https://scholars.lib.ntu.edu.tw/handle/123456789/628700
標題: | NPRL2 down-regulation facilitates the growth of hepatocellular carcinoma via the mTOR pathway and autophagy suppression | 作者: | Wang, Ya-Chin Tsai, Ming-Chao Chen, Yaw-Sen Hsieh, Pei-Min Hung, Chao-Ming Lin, Hung-Yu Hsu, Yao-Chun Yeh, Jen-Hao Hsiao, Pojen Su, Yu-Cheih Ma, Ching-Hou CHIH-YUAN LEE Lin, Chih-Che Shu, Chih-Wen Li, Yu-Chan Tsai, Mei-Hsing Lin, James Yu Peng, Wei-Hao Yu, Ming-Lung Lin, Chih-Wen |
關鍵字: | PROGRESSION; GTPASES | 公開日期: | 十二月-2022 | 出版社: | JOHN WILEY & SONS LTD | 卷: | 6 | 期: | 12 | 起(迄)頁: | 3563 | 來源出版物: | Hepatology communications | 摘要: | Hepatocellular carcinoma (HCC) is a highly invasive malignancy. Recently, GATOR1 (Gap Activity TOward Rags 1) complexes have been shown to play an important role in regulating tumor growth. NPRL2 is a critical component of the GATOR1 complex. Therefore, this study used NPRL2 knockdown to investigate how GATORC1 regulates the prognosis and development of HCC via the mammalian target of rapamycin (mTOR) and autophagy signaling pathways. We established HepG2 cells with NPRL2 knockdown using small interfering RNA (siRNA) and short hairpin RNA (shRNA) systems. The siRNA-mediated and shRNA-mediated NPRL2 down-regulation significantly reduced the expression of NPRL2 and two other GATPOR1 complex components, NPRL3 and DEPDC5, in HepG2 cells; furthermore, the efficient down-regulation of NPRL2 protein expression by both the shRNA and siRNA systems enhanced the proliferation, migration, and colony formation in vitro. Additionally, the NPRL2 down-regulation significantly increased HCC growth in the subcutaneous and orthotopic xenograft mouse models. The NPRL2 down-regulation increased the Rag GTPases and mTOR activation and inhibited autophagy in vitro and in vivo. Moreover, the NPRL2 level in the tumors was significantly associated with mortality, recurrence, the serum alpha fetoprotein level, the tumor size, the American Joint Committee on Cancer stage, and the Barcelona Clinic Liver Cancer stage. Low NPRL2, NPRL3, DEPDC5, and LC3, and high p62 and mTOR protein expression in the tumors was significantly associated with disease-free survival and overall survival in 300 patients with HCC after surgical resection. Conclusion: The efficient down-regulation of NPRL2 significantly increased HCC proliferation, migration, and colony formation in vitro, and increased HCC growth in vivo. Low NPRL2 protein expression in the tumors was closely correlated with poorer clinical outcomes in patients with HCC. These results provide a mechanistic understanding of HCC and aid the development of treatments for HCC. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/628700 | ISSN: | 2471-254X | DOI: | 10.1002/hep4.2019 |
顯示於: | 醫學系 |
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