GIT1 overexpression promotes epithelial-mesenchymal transition and predicts poor prognosis in hepatocellular carcinoma

ABSTRACT

Globally, hepatocellular carcinoma (HCC) is one of the most common causes of cancer-associated mortalities. It has a high rate of metastasis and recurrence, which predict a poor prognosis. G-protein-coupled receptor (GPCR)-kinase interacting protein-1 (GIT1) is a multifunctional scaffold protein that mediates the progression of various tumors. Studies have correlated GIT1 with HCC, however, these correlations have not been fully elucidated. Therefore, we aimed at evaluating the expression of GIT1 in HCC tissues and cells, and to investigate its role and potential mechanisms in HCC progression. The expression levels of GIT1 in HCC tissues and other cancers was determined by using the Oncomine and TCGA databases. Functional analysis of GIT1 in HCC was evaluated through in vitro and in vivo experiments, whereby, HCC cells were transfected with synthetically overexpressed and short hairpin RNA (shRNA) lentivirus-mediated plasmids. Kaplan–Meier and Cox regression methods were used to establish the associations between GIT1 and clinical outcomes of 158 HCC patients. GIT1 was found to be elevated in HCC tissues where it promoted the invasion, migration, and proliferation of HCC cells. Moreover, the overexpression of GIT1 prompted epithelial-mesenchymal transition (EMT) by activating extracellular regulated kinase 1/2 (ERK1/2) pathway, which was shown to be reversed by SCH772984, a specific ERK1/2 inhibitor. GIT1 was also found to be associated with malignant features of HCC, leading to a poorer prognosis. In conclusion, GIT1 promotes HCC progression by inducing EMT and may reflect the course of HCC patients.

Graphical abstract

KEYWORDS:

• Hepatocellular carcinoma
• GIT1
• EMT
• ERK1/2 signaling
• prognosis

Highlights

(1) GIT1 expression is elevated in HCC tissues than that in adjacent non-tumor tissues.

(2) GIT1 accelerated the proliferation, migration and invasion of HCC cells.

(3) GIT1 promotes EMT in HCC cells by modulating ERK1/2.

(4) GIT1 expression is an independent prognostic factor for cumulative HCC recurrence and OS.

Abbreviations

HCC, hepatocellular carcinoma; GIT1, G-protein-coupled receptor (GPCR)-kinase interacting protein-1; EMT, epithelial-mesenchymal transition; TMA, tissue microarray; OS, overall survival; ERK1/2, extracellular regulated kinase 1/2; p-ERK1/2, phosphorylation ERK1/2; ARFGAP, ADP ribosylation factor GTPase-activating protein;

Disclosure statement

The authors declare that they have no competing interests.

Ethical approval

This study was approved by the ethics committee of the Ethics Committee of Clinical Medical College, Yangzhou University.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This study was supported by The National Natural Science Foundation of China (grant number 81871909); ‘13th five-year Plan’ Science and Education strong Health Project leading personnel of Yangzhou (LJRC20181); Provincial-level discipline leader of the NJPH (DTRC201809); TianQing liver disease research fund subject (No. TQGB20200180).