Targeting Mybbp1a suppresses HCC progression via inhibiting IGF1/AKT pathway by CpG islands hypo-methylation dependent promotion of IGFBP5Research in context
Xiaoyu Weng,
Jingbang Wu,
Zhen Lv,
Chuanhui Peng,
Junru Chen,
Cheng Zhang,
Bin He,
Rongliang Tong,
Wendi Hu,
Chaofeng Ding,
Linping Cao,
Diyu Chen,
Jian Wu,
Shusen Zheng
Affiliations
Xiaoyu Weng
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China; Corresponding author at: First Affiliated Hospital, No. 79 Qing Chun Road, Hangzhou, Zhejiang Province, China.
Jingbang Wu
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
Zhen Lv
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Chuanhui Peng
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
Junru Chen
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
Cheng Zhang
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Bin He
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
Rongliang Tong
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
Wendi Hu
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
Chaofeng Ding
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Linping Cao
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
Diyu Chen
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China
Jian Wu
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China; The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China; Corresponding author at: First Affiliated Hospital, No. 79 Qing Chun Road, Hangzhou, Zhejiang Province, China.
Shusen Zheng
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou 310003, China; The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, China; Corresponding author at: First Affiliated Hospital, No. 79 Qing Chun Road, Hangzhou, Zhejiang Province, China.
Background: Myb-binding protein 1A (Mybbp1a) is a nucleolar protein that can regulate rRNA metabolism, the stress response and carcinogenesis. However, the function of Mybbp1a in the progression of hepatocellular carcinoma (HCC) is unclear.We aimed to determine the role of Mybbp1a in HCC and the underlying mechanism. Methods: We investigated the function of Mybbp1a in HCC cell models and the xenograft mouse model. The relationship between Mybbp1a and IGFBP5 was found through expression profile chip. The molecular mechanism of Mybbp1a regulating IGFBP5 was proved through CO-IP, CHIP, Bisulfite Sequencing and Pyrosequencing. Findings: In this study, we observed that Mybbp1a was overexpressed in HCC tissues and associated with the poor prognosis of HCC patients. Suppression of Mybbp1a led to a reduction in the proliferation and migration ability of HCC cells through inhibiting the IGF1/AKT signaling pathway. Further study found that Mybbp1a could form a complex with DNMT1 and induce aberrant hyper-methylation of CpG islands of IGFBP5, which inhibits secretion of IGFBP5 and then activates IGF1/AKT signaling pathway. Interpretation: These findings extend our understanding of the function of Mybbp1a in the progression of HCC. The newly identified Mybbp1a may provide a novel biomarker for developing potential therapeutic targets of HCC. Fund: Science Technology Department of Zhejiang Province (No. 2015C03034), National Health and Family Planning Commission of China (No. 2016138643), Innovative Research Groups of National Natural Science Foundation of China (No. 81721091), Major program of National Natural Science Foundation of China (No. 91542205). Keywords: Myb-binding protein 1A (Mybbp1a), IGF-binding proteins 5(IGFBP5), Hepatocellular carcinoma (HCC), IGF1/AKT pathway, CpG islands methylation
