Int J Med Sci 2021; 18(16):3749-3758. doi:10.7150/ijms.63220 This issue Cite

Research Paper

UBE2O promotes hepatocellular carcinoma cell proliferation and invasion by regulating the AMPKα2/mTOR pathway

Zhan Shi1,2#, Runkun Liu3#, Qiliang Lu4, Zhi Zeng4, Yang Liu4, Junjun Zhao5, Xin Liu2, Lijie Li6, Hui Huang7, Yingmin Yao3, Dongsheng Huang2✉, Qiuran Xu2✉

1. The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China.
2. The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310014, China.
3. Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
4. The Medical College of Qingdao University, Qingdao, 266071, China.
5. Graduate Department, Bengbu Medical College, Bengbu 233030, China.
6. Department of Obstetrics and Gynaecology, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, Hangzhou 310013, China.
7. Affiliated Quzhou People's Hospital, Zhejiang Chinese Medical University, Quzhou 324002, China.
#These authors contributed equally to this work.

Citation:
Shi Z, Liu R, Lu Q, Zeng Z, Liu Y, Zhao J, Liu X, Li L, Huang H, Yao Y, Huang D, Xu Q. UBE2O promotes hepatocellular carcinoma cell proliferation and invasion by regulating the AMPKα2/mTOR pathway. Int J Med Sci 2021; 18(16):3749-3758. doi:10.7150/ijms.63220. https://www.medsci.org/v18p3749.htm
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Abstract

Graphic abstract

The ubiquitin-conjugating enzyme (E2) is a critical component of the ubiquitin-proteasome system and regulates hepatocarcinogenesis by controlling protein degradation. Ubiquitin-conjugating enzyme E2 O (UBE2O), a member of the E2 family, functions as an oncogene in human cancers. Nevertheless, the role of UBE2O in hepatocellular carcinoma (HCC) remains unknown yet. Here, we demonstrated that the UBE2O level was markedly upregulated in HCC compared with adjacent noncancerous tissues. UBE2O overexpression was also confirmed in HCC cell lines. UBE2O overexpression was prominently associated with advanced tumor stage, high tumor grade, venous infiltration, and reduced HCC patients' survivals. UBE2O knockdown inhibited the migration, invasion, and proliferation of HCCLM3 cells. UBE2O overexpression enhanced the proliferation and mobility of Huh7 cells. Mechanistically, UBE2O mediated the ubiquitination and degradation of AMP-activated protein kinase α2 (AMPKα2) in HCC cells. UBE2O silencing prominently increased AMPKα2 level and reduced phosphorylated mechanistic target of rapamycin kinase (p-mTOR), MYC, Cyclin D1, HIF1α, and SREBP1 levels in HCCLM3 cells. UBE2O depletion markedly activated the AMPKα2/mTOR pathway in Huh7 cells. Moreover, AMPKα2 silencing reversed UBE2O downregulation-induced mTOR pathway inactivation. Rapamycin, an inhibitor of mTOR, remarkably abolished UBE2O-induced mTOR phosphorylation and HCC cell proliferation and mobility. To conclude, UBE2O was highly expressed in HCC and its overexpression conferred to the poor clinical outcomes of patients. UBE2O contributed to the malignant behaviors of HCC cells, including cell proliferation, migration, and invasion, by reducing AMPKα2 stability and activating the mTOR pathway.

Keywords: Hepatocellular carcinoma, UBE2O, AMPKα2, mTOR pathway, Tumor progression


Citation styles

APA
Shi, Z., Liu, R., Lu, Q., Zeng, Z., Liu, Y., Zhao, J., Liu, X., Li, L., Huang, H., Yao, Y., Huang, D., Xu, Q. (2021). UBE2O promotes hepatocellular carcinoma cell proliferation and invasion by regulating the AMPKα2/mTOR pathway. International Journal of Medical Sciences, 18(16), 3749-3758. https://doi.org/10.7150/ijms.63220.

ACS
Shi, Z.; Liu, R.; Lu, Q.; Zeng, Z.; Liu, Y.; Zhao, J.; Liu, X.; Li, L.; Huang, H.; Yao, Y.; Huang, D.; Xu, Q. UBE2O promotes hepatocellular carcinoma cell proliferation and invasion by regulating the AMPKα2/mTOR pathway. Int. J. Med. Sci. 2021, 18 (16), 3749-3758. DOI: 10.7150/ijms.63220.

NLM
Shi Z, Liu R, Lu Q, Zeng Z, Liu Y, Zhao J, Liu X, Li L, Huang H, Yao Y, Huang D, Xu Q. UBE2O promotes hepatocellular carcinoma cell proliferation and invasion by regulating the AMPKα2/mTOR pathway. Int J Med Sci 2021; 18(16):3749-3758. doi:10.7150/ijms.63220. https://www.medsci.org/v18p3749.htm

CSE
Shi Z, Liu R, Lu Q, Zeng Z, Liu Y, Zhao J, Liu X, Li L, Huang H, Yao Y, Huang D, Xu Q. 2021. UBE2O promotes hepatocellular carcinoma cell proliferation and invasion by regulating the AMPKα2/mTOR pathway. Int J Med Sci. 18(16):3749-3758.

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