Tags

Type your tag names separated by a space and hit enter

mTORC1 Up-Regulates GP73 to Promote Proliferation and Migration of Hepatocellular Carcinoma Cells and Growth of Xenograft Tumors in Mice.
Gastroenterology. 2015 Sep; 149(3):741-52.e14.G

Abstract

BACKGROUND & AIMS

Levels of the Golgi protein 73 (GP73) increase during development of hepatocellular carcinoma (HCC); GP73 is a serum marker for HCC. However, little is known about the mechanisms or effects of GP73 during hepatic carcinogenesis.

METHODS

GP73 was overexpressed from a retroviral vector in HepG2 cells, which were analyzed in proliferation and migration assays. Xenograft tumors were grown from these cells in nude mice. The effects of monoclonal antibodies against GP73 were studied in mice and cell lines. GP73(-/-), GP73(+/-), and GP73(+/+) mice were given injections of diethylnitrosamine to induce liver injury. Levels of GP73 were reduced in MHCC97H, HCCLM3, and HepG2.215 cell lines using small hairpin RNAs; xenograft tumors were grown in mice from MHCC97H-small hairpin GP73 or MHCC97H-vector cells. We used microarray analysis to compare expression patterns between GP73-knockdown and control MHCC97H cells. We studied the effects of the mechanistic target of rapamycin (mTOR) inhibitor rapamycin on GP73 expression in different cancer cell lines and on growth of tumors in mice. Levels of GP73 and activated mTOR were quantified in human HCC tissues.

RESULTS

Xenograft tumors grown from HepG2 cells that expressed GP73 formed more rapidly and more metastases than control HepG2 cells in mice. A monoclonal antibody against GP73 reduced proliferation of HepG2 cells and growth of xenograft tumors in mice. GP73(-/-) mice had less liver damage after administration of diethylnitrosamine than GP73(+/-) or GP73(+/+) mice. In phosphatase and tensin homolog-null mouse embryonic fibroblasts with constitutively activated mTOR, GP73 was up-regulated compared with control mouse embryonic fibroblasts; this increase was reversed after incubation with rapamycin. Expression of GP73 also was reduced in HCC and other cancer cell lines incubated with rapamycin. mTORC1 appeared to regulate expression of GP73 in cell lines. Activated mTOR correlated with the level of GP73 in human HCC tissues. Injection of rapamycin slowed the growth of xenograft tumors from MHCC97H-vector cells, compared with MHCC97H-short hairpin GP73 cells.

CONCLUSIONS

Increased expression of GP73 promotes proliferation and migration of HCC cell lines and growth of xenograft tumors in mice. mTORC1 regulates the expression of GP73, so GP73 up-regulation can be blocked with rapamycin. mTOR inhibitors or other reagents that reduce the level or activity of GP73 might be developed for the treatment of HCC.

Authors+Show Affiliations

State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.Department of Physiology, Dalian Medical University, Dalian, China.State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.Department of Liver Surgery, Peking Union Medical College Hospital, Beijing, China.Department of Liver Surgery, Peking Union Medical College Hospital, Beijing, China.State Key Laboratory of Medical Molecular Biology, Department of Physiology, Collaborative Innovation Center for Cancer Medicine, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. Electronic address: hbzhang@ibms.pumc.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25980751

Citation

Chen, Xinxin, et al. "MTORC1 Up-Regulates GP73 to Promote Proliferation and Migration of Hepatocellular Carcinoma Cells and Growth of Xenograft Tumors in Mice." Gastroenterology, vol. 149, no. 3, 2015, pp. 741-52.e14.
Chen X, Wang Y, Tao J, et al. MTORC1 Up-Regulates GP73 to Promote Proliferation and Migration of Hepatocellular Carcinoma Cells and Growth of Xenograft Tumors in Mice. Gastroenterology. 2015;149(3):741-52.e14.
Chen, X., Wang, Y., Tao, J., Shi, Y., Gai, X., Huang, F., Ma, Q., Zhou, Z., Chen, H., Zhang, H., Liu, Z., Sun, Q., Peng, H., Chen, R., Jing, Y., Yang, H., Mao, Y., & Zhang, H. (2015). MTORC1 Up-Regulates GP73 to Promote Proliferation and Migration of Hepatocellular Carcinoma Cells and Growth of Xenograft Tumors in Mice. Gastroenterology, 149(3), 741-e14. https://doi.org/10.1053/j.gastro.2015.05.005
Chen X, et al. MTORC1 Up-Regulates GP73 to Promote Proliferation and Migration of Hepatocellular Carcinoma Cells and Growth of Xenograft Tumors in Mice. Gastroenterology. 2015;149(3):741-52.e14. PubMed PMID: 25980751.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - mTORC1 Up-Regulates GP73 to Promote Proliferation and Migration of Hepatocellular Carcinoma Cells and Growth of Xenograft Tumors in Mice. AU - Chen,Xinxin, AU - Wang,Yanan, AU - Tao,Jun, AU - Shi,Yuzhuo, AU - Gai,Xiaochen, AU - Huang,Fuqiang, AU - Ma,Qian, AU - Zhou,Zhenzhen, AU - Chen,Hongyu, AU - Zhang,Haihong, AU - Liu,Zhibo, AU - Sun,Qian, AU - Peng,Haiyong, AU - Chen,Rongrong, AU - Jing,Yanling, AU - Yang,Huayu, AU - Mao,Yilei, AU - Zhang,Hongbing, Y1 - 2015/05/14/ PY - 2014/08/27/received PY - 2015/04/10/revised PY - 2015/05/06/accepted PY - 2015/5/19/entrez PY - 2015/5/20/pubmed PY - 2015/11/10/medline KW - Drug KW - Liver Cancer KW - Mouse Model KW - Signal Transduction SP - 741 EP - 52.e14 JF - Gastroenterology JO - Gastroenterology VL - 149 IS - 3 N2 - BACKGROUND & AIMS: Levels of the Golgi protein 73 (GP73) increase during development of hepatocellular carcinoma (HCC); GP73 is a serum marker for HCC. However, little is known about the mechanisms or effects of GP73 during hepatic carcinogenesis. METHODS: GP73 was overexpressed from a retroviral vector in HepG2 cells, which were analyzed in proliferation and migration assays. Xenograft tumors were grown from these cells in nude mice. The effects of monoclonal antibodies against GP73 were studied in mice and cell lines. GP73(-/-), GP73(+/-), and GP73(+/+) mice were given injections of diethylnitrosamine to induce liver injury. Levels of GP73 were reduced in MHCC97H, HCCLM3, and HepG2.215 cell lines using small hairpin RNAs; xenograft tumors were grown in mice from MHCC97H-small hairpin GP73 or MHCC97H-vector cells. We used microarray analysis to compare expression patterns between GP73-knockdown and control MHCC97H cells. We studied the effects of the mechanistic target of rapamycin (mTOR) inhibitor rapamycin on GP73 expression in different cancer cell lines and on growth of tumors in mice. Levels of GP73 and activated mTOR were quantified in human HCC tissues. RESULTS: Xenograft tumors grown from HepG2 cells that expressed GP73 formed more rapidly and more metastases than control HepG2 cells in mice. A monoclonal antibody against GP73 reduced proliferation of HepG2 cells and growth of xenograft tumors in mice. GP73(-/-) mice had less liver damage after administration of diethylnitrosamine than GP73(+/-) or GP73(+/+) mice. In phosphatase and tensin homolog-null mouse embryonic fibroblasts with constitutively activated mTOR, GP73 was up-regulated compared with control mouse embryonic fibroblasts; this increase was reversed after incubation with rapamycin. Expression of GP73 also was reduced in HCC and other cancer cell lines incubated with rapamycin. mTORC1 appeared to regulate expression of GP73 in cell lines. Activated mTOR correlated with the level of GP73 in human HCC tissues. Injection of rapamycin slowed the growth of xenograft tumors from MHCC97H-vector cells, compared with MHCC97H-short hairpin GP73 cells. CONCLUSIONS: Increased expression of GP73 promotes proliferation and migration of HCC cell lines and growth of xenograft tumors in mice. mTORC1 regulates the expression of GP73, so GP73 up-regulation can be blocked with rapamycin. mTOR inhibitors or other reagents that reduce the level or activity of GP73 might be developed for the treatment of HCC. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/25980751/mTORC1_Up_Regulates_GP73_to_Promote_Proliferation_and_Migration_of_Hepatocellular_Carcinoma_Cells_and_Growth_of_Xenograft_Tumors_in_Mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(15)00677-0 DB - PRIME DP - Unbound Medicine ER -