4486

MST1R

macrophage stimulating 1 receptor;MST1R;macrophage stimulating 1 receptor

MSP receptor|MST1R variant RON30|MST1R variant RON62|PTK8 protein tyrosine kinase 8|RON variant 21|RON variant E2E3|c-met-related tyrosine kinase|macrophage stimulating 1 receptor (c-met-related tyrosine kinase)|macrophage-stimulating protein receptor|p18

3p21.3

protein-coding

A better understanding of tumor metastasis requires development of animal models that authentically reproduce the metastatic process. By modifying an existing mouse model of breast cancer, we discovered that macrophage-stimulating protein promoted breast tumor growth and metastasis to several organs. A special feature of our findings was the occurrence of osteolytic bone metastases, which are prominent in human breast cancer. To explore the clinical relevance of our model, we examined expression levels of three genes involved in activation of the MSP signaling pathway (MSP, MT-SP1, and MST1R) in human breast tumors. We found that overexpression of MSP, MT-SP1, and MST1R was a strong independent indicator of both metastasis and death in human breast cancer patients and significantly increased the accuracy of an existing gene expression signature for poor prognosis. These data suggest that signaling initiated by MSP is an important contributor to metastasis of breast cancer and introduce an independent biomarker for assessing the prognosis of humans with breast cancer.

metastasis is the major cause of death in cancer patients, yet the genetic and epigenetic programs that drive metastasis are poorly understood. Here, we report an epigenetic reprogramming pathway that is required for breast cancer metastasis. Concerted differential DNA methylation is initiated by the activation of the RON receptor tyrosine kinase by its ligand, macrophage stimulating protein (MSP). Through PI3K signaling, RON/MSP promotes expression of the G:T mismatch-specific thymine glycosylase MBD4. RON/MSP and MBD4-dependent aberrant DNA methylation results in the misregulation of a specific set of genes. Knockdown of MBD4 reverses methylation at these specific loci and blocks metastasis. We also show that the MBD4 glycosylase catalytic residue is required for RON/MSP-driven metastasis. Analysis of human breast cancers revealed that this epigenetic program is significantly associated with poor clinical outcome. Furthermore, inhibition of Ron kinase activity with a pharmacological agent blocks metastasis of patient-derived breast tumor grafts in vivo.

Generation of splice variants in the RON receptor tyrosine kinase facilitates the invasive phenotype of colorectal cancers. Here, we report a new splice variant of RON in the human colorectal cancer cell line HCT116. This variant is encoded by a transcript differing from the full-length RON mRNA by an in-frame deletion of 106 amino acids in the extracellular domain of RON beta-chain. The deleted transcript originates by an alternative deletion of exon 2 and exon 3. The molecular weight of this variant is 160 kDa. Thus, we named this variant RONDelta160(E2E3). This variant is a single-chain protein and expressed in the intracellular compartment. We found that RONDelta160(E2E3) had no tyrosine phosphorylation ability, but it has constitutively activated Akt activity in transfected HEK293 epithelial cells. The expression of this variant in HEK293 cells resulted in an increased migratory activity in vitro mediated through the PI-3K/Akt pathway. Our data describes a new splice variant of RON and suggests a novel role for the RON receptor in the progression of metastasis in colorectal cancer.

AIMS AND BACKGROUND: The aims of the current study were to evaluate whether recepteur d'origine nantais (RON) affects tumor cell behavior and oncogenic signaling pathways in colorectal cancer, and to examine the relationship of its expression with various clinicopathological parameters and patient survival. METHODS: Immunohistochemistry, Western blot and RT-PCR were used to detect the expression of the RON gene in human colorectal cancer tissue. To study the biological role of RON in tumor cell behavior and cellular signaling pathways, we used small interfering RNA (siRNA) to knock down RON gene expression in human colorectal cancer cell lines. RESULTS: Knockdown of RON inhibited the induction of the invasive growth phenotype and the activation of oncogenic signaling pathways including Akt, MAPK and beta-catenin. RON overexpression was associated with tumor size, lymphovascular invasion, depth of invasion, lymph node metastasis, distant metastasis, tumor stage and poor survival. CONCLUSIONS: These results suggest that RON overexpression may help in predicting poor clinical outcomes in colorectal cancer.

Nasopharyngeal carcinoma (NPC) is characteristic for its strong association with Epstein-Barr virus (EBV) and high metastatic rate. Recently, overexpressed recepteur d'origine nantais (RON) (MST1R), receptor tyrosine kinase has been reported in human cancers and tumor metastasis. Therefore, the role of RON in EBV-associated NPC and its metastasis was investigated. Here we show that RON was found in NPC but not in control tissues. A significant correlation of latent membrane protein 1 (LMP1) and RON expression was found in NPC (Pearson's chi(2) test; P = 0.0023). At the molecular level, LMP1 stimulates nuclear factor-kappaB binding to the RON promoter through its carboxyl-terminal activation region 1 to induce expression of RON. Knockdown of RON in cells expressing LMP1 significantly reverses LMP1-induced epithelial-mesenchymal transition and suppresses LMP1-induced cell migration and invasion. These results suggest an important role of RON in the tumorigenesis and metastasis of NPC and RON may be a novel therapeutic target for EBV-associated NPC.

BACKGROUND: Recepteur d'originenantais (RON) is a receptor tyrosine kinase (RTK) that belongs to the MET proto-oncogene family. The aim of this study was to investigate the expression of RON receptor tyrosine kinase in human non-small cell lung cancer (NSCLC) and its relationship with clinical pathology of NSCLC and prognosis. METHODS: RON protein expression by immunohistochemistry (IHC) in 96 NSCLC specimens was evaluated and compared with the clinical pathology and prognosis, and 20 para-neoplastic tissues were included as controls. RON mRNA and protein expression in 25 fresh tissue samples of lung cancer and 10 normal lung tissues were also analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. RESULTS: The rate of positive RON expression differed significantly between NSCLC tissues (55.2%, 53/96) and para-neoplastic tissues (5%, 1/20) (P < 0.001). RON protein expression was not found to be associated with gender or age. However, RON expression positively correlated with clinical TNM stage (P = 0.004), histological types (P = 0.001), lymph node metastasis (P = 0.012) and differentiation (P = 0.035). RT-PCR and Western blotting analysis also confirmed that the expression of RON mRNA and protein was significantly increased in the NSCLC tissues versus normal tissues. In addition, RON expression was associated with a poor prognosis for patients with NSCLC (P = 0.045). CONCLUSIONS: The expression of RON protein and mRNA is significant in human NSCLC and low in para-neoplastic and normal tissues. Elevated RON expression may contribute to the occurrence, progression and metastasis of NSCLC, inferring that it could be useful as a new prognostic indicator for patients with NSCLC.