Altered expression of the RON receptor tyrosine kinase in various epithelial cancers and its contribution to tumourigenic phenotypes in thyroid cancer cells

Abstract

Aberrant expression of the RON receptor tyrosine kinase has been implicated in the pathogenesis of epithelial tumours. The aim of this study was to determine RON expression in various normal epithelial cells and their corresponding tumours by immunohistochemistry. The role of RON in regulating tumourigenic phenotypes was also studied using thyroid cancer cells as a model. RON was almost exclusively expressed at variable levels in normal epithelial cells from the digestive track, lung, kidney, pancreas, liver, breast, bladder, skin, and others. Among 15 types of cancer studied, RON was overexpressed in significant numbers in cancers derived from breast (56%), colon (51%), lung (48), thyroid (42%), skin (37%), bladder (36%), and pancreas (33%). In contrast, limited RON overexpression was observed in cancers from stomach, kidney, brain, liver, ovary, and prostate. Detailed analysis of thyroid tissues showed that RON was hardly detected in normal thyroid cells, moderately expressed in adenoma samples, but overexpressed in about half of papillary and follicular cancer specimens. Overexpression correlated with advanced clinical stage and was associated with lymph node metastasis. In cultured thyroid cancer cells, RON was highly expressed, with constitutive phosphorylation. Activation of RON increased cell growth and migration via the MAP kinase and AKT pathways. Silencing RON expression significantly prevented cell growth and increased cell apoptotic death. These findings show that RON overexpression occurs in a particular group of epithelial cancers. The requirement for RON in sustaining tumourigenic phenotypes suggests that it is a potential target for therapeutic intervention.

Synergistic Activities of MET/RON Inhibitor BMS-777607 and mTOR Inhibitor AZD8055 to Polyploid Cells Derived from Pancreatic Cancer and Cancer Stem Cells

“…Previous studies have shown that RON is overexpressed and activated in primary PDAC samples and established cell lines (1)(2)(3)(4)(5)(6). Here, we determined the therapeutic effect of BMS-777607 on RON signaling in L3.6pl cells and CSCs þ24/44/ESA .…”

“…PDAC is a highly malignant disease with limited treatment options (8). Studies using immunohistochemical staining have confirmed that RON is overexpressed in more than 30% of primary PDAC cases (1,5,6). Aberrant RON expression also regulates PDAC cell migration, survival, and invasion through multiple signaling pathways (4-6, 9, 10).…”

“…Overexpression of the recepteur d'origine nantais (RON) receptor tyrosine kinase (RTK) in cancer cells has been implicated in tumorigenic activities and malignant progression (1)(2)(3)(4). Aberrant RON expression also has been molecularly targeted in mouse xenograph models of pancreatic ductal adenocarcinoma (PDAC; refs.…”

RON(MST1R)is a novel prognostic marker and therapeutic target for gastroesophageal adenocarcinoma

“…18 Immunohistochemistry (IHC) of various tumor types revealed RON overexpression, including GEC. 19,20 RON mediates oncogenic phenotypes in lung, thyroid, pancreas, prostate, colon and breast cancer cells [21][22][23][24][25][26][27][28][29] and predicts a poor prognosis in human breast cancer. 30 RON promotes similar, but not identical, MSP-independent and MSP-dependent phenotypes in breast cancer cells.…”

RON - The Con in Colorectal Carcinoma

“…Several cancers of epithelial origin show a marked elevation in RON expression contributing to their malignant phenotype [43]. RON overexpression has high prevalence in CRC where majority of tumor tissues and cell lines from primary and metastatic CRC are shown to be positive for RON expression [43]. It is noteworthy that the inflammatory conditions such as colitis which are positively correlated with risk of CRC also show high RON expression [44].…”