The pathological significance and potential mechanism of ARHGEF6 in lung adenocarcinoma

Abstract

Background: Emerging evidences suggest that ARHGEF6 is involved in cancers but the exact significance and underlying mechanism are unclear. This study aimed to elucidate the pathological significance and potential mechanism of ARHGEF6 in lung adenocarcinoma (LUAD).

Methods: Bioinformatics and experimental methods were used to analyze the expression, the clinical significance, the cellular function and potential mechanisms of ARHGEF6 in LUAD.

Results: ARHGEF6 was downregulated in LUAD tumor tissues and correlated negatively with poor prognosis and tumor stemness, positively with the Stromal score, the Immune score and the ESTIMATE score. The expression level of ARHGEF6 was also associated with drug sensitivity, the abundance of immune cells, the expression levels of Immune checkpoint genes and immunotherapy response. Mast cells, T cells and NK cells were the first three cells with the highest expression of ARHGEF6 in LUAD tissues. Overexpression of ARHGEF6 reduced proliferation and migration of LUAD cells and the growth of xenografted tumors, which could be reversed by re-knockdown of ARHGEF6. Results of RNA sequencing revealed that ARHGEF6 overexpression induced significant changes in the expression profile of LUAD cells, and genes encoding uridine 5'-diphosphate-glucuronic acid transferases (UGTs) and extracellular matrix (ECM) components were downregulated.

Conclusions: ARHGEF6 functions as a tumor suppressor in LUAD and may serve as a new prognostic marker and potential therapeutic target. Regulating tumor microenvironment and immunity, inhibiting the expression of UGTs and ECM components in the cancer cells, and decreasing the stemness of the tumors may among the mechanisms underlying the function of ARHGEF6 in LUAD.

Keywords: ARHGEF6; Extracellular matrix components; Lung adenocarcinoma; Mechanism; Pathological significance; UDP-Glucuronic acid transferases.