UBE2S promotes malignant properties via VHL/HIF‐1α and VHL/JAK2/STAT3 signaling pathways and decreases sensitivity to sorafenib in hepatocellular carcinoma
Abstract Background Ubiquitin‐conjugating enzyme E2S (UBE2S), an E2 enzyme, is associated with the development of various tumors and exerts oncogenic activities. UBE2S is overexpressed in tumors, including hepatocellular carcinoma (HCC). However, the key molecular mechanisms of UBE2S in HCC still ne...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-09-01
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| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.6431 |
| _version_ | 1797672382343675904 |
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| author | Junyi Wu Xiangjie Xu Shasha Wu Weiwei Shi Guang Zhang Yin Cao Zhongxia Wang Junhua Wu Chunping Jiang |
| author_facet | Junyi Wu Xiangjie Xu Shasha Wu Weiwei Shi Guang Zhang Yin Cao Zhongxia Wang Junhua Wu Chunping Jiang |
| author_sort | Junyi Wu |
| collection | DOAJ |
| description | Abstract Background Ubiquitin‐conjugating enzyme E2S (UBE2S), an E2 enzyme, is associated with the development of various tumors and exerts oncogenic activities. UBE2S is overexpressed in tumors, including hepatocellular carcinoma (HCC). However, the key molecular mechanisms of UBE2S in HCC still need additional research. The aim of this study was to explore the role of UBE2S in HCC. Methods The expression levels of UBE2S in HCC tissues and cells were detected by western blot analysis, quantitative real‐time polymerase chain reaction analysis (qRT–PCR), and immunohistochemistry (IHC). A 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assay, wound healing assay, colony formation assay transwell assay, and animal models were used to detect the proliferation and migration ability of HCC cells. Western blot analysis, qRT–PCR, immunofluorescence, small‐interfering RNA (siRNA), and plasmid transfection and coimmunoprecipitation (Co‐IP) assays were performed to detect the interaction among UBE2S, von Hippel–Lindau (VHL), hypoxia‐inducible factor 1‐alpha (HIF‐1α), Janus kinase‐2 (JAK2), and signal transducer and activator of transcription 3 (STAT3). Results In this study, we found that high UBE2S expression was associated with poor prognosis in HCC patients. In addition, UBE2S expression was upregulated in HCC tissues and cell lines. Knockdown of UBE2S inhibited the proliferation and migration of HCC cells in vitro and in vivo by directly interacting with VHL to downregulate the HIF‐1α and JAK2/STAT3 signaling pathways. Accordingly, overexpression of UBE2S significantly enhanced the proliferation and migration of HCC cells in vitro via VHL to upregulate HIF‐1α and JAK2/STAT3 signaling pathways. Furthermore, we found that downregulation of UBE2S expression enhanced the sensitivity of HCC cells to sorafenib in vivo and in vitro. Conclusion UBE2S enhances malignant properties via the VHL/HIF‐1α and VHL/JAK2/STAT3 signaling pathways and reduces sensitivity to sorafenib in HCC. The findings of this study may open a new approach for HCC diagnosis and provide a potential option for the treatment of HCC. |
| first_indexed | 2024-03-11T21:29:14Z |
| format | Article |
| id | doaj.art-cfa8b9d90dea41cebbdd08ec836a699d |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-03-11T21:29:14Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-cfa8b9d90dea41cebbdd08ec836a699d2023-09-27T11:46:08ZengWileyCancer Medicine2045-76342023-09-011217180781809710.1002/cam4.6431UBE2S promotes malignant properties via VHL/HIF‐1α and VHL/JAK2/STAT3 signaling pathways and decreases sensitivity to sorafenib in hepatocellular carcinomaJunyi Wu0Xiangjie Xu1Shasha Wu2Weiwei Shi3Guang Zhang4Yin Cao5Zhongxia Wang6Junhua Wu7Chunping Jiang8Jinan Microecological Biomedicine Shandong Laboratory Shounuo City Light West Block Jinan Shandong ChinaNanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine Nanjing University of Chinese Medicine Nanjing Jiangsu ChinaDepartment of Clinical Medicine and Rehabilitation Jiangsu College of Nursing Huai'an Jiangsu ChinaState Key Laboratory of Pharmaceutical Biotechnology, National Institute of Healthcare Data Science at Nanjing University, Jiangsu Key Laboratory of Molecular Medicine Medical School of Nanjing University, Nanjing University Nanjing Jiangsu ChinaNanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine Nanjing University of Chinese Medicine Nanjing Jiangsu ChinaNanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine Nanjing University of Chinese Medicine Nanjing Jiangsu ChinaNanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine Nanjing University of Chinese Medicine Nanjing Jiangsu ChinaJinan Microecological Biomedicine Shandong Laboratory Shounuo City Light West Block Jinan Shandong ChinaJinan Microecological Biomedicine Shandong Laboratory Shounuo City Light West Block Jinan Shandong ChinaAbstract Background Ubiquitin‐conjugating enzyme E2S (UBE2S), an E2 enzyme, is associated with the development of various tumors and exerts oncogenic activities. UBE2S is overexpressed in tumors, including hepatocellular carcinoma (HCC). However, the key molecular mechanisms of UBE2S in HCC still need additional research. The aim of this study was to explore the role of UBE2S in HCC. Methods The expression levels of UBE2S in HCC tissues and cells were detected by western blot analysis, quantitative real‐time polymerase chain reaction analysis (qRT–PCR), and immunohistochemistry (IHC). A 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assay, wound healing assay, colony formation assay transwell assay, and animal models were used to detect the proliferation and migration ability of HCC cells. Western blot analysis, qRT–PCR, immunofluorescence, small‐interfering RNA (siRNA), and plasmid transfection and coimmunoprecipitation (Co‐IP) assays were performed to detect the interaction among UBE2S, von Hippel–Lindau (VHL), hypoxia‐inducible factor 1‐alpha (HIF‐1α), Janus kinase‐2 (JAK2), and signal transducer and activator of transcription 3 (STAT3). Results In this study, we found that high UBE2S expression was associated with poor prognosis in HCC patients. In addition, UBE2S expression was upregulated in HCC tissues and cell lines. Knockdown of UBE2S inhibited the proliferation and migration of HCC cells in vitro and in vivo by directly interacting with VHL to downregulate the HIF‐1α and JAK2/STAT3 signaling pathways. Accordingly, overexpression of UBE2S significantly enhanced the proliferation and migration of HCC cells in vitro via VHL to upregulate HIF‐1α and JAK2/STAT3 signaling pathways. Furthermore, we found that downregulation of UBE2S expression enhanced the sensitivity of HCC cells to sorafenib in vivo and in vitro. Conclusion UBE2S enhances malignant properties via the VHL/HIF‐1α and VHL/JAK2/STAT3 signaling pathways and reduces sensitivity to sorafenib in HCC. The findings of this study may open a new approach for HCC diagnosis and provide a potential option for the treatment of HCC.https://doi.org/10.1002/cam4.6431malignant propertiessorafenibUBE2SVHL |
| spellingShingle | Junyi Wu Xiangjie Xu Shasha Wu Weiwei Shi Guang Zhang Yin Cao Zhongxia Wang Junhua Wu Chunping Jiang UBE2S promotes malignant properties via VHL/HIF‐1α and VHL/JAK2/STAT3 signaling pathways and decreases sensitivity to sorafenib in hepatocellular carcinoma Cancer Medicine malignant properties sorafenib UBE2S VHL |
| title | UBE2S promotes malignant properties via VHL/HIF‐1α and VHL/JAK2/STAT3 signaling pathways and decreases sensitivity to sorafenib in hepatocellular carcinoma |
| title_full | UBE2S promotes malignant properties via VHL/HIF‐1α and VHL/JAK2/STAT3 signaling pathways and decreases sensitivity to sorafenib in hepatocellular carcinoma |
| title_fullStr | UBE2S promotes malignant properties via VHL/HIF‐1α and VHL/JAK2/STAT3 signaling pathways and decreases sensitivity to sorafenib in hepatocellular carcinoma |
| title_full_unstemmed | UBE2S promotes malignant properties via VHL/HIF‐1α and VHL/JAK2/STAT3 signaling pathways and decreases sensitivity to sorafenib in hepatocellular carcinoma |
| title_short | UBE2S promotes malignant properties via VHL/HIF‐1α and VHL/JAK2/STAT3 signaling pathways and decreases sensitivity to sorafenib in hepatocellular carcinoma |
| title_sort | ube2s promotes malignant properties via vhl hif 1α and vhl jak2 stat3 signaling pathways and decreases sensitivity to sorafenib in hepatocellular carcinoma |
| topic | malignant properties sorafenib UBE2S VHL |
| url | https://doi.org/10.1002/cam4.6431 |
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