorial HospitalLiver Research Center, Chang Gung Memorial HospitalAbstract Background A number of effective antiviral agents for chronic hepatitis B are available worldwide, and these agents have exhibited satisfactory virologic suppression, but suboptimal responses still occur in some patients. We aimed to explore the contribution of long non-coding RNAs (lncRNAs) in mediating suboptimal responses in chronic hepatitis B patients, which remains to be fully elucidated. Methods Cox regression models were used to analyze associations between suboptimal response and clinical factors. Hepatitis B virus X (HBx) gene was sequenced from entecavir-treated patients who developed hepatocellular carcinoma (HCC). Functional assays were conducted using Transwell assays, MTT assays, and xenograft model. Results Suboptimal response was found to be a significant independent predictor of HCC development. Five of the six patients who developed HCC in the suboptimal response period were found to have HBx mutations (HBx-L100 insertion, HBx-G32R/K130M, HBx-Q87G/k130M/C143R, HBx-L123S, and HBx-H94Y/K130M). Overexpression of the HBx-H94Y/K130M mutation in HepG2.2.15 cells showed significantly increased cccDNA accumulation and enhanced cell migration compared to controls and other HBx mutants. RNA-seq analysis identified RPL13AP25 as a direct target of HBx-H94Y/K130M. RPL13AP25 was highly expressed in HCC tissues, and its elevated expression was associated with poor overall survival and enhanced cell motility and cccDNA accumulation both in vitro and in vivo. Mechanistically, both HBx-H94Y/K130M and RPL13AP25 enhanced the hyperphosphorylation of eIF4EBP1, leading to its dissociation from eIF4E, which subsequently enhances protein synthesis and ultimately contributes to HCC. Conclusions The HBx-H94Y/K130M mutant, selected during the period of suboptimal virological response, appears to promote cccDNA accumulation, likely through the upregulation of RPL13AP25, which contributed to HCC progression.https://doi.org/10.1186/s12935-025-03873-0 |
| spellingShingle | Yang-Hsiang Lin Ming-Wei Lai Yu-De Chu Kwang-Huei Lin Chao-Wei Hsu Rong-Nan Chien Po-Heng Chuang Chih-Lang Lin Chau-Ting Yeh HBx mutant-regulated RPL13AP25 mediates suboptimal virological response to entecavir and HCC progression Cancer Cell International |
| title | HBx mutant-regulated RPL13AP25 mediates suboptimal virological response to entecavir and HCC progression |
| title_full | HBx mutant-regulated RPL13AP25 mediates suboptimal virological response to entecavir and HCC progression |
| title_fullStr | HBx mutant-regulated RPL13AP25 mediates suboptimal virological response to entecavir and HCC progression |
| title_full_unstemmed | HBx mutant-regulated RPL13AP25 mediates suboptimal virological response to entecavir and HCC progression |
| title_short | HBx mutant-regulated RPL13AP25 mediates suboptimal virological response to entecavir and HCC progression |
| title_sort | hbx mutant regulated rpl13ap25 mediates suboptimal virological response to entecavir and hcc progression |
| url | https://doi.org/10.1186/s12935-025-03873-0 |
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