Research Paper|Volume 12, Issue 4|pp 3962—3975

SOCS1 blocks G1-S transition in hepatocellular carcinoma by reducing the stability of the CyclinD1/CDK4 complex in the nucleus

Jun Ding^1,^2,^3,⁴, Kangdi Xu^2,^3,^4,⁸, Suwan Sun^5,^6,⁷, Chao Qian^1,^2,^3,⁴, Shengyong Yin^2,^3,⁴, Haiyang Xie^2,^3,⁴, Lin Zhou^3,^4,⁵, Shusen Zheng^1,^2,^3,^4,⁵, Wei Zhang^1,^2,^3,⁴

¹Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
²Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province, China
³Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, Zhejiang Province, China
⁴Key Laboratory of Organ Transplantation, Hangzhou, Zhejiang Province, China
⁵Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, Zhejiang Province, China
⁶State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
⁷National Clinical Research Center for Infectious Diseases, Hangzhou, Zhejiang Province, China
⁸Ningbo Medical Center LIHUILI Hospital, Ningbo, Zhejiang Province, China

Received: October 1, 2019Accepted: February 4, 2020Published: February 25, 2020

https://doi.org/10.18632/aging.102865

Copyright © 2020 Ding et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Inhibitors of the CDK family of proteins have been approved for the treatment of a variety of tumours; however, the development of new drugs administered in combination with CDK inhibitors is expected to improve the therapeutic effect. We identified the function of suppressor of cytokine signalling 1 (SOCS1) in hepatocellular carcinoma (HCC) cell models and the xenograft mouse model. When SOCS1 expression was artificially upregulated, HCC cell lines were arrested at the G1-S transition in the cell cycle. Interestingly, during this process, total CyclinD1 protein increased, but the effective proportion decreased. We found that the deficiency of CyclinD1 in the nucleus is probably due to the decrease in the stability of nuclear CyclinD1 caused by the ubiquitin-based degradation of P21, thus inhibiting the progression of the cell cycle to S phase. After P21 expression was increased, the levels of the component that inactivates CyclinD1 decreased as expected. It showed that P21 has a partial promoting effect on cancer. SOCS1 is a good indicator of prognosis, tumour size and long-term survival after resection. SOCS1 is expected to become a drug target in combined with CDK family inhibitors.