Phosphatase regenerating liver 3 participates in Integrinβ1/FAK-Src/MAPK signaling pathway and contributes to the regulation of malignant behaviors in hepatocellular carcinoma cells

Guobin Chen; Zhenzhen Zhang; Jinghuan Li; Chao Hu; Dongmei Gao; Jun Chen; Lan Zhang; Xiaoying Xie

doi:10.21037/jgo-22-976

Phosphatase regenerating liver 3 participates in Integrinβ1/FAK-Src/MAPK signaling pathway and contributes to the regulation of malignant behaviors in hepatocellular carcinoma cells

J Gastrointest Oncol. 2023 Apr 29;14(2):863-873. doi: 10.21037/jgo-22-976. Epub 2023 Mar 6.

Authors

Guobin Chen^#^{1

2}, Zhenzhen Zhang^#^{1

2}, Jinghuan Li³, Chao Hu³, Dongmei Gao³, Jun Chen³, Lan Zhang³, Xiaoying Xie^{1

2

3}

Affiliations

¹ Department of Hepatic Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, China.
² Xiamen Clinical Research Center for Cancer Therapy, Xiamen, China.
³ Department of Hepatic Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.

^# Contributed equally.

Abstract

Background: Hepatocellular carcinoma (HCC) is the leading cause of mortality worldwide. Phosphatase regenerating liver 3 (PRL-3) was associated with cancer metastasis. However, the significance of PRL-3 in the prognosis of HCC remains elusive. The aim of this study was to elucidate the role of PRL-3 in HCC metastasis and its prognosis.

Methods: The expressions of PRL-3 in cancer tissues isolated from 114 HCC patients, who underwent curative hepatectomy from May to November in 2008, were analyzed by immunohistochemistry, and its prognostic significance was evaluated. Thereafter, the migration, invasion, and metastatic alterations in MHCC97H cells with PRL-3 overexpression or knockdown were explored and compared with the tumor size and lung metastasis in orthotopic HCC model of nude mice derived from MHCC97H cells with PRL-3 overexpression or knockdown. The underlying mechanism involving PRL-3-mediated effect on HCC migration, invasion, and metastasis was further examined.

Results: Univariate and multivariate analysis demonstrated PRL-3 overexpression was an independent prognostic factor for poor overall survival (OS) and progression-free survival (PFS) of the HCC patients. Increased PRL-3 expression in MHCC97H cells was in accordance with the enhanced metastasis potential. PRL-3 knockdown inhibited the migration, invasiveness, and clone forming ability in MHCC97H cells, whereas PRL-3 overexpression reverted the above behavior. The growth of xenograft tumor in the liver was suppressed, and the lung metastasis in nude mice was inhibited by PRL-3 downregulation. The knockdown of PRL-3 could downregulate the expressions of Integrinβ1 and p-Src (Tyr416), p-Erk (Thr202/Tyr204) activation, and reduce MMP9 expression. Both MEK1/2 inhibitor (U0126) and Src inhibitor could repress PRL-3-induced invasiveness and migration in MHCC97H cells.

Conclusions: PRL-3 was significantly overexpressed and an independent prognostic factor to predict the death of HCC patients. Mechanically, PRL-3 plays a critical role in HCC invasive and metastasis via Integrinβ1/FAK-Src/RasMAPK signaling. Validation of PRL-3 as a clinical prediction marker in HCC warrants further research.

Keywords: Integrinβ1; Phosphatase regenerating liver3 (PRL-3); hepatocellular carcinoma (HCC); malignant behavior.