Proprotein Convertase Subtilisin/Kexin Type 9 Promotes Gastric Cancer Metastasis and Suppresses Apoptosis by Facilitating MAPK Signaling Pathway Through HSP70 Up-Regulation

Beili Xu; Shuyu Li; Yong Fang; Yanting Zou; Dongqiang Song; Shuncai Zhang; Yu Cai

doi:10.3389/fonc.2020.609663

Proprotein Convertase Subtilisin/Kexin Type 9 Promotes Gastric Cancer Metastasis and Suppresses Apoptosis by Facilitating MAPK Signaling Pathway Through HSP70 Up-Regulation

Front Oncol. 2021 Jan 7:10:609663. doi: 10.3389/fonc.2020.609663. eCollection 2020.

Authors

Beili Xu¹, Shuyu Li¹, Yong Fang², Yanting Zou¹, Dongqiang Song³, Shuncai Zhang¹, Yu Cai¹

Affiliations

¹ Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.
² Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
³ Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.

Abstract

Objective: To examine the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) on gastric cancer (GC) progression and prognosis, and to explore the underlying mechanism.

Methods: PCSK9 expression levels in human GC tissues were determined by quantitative real-time PCR, western blotting, and immunohistochemical assay. PCSK9 serum levels were detected by enzyme-linked immunosorbent assay. The relationships of PCSK9 and GC progression and survival were analyzed using the Chi-square test, Kaplan-Meier analysis, and Cox proportional hazards model. The effect of PCSK9 on cell invasion, migration, and apoptosis were determined in human GC cell lines and mouse xenograft model separately using PCSK9 knockdown and overexpression strategies. The PCSK9 interacting molecules, screened by co-immunoprecipitation combined with LC-MS/MS, were identified by immunofluorescence localization and western blotting. Additionally, the mitogen-activated protein kinase (MAPK) pathway was assessed by western blotting.

Results: PCSK9 mRNA and protein levels were significantly elevated in GC tissues compared with the paired normal tissues at our medical center (P < 0.001). Notably, the up-regulation of PCSK9 expression in GC tissues was related to tumor progression and poor survival. GC patients had higher serum levels of PCSK9 than the age-matched healthy controls (P < 0.001); PCSK9 promoted invasive and migratory ability and inhibited apoptosis in GC cells with no apparent affection in cell proliferation. The silencing of PCSK9 reversed these effects, suppressing tumor metastasis in vitro and in vivo. Furthermore, PCSK9 maintained these functions through up-regulating heat shock protein 70 (HSP70), ultimately facilitating the mitogen-activated protein kinase (MAPK) pathway.

Conclusion: Collectively, our data revealed that high PCSK9 expression levels in GC tissue were correlated with GC progression and poor prognosis and that PCSK9 could promote GC metastasis and suppress apoptosis by facilitating MAPK signaling pathway through HSP70 up-regulation. PCSK9 may represent a novel potential therapeutic target in GC.

Keywords: MAPK pathway; gastric cancer; heat shock protein 70; prognosis; proprotein convertase subtilisin/kexin type 9.