Small interfering RNA-directed targeting of RON alters invasive and oncogenic phenotypes of human hepatocellular carcinoma cells

Abstract

Abstract. The recepteur d'origine nantais (RON) receptor tyrosine kinase is highly expressed in various cancers including human hepatocellular carcinoma (HCC) and involved in tumor progression. The aims of the current study were to evaluate whether RON affects tumor cell behavior and oncogenic signaling cascades in HCC cells. We investigated the biologic role of RON on tumor cell behavior and oncogenic signaling cascades including Akt, c-Raf and extracellular signal-regulated kinase (ERK) by using the small interfering RNA (siRNA) in HCC cell lines, chang, HepG2 and Huh7. Knockdown of RON suppressed tumor cell migration and invasion in all tested HCC cell lines. The proportion of apoptotic cells induced by knockdown of RON was greater than that induced by transfection of the scramble siRNA in all tested HCC cell lines. Knockdown of RON resulted in cell cycle arrest in the G 2 /M phase of chang and Huh7 cells, and sub G 1 phase of HepG2 cells. Knockdown of RON activated cleaved caspase-3 and PARP, and down-regulated the expression of Bcl-2, Bcl-xL and survivin, leading to induction of apoptosis in all tested cell lines. Knockdown of RON negatively regulates the progression of the cell cycle by decreasing cyclin D1 and D3, and increasing p21 and p27 in all tested cell lines. The phosphorylation of Akt, c-Raf and ERK1/2 signal proteins was significantly blocked by knockdown of RON in all tested cell lines. These results suggest that RON is associated with invasive and oncogenic phenotypes such as tumor cell migration, invasion, resistance to apoptosis and cell cycle arrest through the modulation of Akt, c-Raf and ERK signaling cascades in HCC cells.

Decorin deficiency promotes hepatic carcinogenesis

“…In our animal models we discovered that a novel RTK, not previously linked to decorin bioactivity, is MSPR, also called RON, the receptor for the hepatocyte growth factor-like protein. This is interesting insofar as RON has been implicated in the development and progression of human HCCs (Chen et al, 1997; Cho et al, 2011). …”

RON in hepatobiliary and pancreatic cancers: Pathogenesis and potential therapeutic targets

“…In an HCC cell line study, RON was shown to be associated with oncogenic and invasive phenotypes ( e.g. , resistance to apoptosis, tumor cell migration, and tumor cell invasion) via AKT, c-Raf, and extracellular regulated kinase (ERK) signaling cascade modulation[ 66 ]. Clinically, RON and MET expression in patients with HCC after curative resection suggested no association of RON with overall survival and overall recurrence rates.…”

Modulating the Crosstalk between the Tumor and Its Microenvironment Using RNA Interference: A Treatment Strategy for Hepatocellular Carcinoma

“…A study showed that small ubiquitin-like modifier (SUMO) specific protease 1 silencing resulted in a downregulation of HGF-induced proliferation and migration of HCC cells through effects on the HGF/c-Met pathway [ 109 ]. Additionally, in order to inhibit the proliferation of HCC cell lines (HepG2 and Huh7), siRNA targeting a tyrosine kinase receptor known as macrophage-stimulating protein receptor was shown to efficiently suppress tumor cell migration and invasion and enhance apoptosis by activating cleaved caspase-3 and poly (ADP-ribose) polymerase through the modulation of the Akt, c-Raf and ERK signaling pathway [ 110 ]. A study in 2019 by Zhang and colleagues evaluated the expression of sirtuin 6 (SIRT6) in a variety of HCC cell lines and its effect on the Erk1/2 signaling pathway favoring proliferation and inhibiting apoptosis.…”