STYK1 promotes epithelial-mesenchymal transition and tumor metastasis in human hepatocellular carcinoma through MEK/ERK and PI3K/AKT signaling.

Zhaowen Wang,Xing Sun,Junwei Fan,Jianhua Liao,Biao Deng,Shaohan Wu,Lei Qu,Zhihai Peng

doi:10.1038/srep33205

Abstract

Serine/threonine/tyrosine kinase 1 (STYK1) is known to be involved in tumor progression. However, its molecular role and mechanism in hepatocellular carcinoma (HCC) remains unknown. We evaluated the effect of STYK1 expression in HCC tissues and investigated the underlying mechanisms associated with progression. HCC tissues expressed greater levels of STYK1 than paired non-tumor tissues. Patients with HCC expressing low levels of STYK1 showed both, greater disease-free (p < 0.0001) and overall (p = 0.0004) survival than those expressing high levels of STYK1. Decreased expression of STYK1 was significantly associated with decreased cell proliferation, reduced migratory capability, and reduced invasive capability. Overexpression of STYK1 was significantly associated with increased cell proliferation, migratory capability, and invasive capability in vitro, as well as increased volume of tumor, weight of tumor, and number of pulmonary metastases in vivo. Furthermore, STYK1’s mechanism of promoting cancer cell mobility and epithelial-mesenchymal transition (EMT) was found to be via the MEK/ERK and PI3K/AKT pathways, resulting in increased expression of mesenchymal protein markers: snail, fibronectin, and vimentin, and decreased E-cadherin expression. Our results suggest that STYK1 acts as an oncogene by inducing cell invasion and EMT via the MEK/ERK and PI3K/AKT signaling pathways and it therefore may be a potential therapeutic target in HCC.

Highlights

Tumorigenesis, and metastasis by activating of phosphoinositide 3-kinase (PI3K)/AKT and inactivating GSK-3βsignaling pathway, which are implicated in tumorigenesis and development of HCC7,15
We detected the expression of STYK1 in human normal liver cell line LO2 and 5 Hepatocellular carcinoma (HCC) cell lines (7402, 7721, Hep3B, 97H, and LM3), and results demonstrated a higher expression of STYK1 in HCC cell lines, compared with LO2 (Fig. 1B)
These results suggested that STYK1 might play an important role in HCC progression and development

Summary

Introduction

Tumorigenesis, and metastasis by activating of phosphoinositide 3-kinase (PI3K)/AKT and inactivating GSK-3βsignaling pathway, which are implicated in tumorigenesis and development of HCC7,15. Accumulating evidence has shown that epithelial-to-mesenchymal transition (EMT), characterized by the progression of epithelial phenotype to mesenchymal phenotype, plays a critical role in cancer invasion and metastasis during tumor progression[16,17,18]. In HCC, EMT results in increased venous invasion, metastasis, and a poorer prognosis[5,20,21]. Despite evidence of STYK1 acting as an oncogene and being involved in a variety of cancers, the role of STYK1 in regulating HCC metastasis and EMT remains unclear. We investigated the precise mechanism/pathway by which STYK1 contributes to invasion and EMT events in vitro and in vivo. These findings may provide a potential therapeutic target to inhibit HCC progression and metastasis

Methods

Results

Conclusion