SERPINA11 Inhibits Metastasis in Hepatocellular Carcinoma by Suppressing MEK/ERK Signaling Pathway

Ye Song; Zhuo Li; Lei Li; Houming Zhou; Ting-Ting Zeng; Chuan Jin; Jin-Rong Lin; Sha Gao; Yan Li; Xin-Yuan Guan; Ying-Hui Zhu

doi:10.2147/JHC.S315634

SERPINA11 Inhibits Metastasis in Hepatocellular Carcinoma by Suppressing MEK/ERK Signaling Pathway

J Hepatocell Carcinoma. 2021 Jul 6:8:759-771. doi: 10.2147/JHC.S315634. eCollection 2021.

Authors

Ye Song^#^{1

2}, Zhuo Li^#¹, Lei Li^#³, Houming Zhou⁴, Ting-Ting Zeng¹, Chuan Jin², Jin-Rong Lin², Sha Gao², Yan Li¹, Xin-Yuan Guan^{1

3}, Ying-Hui Zhu¹

Affiliations

¹ Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People's Republic of China.
² Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, 510000, People's Republic of China.
³ Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China.
⁴ Department of Chinese Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: By using integrative RNA sequencing analysis, we identified a novel tumor suppressor, serpin family A member 11 (SERPINA11), which is a serine proteinase inhibitor that belongs to the serpin superfamily. However, the function of SERPINA11 in hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to investigate the role and molecular mechanism of SERPINA11 in HCC.

Methods: Gene expression patterns of SERPINA11 were analyzed in tissue samples of HCC patients by qRT-PCR. In vitro and in vivo experiments were performed to characterize the function and molecular mechanism of SERPINA11 in the tumor metastasis capacity.

Results: SERPINA11 was downregulated in approximately 50% of HCC and significantly associated with metastasis and poor outcome of patients. Functional study demonstrated that SERPINA11 could inhibit cell growth, cell migration and tumor metastasis. Mechanistic investigations suggested that SERPINA11 accelerated urokinase-type plasminogen activator (uPA) degradation to suppress extracellular signal-regulated kinase (ERK1/2) phosphorylation, and thereby subdued metastatic capabilities of HCC cells.

Conclusion: SERPINA11 plays an important tumor suppressive role in HCC, with possible use as a biomarker and an intervention point for new therapeutic strategies.

Keywords: ERK; HCC; SERPINA11; metastasis; uPA.

Grants and funding

This work was supported by National Natural Science Foundation of China (81802335, 81872007, 81772554); Natural Science Foundation of Guangdong Province (2018A030310175, 2018A030313034, 2021A1515010589); Young Doctoral Plan of Guangzhou Medical University (2016C42); Young Doctoral Plan of Guangdong Health Commission (B2018059); General Guidance Plan of Guangzhou Health commission (20181A010062); Young Talent Teachers Plan of Sun Yat-sen University (15ykpy33); National Basic Research Program of China (2012CB967001); China National Key Sci-Tech Special Project of Infectious Diseases (2018ZX10723204-006-005); Shenzhen Peacock team Project (KQDT2015033117210153).