cMET promotes metastasis and epithelial‐mesenchymal transition in colorectal carcinoma by repressing RKIP

Abstract

Increasing evidence indicates that c‐mesenchymal‐epithelial transition factor (cMET) plays an important role in the malignant progression of colorectal cancer (CRC). However, the underlying mechanism is not fully understood. As a metastasis suppressor, raf kinase inhibitory protein (RKIP) loss has been reported in many cancer types. In this study, the expression levels of cMET and RKIP in CRC tissues and cell lines were determined, and their crosstalk and potential biological effects were explored in vitro and in vivo. Our results showed that cMET was inversely correlated with RKIP. Both cMET upregulation and RKIP downregulation indicated poor clinical outcomes. Moreover, the MAPK/ERK signaling pathway was implicated in the regulation of cMET and RKIP. Overexpression of cMET promoted tumor cell epithelial‐mesenchymal transition, invasion, migration, and chemoresistance, whereas the effects could be efficiently inhibited by increased RKIP. Notably, small hairpin RNA‐mediated cMET knockdown dramatically suppressed cell proliferation, although no RKIP‐induced influence on cell growth was observed in CRC. Altogether, cMET overexpression may contribute to tumor progression by inhibiting the antioncogene RKIP, providing preclinical justification for targeting RKIP to treat cMET‐induced metastasis of CRC.

The RAF Kinase Inhibitor Protein (RKIP): Good as Tumour Suppressor, Bad for the Heart

“…EMT is a major step in cancer metastasis and accounts for the loss of cell-cell contacts and tumour cell dissemination within the body [ 70 , 71 , 72 ]. Several studies have documented that RKIP mediates reversal of the EMT transformation of cancer cells by various mechanisms [ 73 , 74 , 75 , 76 ]. Reversal of EMT transformation by RKIP could involve the inhibition of NOTCH1-Notch1 signalling by decreasing the Notch1 intracellular domain, NICD, which is involved in EMT and metastasis [ 76 ].…”

Epithelial to Mesenchymal Transition: A Challenging Playground for Translational Research. Current Models and Focus on TWIST1 Relevance and Gastrointestinal Cancers

“…The final step of cancer spreading, if reached, is metastasis development and outgrowth, which will ultimately determine patient fate, and despite the continuous development of surgical and pharmacological treatments, many patients still die from metastasis. c-MET, a kinase receptor for Hepatocyte growth factor (HGF), drives tumorigenesis repressing the Raf kinase inhibitory protein (RKIP), whose loss has been reported in many cancer types overexpressing c-MET, including 50% of CRC [224]. Several c-MET inhibitors have been developed as anticancer drugs.…”

“…c-MET, a kinase receptor for Hepatocyte growth factor (HGF), drives tumorigenesis repressing the Raf kinase inhibitory protein (RKIP), whose loss has been reported in many cancer types overexpressing c-MET, including 50% of CRC [ 224 ]. Several c-MET inhibitors have been developed as anticancer drugs.…”

c-Met-Targeting 19F MRI Nanoparticles with Ultralong Tumor Retention for Precisely Detecting Small or Ill-Defined Colorectal Liver Metastases

“…[3][4][5] Over-expression of the c-mesenchymal-epithelial transition factor (c-Met) gene has been proposed as a prognostic factor, contributing to the malignant transformation of colonic epithelial cells and the development of CLMs. [6][7][8] In addition, recent studies have shown an attractive antitumor activity of c-Met targeted drugs in CRC and CLMs. [9][10][11][12] Therefore, it is of great significance to take c-Met as the target for precise imaging diagnosis and monitoring the targeted therapy to patients with CLMs.…”