PMID- 32610114 OWN - NLM STAT- MEDLINE DCOM- 20211111 LR - 20211111 IS - 1600-0641 (Electronic) IS - 0168-8278 (Linking) VI - 73 IP - 6 DP - 2020 Dec TI - Dampened VEPH1 activates mTORC1 signaling by weakening the TSC1/TSC2 association in hepatocellular carcinoma. PG - 1446-1459 LID - S0168-8278(20)30400-1 [pii] LID - 10.1016/j.jhep.2020.06.027 [doi] AB - BACKGROUND & AIMS: Abnormal activation of mTORC1 signaling occurs at high frequency in hepatocellular carcinoma (HCC). However, the underlying causes of this aberrant activation remain elusive. In this study, we identified ventricular zone expressed pleckstrin homology domain-containing 1 (VEPH1) as a novel tumor suppressor that acts via the mTORC1 axis. METHODS: We performed quantitative reverse-transcription PCR (92 pairs), western blot (30 pairs), and immunostaining (225 cases) assays in HCC tissue samples to evaluate VEPH1 expression. We explored the functional effects of VEPH1 on tumor growth and metastasis. Molecular and biochemical strategies were used to gain insight into mechanisms underlying the tumor-suppressive function of VEPH1. RESULTS: VEPH1 is frequently silenced in HCC tissues, primarily resulting from let-7d upregulation. Decreased VEPH1 expression is associated with poor prognosis and aggressive tumor phenotypes in patients with HCC. VEPH1 mediates its tumor-suppressing activity through regulation of cell proliferation, migration and invasion in vitro and in vivo. The VEPH1 fragments 580-625aa and 447-579 aa bind directly to TSC1 (719-1,164aa) and TSC2 (1-420 aa), respectively, enhancing TSC1/TCS2 binding and promoting translocation of TSC2 to the membrane, which leads to increased TSC2 Ser(1387) phosphorylation. Subsequently, Rheb is inactivated by the GTPase activity of TSC2, inhibiting mTORC1 signaling and contributing to changes in HCC carcinogenesis and metastasis. Rapamycin, the mTOR inhibitor, can inhibit the pro-tumorigenic effect of VEPH1 knockdown. Loss of VEPH1 correlates with decreased TSC2 Ser(1387) phosphorylation and increased mTOR activity in HCC specimens. CONCLUSIONS: The loss of VEPH1 leads to aberrantly activated mTORC1 signaling in HCC; rapamycin (or rapalogs) may serve as an effective treatment option for patients with HCC and dampened VEPH1 expression. LAY SUMMARY: Abnormally activated mammalian target of rapamycin (mTOR) signaling is associated with poor tumor differentiation, early tumor recurrence and worse overall survival in patients with hepatocellular carcinoma. Herein, we identify low VEPH1 expression as a potential cause of abnormally activated mTOR signaling in hepatocellular carcinoma tissues. mTOR inhibitors could thus be an effective treatment option for patients with HCC and low VEPH1 expression. CI - Copyright (c) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. FAU - Dong, Pingping AU - Dong P AD - Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China; Department of Surgery, Centre for Cancer Research, Faculty of Medicine, The University of Hong Kong, Hong Kong, China. FAU - Wang, Xiaoxiao AU - Wang X AD - NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. FAU - Liu, Longzi AU - Liu L AD - Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China. FAU - Tang, Wenqing AU - Tang W AD - Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. FAU - Ma, Lijie AU - Ma L AD - NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. FAU - Zeng, Wenjiao AU - Zeng W AD - Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China. FAU - Sun, Shaoyang AU - Sun S AD - Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. FAU - Zhang, Li AU - Zhang L AD - NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. FAU - Zhang, Ningping AU - Zhang N AD - Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; Toronto Center for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Ontario, Canada. FAU - Shen, Xizhong AU - Shen X AD - Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, China. FAU - Janssen, Harry L A AU - Janssen HLA AD - Toronto Center for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Ontario, Canada. FAU - Dong, Ling AU - Dong L AD - Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: dong.ling@zs-hospital.sh.cn. FAU - Zhang, Si AU - Zhang S AD - NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: zhangsi@fudan.edu.cn. FAU - Chen, She AU - Chen S AD - NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: shechen@fudan.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200628 PL - Netherlands TA - J Hepatol JT - Journal of hepatology JID - 8503886 RN - 0 (Antibiotics, Antineoplastic) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (TSC1 protein, human) RN - 0 (TSC2 protein, human) RN - 0 (Tuberous Sclerosis Complex 1 Protein) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - 0 (Tumor Suppressor Proteins) RN - 0 (VEPH1 protein, human) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Antibiotics, Antineoplastic/pharmacology MH - *Carcinoma, Hepatocellular/diagnosis/genetics/metabolism/therapy MH - Humans MH - Intracellular Signaling Peptides and Proteins/*metabolism MH - *Liver Neoplasms/diagnosis/genetics/metabolism/therapy MH - Mechanistic Target of Rapamycin Complex 1/*metabolism MH - Neoplasm Staging MH - Pleckstrin Homology Domains MH - Prognosis MH - Signal Transduction/drug effects MH - Sirolimus/*pharmacology MH - Tuberous Sclerosis Complex 1 Protein/*metabolism MH - Tuberous Sclerosis Complex 2 Protein/*metabolism MH - Tumor Suppressor Proteins/metabolism OTO - NOTNLM OT - Aggressiveness OT - Cancer OT - EMT OT - HCC OT - Metastasis OT - Tumorigenesis COIS- Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. EDAT- 2020/07/02 06:00 MHDA- 2021/11/12 06:00 CRDT- 2020/07/02 06:00 PHST- 2019/09/04 00:00 [received] PHST- 2020/06/10 00:00 [revised] PHST- 2020/06/16 00:00 [accepted] PHST- 2020/07/02 06:00 [pubmed] PHST- 2021/11/12 06:00 [medline] PHST- 2020/07/02 06:00 [entrez] AID - S0168-8278(20)30400-1 [pii] AID - 10.1016/j.jhep.2020.06.027 [doi] PST - ppublish SO - J Hepatol. 2020 Dec;73(6):1446-1459. doi: 10.1016/j.jhep.2020.06.027. Epub 2020 Jun 28.