Receptor tyrosine kinase, RON, promotes tumor progression by regulating EMT and the MAPK signaling pathway in human oral squamous cell carcinoma

Young‑Eun Joo,Dong Hoon Lee,Kyung‑Hwa Lee,Ik‑Joo Chung,Tae Mi Yoon,Sang Chul Lim,Sun‑Ae Kim,Myung‑Giun Noh,Joon Kyoo Lee

doi:10.3892/ijo.2019.4836

Abstract

The receptor tyrosine kinase, recepteur d'origine nantais(RON), is known to be associated with the progression, metastasis, and prognosis of various types of cancers. Nevertheless, the role of RON in human oral squamous cell carcinoma(OSCC) is unclear. This study evaluated whether RON affects oncogenic behavior, oncogenic signaling pathways, and clinical outcomes, including survival, in human OSCC. Reverse transcription‑PCR, quantitative PCR, western blotting and immunohistochemical staining were used to determine mRNA and protein expression levels of RON. Cell invasion, migration and apoptosis assays were used to assess the functional effects of small interfering RNA‑mediated knockdown of RON or snail family transcriptional repressor2(SLUG). RON knockdown suppressed tumor cell invasion and migration and enhanced apoptosis in human OSCC cells. RON knockdown also decreased the phosphorylation of MAPK signaling proteins, such as ERK1/2, JNK and p38. In addition, RON knockdown suppressed the expression of the epithelial mesenchymal transition (EMT)‑related transcription factor, SLUG. SLUG knockdown blocked the enhancement of cell invasion and migration induced by macrophage‑stimulation protein (MSP)‑mediated RON activation in OSCC cells. The cell morphology was changed to spindle‑like shape under MSP‑mediated RON activation in OSCC cells. RON was overexpressed in both fresh and paraffin‑embedded human OSCC tissues. Taken together, these results indicate that RON contributed to tumor progression by regulating the EMT‑related factor, SLUG, and the MAPK pathway in OSCC. This study may provide a theoretical basis for the application of RON‑targeting agents, currently being studied in various cancer fields, for the treatment of OSCC.

Highlights

Oral cancer is the 11th most prevalent cancer worldwide and the 3rd most common cancer in developing nations [1,2]
These results indicate that recepteur d'origine nantais (RON) contributed to tumor progression by regulating the epithelial mesenchymal transition (EMT)‐related factor, SLUG, and the mitogen‐activated protein kinase (MAPK) pathway in oral squamous cell carcinoma (OSCC)
To examine the role of RON in tumor progression, the present study used Small interfering RNAs (siRNAs) to inhibit the endogenous expression of RON in the human OSCC cells, PCI50 and SCC25

Summary

Introduction

Oral cancer is the 11th most prevalent cancer worldwide and the 3rd most common cancer in developing nations [1,2]. Squamous cell carcinoma represents ~90% of oral cancer cases. The standard treatment strategies for patients with resectable advanced‐stage oral squamous cell carcinoma (OSCC) are surgery following adjuvant radiotherapy or concurrent chemoradiotherapy [3]. OSCC frequently leads to lymphatic metastasis, which is associated with the depth of invasion of the primary tumor. This represents the most important predictor of survival in patients with OSCC and has led to a major change in the T stage classification described in the 8th edition of the American Joint Committee on Cancer [4,5]. In order to provide more effective treatment for patients with OSCC and to improve their clinical outcomes, an increased understanding of the molecular and biological mechanisms of tumor invasion and metastasis in OSCC is required

Methods

Results

Conclusion