MET

Gene Summary

Gene:MET; MET proto-oncogene, receptor tyrosine kinase
Aliases: HGFR, AUTS9, RCCP2, c-Met
Location:7q31
Summary:The proto-oncogene MET product is the hepatocyte growth factor receptor and encodes tyrosine-kinase activity. The primary single chain precursor protein is post-translationally cleaved to produce the alpha and beta subunits, which are disulfide linked to form the mature receptor. Various mutations in the MET gene are associated with papillary renal carcinoma. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:hepatocyte growth factor receptor
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
Show (62)
Pathways:What pathways are this gene/protein implicaed in?
Show (8)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (15)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MET (cancer-related)

Kosaka T, Oya M
[Molecular targeting drug of kinase inhibitors for castration resistant prostate cancer].
Nihon Rinsho. 2014; 72(12):2186-92 [PubMed] Related Publications
Prostate cancer (PCa) is the most common cancer type in men. One of the most troublesome aspects of PCa is that androgen-dependent PCa inevitably progresses to highly aggressive and life-threatening castration resistant prostate cancer (CRPC). Kinases are key regulators of critical cancer processes such as cancer cell proliferation, invasion, differentiation or angiogenesis. Recent advances have shed light on molecular targeting inhibitors of kinases in CRPC. Aberrant expression of certain kinases has been implicated in the development and progression of PCa. Among them, some kinase inhibitors have emerged as promising drug targets for CRPC. In this review, we provide an overview of new therapeutic agents which arrived in an advanced stage of clinical testing, especially focusing on the targets of HGF/c-Met and PI3K/AKT/mTOR signaling pathways.

Kobold S, Steffen J, Chaloupka M, et al.
Selective bispecific T cell recruiting antibody and antitumor activity of adoptive T cell transfer.
J Natl Cancer Inst. 2015; 107(1):364 [PubMed] Related Publications
BACKGROUND: One bottleneck for adoptive T cell therapy (ACT) is recruitment of T cells into tumors. We hypothesized that combining tumor-specific T cells, modified with a marker antigen and a bispecific antibody (BiAb) that selectively recognizes transduced T cells and tumor cells would improve T cell recruitment to tumors and enhance therapeutic efficacy.
METHODS: SV40 T antigen-specific T cells from T cell receptor (TCR)-I-transgenic mice were transduced with a truncated human epidermal growth factor receptor (EGFR) as a marker protein. Targeting and killing by combined ACT and anti-EGFR-anti-EpCAM BiAb therapy was analyzed in C57Bl/6 mice (n = six to 12 per group) carrying subcutaneous tumors of the murine gastric cancer cell line GC8 (SV40(+) and EpCAM(+)). Anti-EGFR x anti-c-Met BiAb was used for targeting of human tumor-specific T cells to c-Met(+) human tumor cell lines. Differences between experimental conditions were analyzed using the Student's t test, and differences in tumor growth with two-way analysis of variance. Overall survival was analyzed by log-rank test. All statistical tests were two-sided.
RESULTS: The BiAb linked EGFR-transduced T cells to tumor cells and enhanced tumor cell lysis. In vivo, the combination of ACT and Biab produced increased T cell infiltration of tumors, retarded tumor growth, and prolonged survival compared with ACT with a control antibody (median survival 95 vs 75 days, P < .001). In human cells, this strategy enhanced recruitment of human EGFR-transduced T cells to immobilized c-Met and recognition of tyrosinase(+) melanoma cells by TCR-, as well as of CEA(+) colon cancer cells by chimeric antigen receptor (CAR)-modified T cells.
CONCLUSIONS: BiAb recruitment of tumor-specific T cells transduced with a marker antigen to tumor cells may enhance efficacy of ACT.

Carter CA, Nations JA, Lazarus A
Molecular targets in the treatment of non-small-cell lung cancer: is there hope on the horizon?
Postgrad Med. 2014; 126(7):139-48 [PubMed] Related Publications
Non-small-cell lung cancer (NSCLC) is a growing concern worldwide, and its incidence continues to increase in developing countries. It has a strong association with smoking. Lung cancer remains the leading cause of cancer-related deaths in most industrialized countries and in the United States. In the last 10 years, there have been significant advancements in the understanding of molecular oncogenes and how they play a role in driving lung cancer to both grow and metastasize. Understanding this rapidly expanding field has the potential to extend life, and it is an important field for all providers to conceptualize if they are treating patients with lung cancer. Currently, > 50% of all NSCLC is linked to 1 of several known genetic driver mutations. Using online databases, expert opinion, and practice-changing trials, we review the current standards of molecular testing of NSCLC and the expanding evidence of oncogenic drivers in nonsquamous NSCLC.

Sun S, Liu S, Duan SZ, et al.
Targeting the c-Met/FZD8 signaling axis eliminates patient-derived cancer stem-like cells in head and neck squamous carcinomas.
Cancer Res. 2014; 74(24):7546-59 [PubMed] Related Publications
Cancer stem-like cells (CSC) thought to contribute to head and neck squamous carcinomas (HNSCC) may offer attractive therapeutic targets if a tractable approach can be developed. In this study, we report that silencing c-Met is sufficient to suppress sphere formation, tumor initiation, and metastatic properties of HN-CSC. Pharmacologic inhibition of c-Met with the selective inhibitor PF-2341066 preferentially targeted CSC and synergized with conventional chemotherapy to improve efficacy in a mouse xenograft model of HNSCC, impeding tumor growth and reducing metastasis. Mechanistic investigations showed that CSC elimination was due to downregulation of Wnt/β-catenin signaling in HN-CSC and that the Wnt pathway receptor FZD8 was essential for interactions of c-Met and Wnt/β-catenin signaling in HN-CSC. Notably, ectopic expression of FZD8 rescued the impaired phenotype of HN-CSC where c-Met was inhibited. Furthermore, c-Met upregulated FZD8 through the ERK/c-Fos cascade in HN-CSC. Taken together, our results offer a preclinical proof-of-concept for targeting the c-Met/FZD8 signaling axis as a CSC-directed therapy to improve HNSCC treatment.

Boccaccio C, Comoglio PM
MET, a driver of invasive growth and cancer clonal evolution under therapeutic pressure.
Curr Opin Cell Biol. 2014; 31:98-105 [PubMed] Related Publications
The MET oncogene, encoding the hepatocyte growth factor receptor, drives invasive growth, a genetic program largely overlapping with epithelial-mesenchymal transition, and governing physiological and pathological processes such as tissue development and regeneration, as well as cancer dissemination. Recent studies show that MET enables cells to overcome damages inflicted by cancer anti-proliferative targeted therapies, radiotherapy or anti-angiogenic agents. After exposure to such therapies, clones of MET-amplified cancer cells arise within the context of genetically heterogeneous tumors and-exploiting an ample platform of signaling pathways-drive recurrence. In cancer stem cells, not only amplification, but also MET physiological expression, inherited from the cell of origin (a stem/progenitor), can contribute to tumorigenesis and therapeutic resistance, by sustaining the inherent self-renewing, self-preserving and invasive growth phenotype.

Rynkiewicz NK, Fedele CG, Chiam K, et al.
INPP4B is highly expressed in prostate intermediate cells and its loss of expression in prostate carcinoma predicts for recurrence and poor long term survival.
Prostate. 2015; 75(1):92-102 [PubMed] Related Publications
BACKGROUND: Phosphoinositide 3-kinase (PI3K)/Akt pathway is frequently activated in prostate carcinoma due to the loss of tumor suppressor PTEN, which leads to increased Akt activity. Expression of INPP4B, another negative regulator of the PI3K/Akt pathway, is also reduced in prostate carcinoma. However, uncertainty exists regarding the association of INPP4B expression and biochemical and clinical relapse of prostate carcinoma.
METHODS: INPP4B expression in benign prostate acini was analyzed by co-immunofluorescence with cytokeratins (CK) 5, 8, 19, androgen receptor (AR), c-MET, chromogranin A and Ki67. INPP4B expression in prostate carcinoma was analyzed in two independent cohorts (n = 406). The association of INPP4B with biochemical and clinical prostate carcinoma relapse was assessed by Kaplan-Meier and Cox proportional hazards modeling.
RESULTS: INPP4B was expressed in luminal epithelium within benign ducts, and was highly expressed in CK5+/CK8+/CK19+/AR-/c-MET+/Ki67- intermediate cells in proliferative inflammatory atrophic acini. Overall, INPP4B expression was reduced in prostate carcinoma compared to benign epithelium. Absent/low INPP4B expression was associated with reduced biochemical relapse-free survival (P = 0.01) and increased risk of clinical relapse (P = 0.01). Absence of INPP4B expression was an independent predictor of clinical relapse free survival (P = 0.004) when modeled with Gleason score (P = 0.027) and pathologic stage (P = 0.07).
CONCLUSIONS: INPP4B is highly expressed in intermediate cells within proliferative inflammatory atrophic ducts, and expression is reduced in prostate carcinoma. Absence of INPP4B expression is associated with poor outcome following radical prostatectomy, and represents an independent prognostic marker of prostate carcinoma clinical recurrence.

Satoh K, Nimura S, Aoki M, et al.
Tumor budding in colorectal carcinoma assessed by cytokeratin immunostaining and budding areas: possible involvement of c-Met.
Cancer Sci. 2014; 105(11):1487-95 [PubMed] Related Publications
Tumor budding/sprouting has been shown to be an independent adverse prognostic factor in T1 and T3N0 colorectal carcinomas, however, its assessment could be improved by more accurate identification of budding carcinoma cells and consideration of budding areas. Moreover, tumor budding mechanisms are yet to be defined. In this study, we evaluated the identification of budding tumor cells by either H&E staining alone or H&E with immunohistochemistry and developed a scoring system based on budding grades and areas. We examined whether the budding score correlated with clinicopathologic features and prognosis and the association between tumor budding/sprouting and c-Met protein expression and phosphorylation and MET gene copy numbers because c-Met is known to play an important role in colorectal carcinoma tumorigenesis. Cytokeratin immunohistochemistry could identify tumors with shorter disease-free survival (DFS) from the low-grade budding group assessed with H&E alone. High budding scores based on budding grade and area were more significantly correlated with DFS than scores obtained using the budding grade alone. In tumors with a high budding score, c-Met expression and phosphorylation levels and MET gene copy numbers were significantly increased at the invasive front compared with those in superficial tumor portions. This study showed for the first time that high levels of phospho-c-Met at the invasive front were significantly associated with a high budding score and shorter DFS. In conclusion, a budding score assessed by budding grades and budding-positive areas correlates highly with clinicopathologic aggressive features of colorectal carcinoma.

Gessi M, Demir H, Goschzik T, Pietsch T
MET T992I mutation in a case of ependymoblastoma/embryonal tumour with multilayered rosettes.
J Clin Pathol. 2014; 67(11):1017-8 [PubMed] Related Publications

Lin LC, Hsu SL, Wu CL, Hsueh CM
TGFβ can stimulate the p(38)/β-catenin/PPARγ signaling pathway to promote the EMT, invasion and migration of non-small cell lung cancer (H460 cells).
Clin Exp Metastasis. 2014; 31(8):881-95 [PubMed] Related Publications
Signaling pathway(s) responsible for transforming growth factor β (TGFβ)-induced epithelial mesenchymal transition (EMT), invasion and migration of H460 cells (non-small cell lung cancer/NSCLC) was identified in the study. The results showed that TGFβ-induced p(38)/β-catenin/PPARγ signaling pathway played a critical role in the promotion of EMT, invasion and migration of H460 cells. All these pathological outcomes attributed to PPARγ-increased expression of p-EGFR, p-c-MET and Vimentin and the decrease of E-cadherin. Transforming growth factor β and p(38)-induced β-catenin not only stimulated the expression of PPARγ but also physically interacted with it. Blocking the ligand binding domain of PPARγ (with GW9662) could significantly interfere the binding between PPARγ and β-catenin, and interrupt the nuclear infiltration of both factors. These findings suggested that β-catenin was an upstream regulator and a ligand of PPARγ, and the binding between these two molecules was critical for their nuclear infiltration. Transforming growth factor β-induced tumor invasion and migration was also seen in U373 cells (brain glioma, with high inducible PPARγ) in a PPARγ-dependent manner, but not in CH27 cells (squamous NSCLC, with low PPARγ). PPARγ shRNA, GW9662, JW67 and 2,4-diaminoquinazoline were all revealed to have important values in the control of the intrinsic and TGFβ-induced EMT, tumor invasion and migration of H460 cells. The results further suggested that PPARγ and β-catenin may be the potential markers for the early diagnosis and/or treatment of metastatic tumors.

Lapa C, Linsenmann T, Monoranu CM, et al.
Comparison of the amino acid tracers 18F-FET and 18F-DOPA in high-grade glioma patients.
J Nucl Med. 2014; 55(10):1611-6 [PubMed] Related Publications
UNLABELLED: High-grade gliomas (HGGs) are the most common malignant primary tumors of the central nervous system. PET probes of amino acid transport such as O-(2-(18)F-fluoroethyl)-l-tyrosine ((18)F-FET), 3,4-dihydroxy-6-(18)F-fluoro-l-phenylalanine ((18)F-DOPA), and (11)C-methionine ((11)C-MET) detect primary and recurrent tumors with a high accuracy. (18)F-FET is predominantly used in Europe, whereas amino acid transport imaging is infrequently done in the United States. The aim of this study was to determine whether (18)F-FET and (18)F-DOPA PET/CT provide comparable information in HGG.
METHODS: Thirty (18)F-FET and (18)F-DOPA PET/CT scans were obtained before surgery or biopsy in 27 patients with high clinical suspicion for primary or recurrent HGG (5 primary, 22 recurrent tumors). (18)F-FET and (18)F-DOPA PET/CT images were compared visually and semiquantitatively (maximum standardized uptake value [SUV(max)], mean SUV [SUV(mean)]). Background (SUV(max) and SUV(mean)) and tumor-to-background ratios (TBRs) were calculated for both PET probes. The degree of (18)F-DOPA uptake in the basal ganglia (SUV(mean)) was also assessed.
RESULTS: Visual analysis revealed no difference in tumor uptake pattern between the 2 PET probes. The SUV(mean) and SUV(max) for (18)F-FET were higher than those of (18)F-DOPA (4.0 ± 2.0 and 4.9 ± 2.3 vs. 3.5 ± 1.6 and 4.3 ± 2.0, respectively; all P < 0.001). TBRs for SUV(mean) but not for SUV(max) were significantly higher for (18)F-FET than (18)F-DOPA (TBR SUV(mean): 3.8 ± 1.7 vs. 3.4 ± 1.2, P = 0.004; TBR SUV(max): 3.3 ± 1.6 and 3.0 ± 1.1, respectively; P = 0.086). (18)F-DOPA uptake by the basal ganglia was present (SUV(mean), 2.6 ± 0.7) but did not affect tumor visualization.
CONCLUSION: Whereas visual analysis revealed no significant differences in uptake pattern for (18)F-FET and (18)F-DOPA in patients with primary or recurrent HGG, both SUVs and TBRs for SUV(mean) were significantly higher for (18)F-FET. However, regarding tumor delineation, both tracers performed equally well and seem equally feasible for imaging of primary and recurrent HGG. These findings suggest that both PET probes can be used based on availability in multicenter trials.

Jang WJ, Jung SK, Kang JS, et al.
Anti-tumor activity of WK88-1, a novel geldanamycin derivative, in gefitinib-resistant non-small cell lung cancers with Met amplification.
Cancer Sci. 2014; 105(10):1245-53 [PubMed] Related Publications
Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been introduced for the treatment of non-small cell lung cancer (NSCLC), the emergence of secondary T790M mutation in EGFR or amplification of the Met proto-oncogene restrain the clinical success of EGFR-TKIs. Since heat shock protein-90 (Hsp90) stabilizes various oncoproteins including EGFR and c-Met, the inhibition of Hsp90 activity appears as a rational strategy to develop anticancer drugs. Despite preclinical efficacy of geldanamycin-anasamycin (GA)-derivatives containing benzoquinone moiety as Hsp90 inhibitors, the hepatotoxicity of these GA-derivatives restricts their therapeutic benefit. We have prepared WK-88 series of GA-derivatives, which lack the benzoquinone moiety. In this study, we have examined the anticancer effects of WK88-1 in Met-amplified- and gefitinib-resistant (HCC827GR) NSCLC cells and its parental HCC827 cells. Treatment with WK88-1 reduced the cell viability in both HCC827 and HCC827GR cells, which was associated with marked decrease in the constitutive expression of Hsp90 client proteins, such as EGFR, ErbB2, ErbB3, Met and Akt. Moreover, WK88-1 attenuated phosphorylation of these Hsp90 client proteins and reduced the anchorage-independent growth of HCC827GR cells. Administration of WK88-1 did not cause hepatotoxicity in animals and significantly reduced the growth of HCC827GR cells xenograft tumors in nude mice. Our study provides evidence that ErbB3 might be a client for Hsp90 in Met-amplified NSCLCs. In conclusion, we demonstrate that inhibition of Hsp90 dampens the activation of EGFR- or c-Met-mediated survival of Met-amplified NSCLCs and that WK88-1 as a Hsp90 inhibitor alleviates gefitinib resistance in HCC827GR cells.

Garber K
MET inhibitors start on road to recovery.
Nat Rev Drug Discov. 2014; 13(8):563-5 [PubMed] Related Publications

Zhou W, Jubb AM, Lyle K, et al.
PAK1 mediates pancreatic cancer cell migration and resistance to MET inhibition.
J Pathol. 2014; 234(4):502-13 [PubMed] Related Publications
Pancreatic adenocarcinoma (PDAC) is a major unmet medical need and a deeper understanding of molecular drivers is needed to advance therapeutic options for patients. We report here that p21-activated kinase 1 (PAK1) is a central node in PDAC cells downstream of multiple growth factor signalling pathways, including hepatocyte growth factor (HGF) and MET receptor tyrosine kinase. PAK1 inhibition blocks signalling to cytoskeletal effectors and tumour cell motility driven by HGF/MET. MET antagonists, such as onartuzumab and crizotinib, are currently in clinical development. Given that even highly effective therapies have resistance mechanisms, we show that combination with PAK1 inhibition overcomes potential resistance mechanisms mediated either by activation of parallel growth factor pathways or by direct amplification of PAK1. Inhibition of PAK1 attenuated in vivo tumour growth and metastasis in a model of pancreatic adenocarcinoma. In human tissues, PAK1 is highly expressed in a proportion of PDACs (33% IHC score 2 or 3; n = 304) and its expression is significantly associated with MET positivity (p < 0.0001) and linked to a widespread metastatic pattern in patients (p = 0.067). Taken together, our results provide evidence for a functional role of MET/PAK1 signalling in pancreatic adenocarcinoma and support further characterization of therapeutic inhibitors in this indication.

Hudson J, Ha JR, Sabourin V, et al.
p66ShcA promotes breast cancer plasticity by inducing an epithelial-to-mesenchymal transition.
Mol Cell Biol. 2014; 34(19):3689-701 [PubMed] Article available free on PMC after 01/04/2015 Related Publications
Breast cancers are stratified into distinct subtypes, which influence therapeutic responsiveness and patient outcome. Patients with luminal breast cancers are often associated with a better prognosis relative to that with other subtypes. However, subsets of patients with luminal disease remain at increased risk of cancer-related death. A critical process that increases the malignant potential of breast cancers is the epithelial-to-mesenchymal transition (EMT). The p66ShcA adaptor protein stimulates the formation of reactive oxygen species in response to stress stimuli. In this paper, we report a novel role for p66ShcA in inducing an EMT in HER2(+) luminal breast cancers. p66ShcA increases the migratory properties of breast cancer cells and enhances signaling downstream of the Met receptor tyrosine kinase in these tumors. Moreover, Met activation is required for a p66ShcA-induced EMT in luminal breast cancer cells. Finally, elevated p66ShcA levels are associated with the acquisition of an EMT in primary breast cancers spanning all molecular subtypes, including luminal tumors. This is of high clinical relevance, as the luminal and HER2 subtypes together comprise 80% of all newly diagnosed breast cancers. This study identifies p66ShcA as one of the first prognostic biomarkers for the identification of more aggressive tumors with mesenchymal properties, regardless of molecular subtype.

Korhan P, Erdal E, Atabey N
MiR-181a-5p is downregulated in hepatocellular carcinoma and suppresses motility, invasion and branching-morphogenesis by directly targeting c-Met.
Biochem Biophys Res Commun. 2014; 450(4):1304-12 [PubMed] Related Publications
c-Met receptor tyrosine kinase has been regarded as a promising therapeutic target for hepatocellular carcinoma (HCC). Recently, microRNAs (miRNAs) have been shown as a novel mechanism to control c-Met expression in cancer. In this study, we investigate the potential contribution of miR-181a-5p dysregulation to the biology of c-Met overexpression in HCC. Herein, we found an inverse expression pattern between miR-181a-5p and c-Met expression in normal, cirrhotic and HCC liver tissues. Luciferase assay confirmed that miR-181a-5p binding to the 3'-UTR of c-Met downregulated the expression of c-Met in HCC cells. Overexpression of miR-181a-5p suppressed both HGF-independent and -dependent activation of c-Met and consequently diminished branching-morphogenesis and invasion. Combined treatment with miR-181a-5p and c-Met inhibitor led to a further inhibition of c-Met-driven cellular activities. Knockdown of miR-181a-5p promoted HGF-independent/-dependent signaling of c-Met and accelerated migration, invasion and branching-morphogenesis. In conclusion, our results demonstrated for the first time that c-Met is a functional target gene of miR-181a-5p and the loss of miR-181a-5p expression led to the activation of c-Met-mediated oncogenic signaling in hepatocarcinogenesis. These findings display a novel molecular mechanism of c-Met regulation in HCC and strategies to increase miR-181a5p level might be an alternative approach for the enhancement of the inhibitory effects of c-Met inhibitors.

Yang X, Yang Y, Tang S, et al.
Anti-tumor effect of polysaccharides from Scutellaria barbata D. Don on the 95-D xenograft model via inhibition of the C-met pathway.
J Pharmacol Sci. 2014; 125(3):255-63 [PubMed] Related Publications
Polysaccharides isolated from Scutellaria barbata (PSB) have been reported to have anti-tumor effects. To investigate the underlying mechanism, a highly invasive, metastatic and phospho-c-Met overexpression lung carcinoma cell, 95-D cell line was used. The results showed that in vitro, PSB not only could inhibit the proliferation of 95-D cell line (IC(50) = 35.2 μg/mL), but also down-regulated the expression of phospho-c-Met and its downstream signaling molecules including phospho-Erk and phospho-Akt. In vivo, PSB inhibited tumor growth in the 95-D subcutaneous xenograft model in a dose-dependent manner; after once-daily intraperitoneal injection for 3 weeks, tumor growth inhibition T/C ratio for 100 and 200 mg/kg treatments was 42.72% and 13.6%, respectively. In the end of the in vivo study, tumor tissues were harvested for further evaluation of the phosphorylation level of c-Met, AKT, and ERK. Ex vivo results demonstrated that the phosphorylation of c-Met and its downstream signaling molecules were also significantly inhibited by PSB. Immunohistochemistry analysis showed dose-dependent inhibition of tumor cell proliferation (Ki67) and reduction of microvessel density (CD31). In summary, the results indicated that PSB exerted anti-tumor growth activity on human lung cancer 95-D in vitro and in vivo by directly regulating the c-Met signaling pathway and the anti-tumor effects were mainly based on its anti-proliferation and anti-angiogenesis action.

Zheng Y, Gery S, Sun H, et al.
KPT-330 inhibitor of XPO1-mediated nuclear export has anti-proliferative activity in hepatocellular carcinoma.
Cancer Chemother Pharmacol. 2014; 74(3):487-95 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
PURPOSE: Exportin-1 (XPO1, CRM1) mediates the nuclear export of several key growth regulatory and tumor suppressor proteins. Cancer cells often overexpress XPO1 resulting in cytoplasmic mislocalization and aberrant activity of its target proteins. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to and inhibit the function of XPO1 have been recently developed. The aim of this study was to investigate the efficacy of the clinical staged, orally available, SINE compound, KPT-330 in hepatocellular carcinoma (HCC).
METHODS: In silico, meta-analysis showed that XPO1 is overexpressed in HCC. Six HCC cell lines were treated with KPT-330, and cell proliferation and expression of cell growth regulators were examined by cell proliferation assays and Western blot analysis, respectively. The in vivo anti-cancer activity of KPT-330 was examined in a HCC xenograft murine model.
RESULTS: KPT-330 reduced the viability of HCC cell lines in vitro and this anti-proliferative effect was associated with cell cycle arrest and induction of apoptosis. The expression of the pro-apoptotic protein PUMA was markedly up-regulated by KPT-330. In addition, SINE treatment increased the expression of the tumor suppressor proteins p53 and p27, while it reduced the expression of HCC promoting proteins, c-Myc and c-Met. XPO1 levels itself were also down-regulated following KPT-330 treatment. Finally, a HCC xenograft murine model showed that treatment of mice with oral KPT-330 significantly inhibited tumor growth with little evidence of toxicity.
CONCLUSION: Our results suggest that SINE compounds, such as KPT-330, are promising novel drugs for the targeted therapy of HCC.

Qin Y, McAllister SS
SPSB1 may have MET its match during breast cancer recurrence.
Cancer Discov. 2014; 4(7):760-1 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
SUMMARY: Disease recurrence is the most common cause of death for patients with breast cancer, yet little is known about the molecular mechanisms underlying this process. Using inducible transgenic mouse model systems, Feng and colleagues identified SPSB1 as a determinant of breast cancer recurrence by virtue of its ability to protect tumor cells from apoptosis through c-MET activation.

Pentheroudakis G, Kotteas EA, Kotoula V, et al.
Mutational profiling of the RAS, PI3K, MET and b-catenin pathways in cancer of unknown primary: a retrospective study of the Hellenic Cooperative Oncology Group.
Clin Exp Metastasis. 2014; 31(7):761-9 [PubMed] Related Publications
Cancer of unknown primary origin (CUP) had a poor prognosis, determined by clinico-histological characteristics, partly due to the lack of insights on its biology. We screened tumour DNA from 87 patients with CUP for CTNNB1 (coding exons 2,3,4,5), MET (coding exon 18), PIK3CA (coding exons 9,20), KRAS (coding exons 1,2), BRAF (coding exon 15) gene mutations by using dd-sequencing and evaluated their impact on prognosis. Mutated gene incidences in the 87 CUP cases were: KRAS 11 (12.6 %), BRAF 5 (5.7 %), PIK3CA 8 (9 %), MET 6 (6.7 %) and CTNNB1 18 (20.7 %). Several mutations in the KRAS gene were not the commonly encountered mutations in other solid tumours. Activating mutations were observed in 10.2 % in KRAS, 4.5 % in BRAF, 6.6 % in PIK3CA, 4.5 % in MET, and 19.5 % in CTNNB1. Activating mutations in PIK3CA coding exon 9 were inversely correlated with MET coding exon 18 activating mutations (p = 0.036). MET activating mutations were prognostic for poor Progression-Free Survival (median PFS 5 vs 9 months, p = 0.009) and Overall Survival (median OS 7 vs 20 months, p = 0.005). The complex profile of either CTNNB1 or MET mutations also had an adverse prognostic significance (median OS 11 vs 21 months, p = 0.015). No other gene mutation exhibited prognostic significance. In multivariate analysis, poor performance status, male gender, visceral disease and adenocarcinoma histology, but not gene mutations, were independently associated with poor patient outcome. CTNNB1 gene mutations are frequent, and along with MET mutations have an adverse prognostic effect in patients with CUP.

Boynukalin FK, Comunoglu C, Türkmen I, et al.
C-Met expression pattern in uterine leiomyoma.
Clin Exp Obstet Gynecol. 2014; 41(3):254-7 [PubMed] Related Publications
AIM: Growth factors take place in the formation and growth of uterine leiomyomas (LMs). Transforming growth factor beta (TGF-beta), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), and insulin-like growth factor (IGF) contribute to the pathophysiology of LMs when they bind with a specific membrane receptor and transmit a signal into the cell. Little is known about hepatocyte growth factor (HGF) and its receptor system c-Met in formation and growth of uterine LMs. The aim of this study was to evaluate the c-Met receptor expression on human myometrium and uterine LMs.
MATERIALS AND METHODS: The study was performed on human myometrium and uterine LMs. Expression of c-Met receptor was evaluated by immunohistochemical analysis.
RESULTS: Overexpression of c-Met was found in all LM cases and in none of normal myometrium samples c-Met overexpression was seen.
CONCLUSION: HGF and c-Met receptor complex seem to have role in development of uterine LMs.

Boccaccio C, Luraghi P, Comoglio PM
MET-mediated resistance to EGFR inhibitors: an old liaison rooted in colorectal cancer stem cells.
Cancer Res. 2014; 74(14):3647-51 [PubMed] Related Publications
Inhibitors of EGFR are currently approved for the therapy of metastatic colorectal cancer (as well as other tumors), but their benefits are limited by inherent and acquired resistance, whose mechanisms are the subject of intense investigation. It is known that such resistance relies on a handful of genetic lesions and/or extracellular signals bypassing the requirement of EGF for cell proliferation and survival. As recently shown, these mechanisms may imply oncogenic activation of MET or its stimulation by the ligand hepatocyte growth factor. However, it is still largely obscure if sensitivity or resistance to EGFR inhibitors operates in cancer stem cells. Convincing evidence indicates that this elusive cell subpopulation is present at the roots of colorectal cancer. Conceivably, cancer stem cells accumulate the genetic lesions driving tumor onset and progression, as well as the genetic determinants of sensitivity or resistance to conventional and targeted therapies. Recent studies enlighten the expression of functional EGFR and MET in colorectal cancer stem cells and the outcome of their inhibition. Evidence is provided that, in patients sensitive to EGFR therapy, association of MET inhibitors fosters cancer stem cell eradication and durable tumor regression.

Zhou JY, Chen X, Zhao J, et al.
MicroRNA-34a overcomes HGF-mediated gefitinib resistance in EGFR mutant lung cancer cells partly by targeting MET.
Cancer Lett. 2014; 351(2):265-71 [PubMed] Related Publications
In non-small-cell lung cancer (NSCLC) that harbours an activating epidermal growth factor receptor (EGFR) mutation, over-expression of hepatocyte growth factor (HGF) is an important mechanism involved in the acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) by restoring activity of the PI3K/Akt pathway via phosphorylation of MET. In our study, we found that the forced expression of miR-34a inhibited cell growth and induced apoptosis partly by targeting MET in HGF-induced gefitinib-resistant HCC827 and PC-9 cells. Furthermore, dramatic tumour regression was observed in the miR-34a plus gefitinib group in HGF-induced gefitinib resistant mouse xenograft models. This study demonstrates for the first time that miR-34a rescues HGF-induced gefitinib resistance in EGFR mutant NSCLC cells.

Wolnicka-Glubisz A, Strickland FM, Wielgus A, et al.
A melanin-independent interaction between Mc1r and Met signaling pathways is required for HGF-dependent melanoma.
Int J Cancer. 2015; 136(4):752-60 [PubMed] Article available free on PMC after 15/02/2016 Related Publications
Melanocortin 1 receptor (MC1R) signaling stimulates black eumelanin production through a cAMP-dependent pathway. MC1R polymorphisms can impair this process, resulting in a predominance of red phaeomelanin. The red hair, fair skin and UV sensitive phenotype is a well-described melanoma risk factor. MC1R polymorphisms also confer melanoma risk independent of pigment. We investigated the effect of Mc1r deficiency in a mouse model of UV-induced melanoma. C57BL/6-Mc1r+/+-HGF transgenic mice have a characteristic hyperpigmented black phenotype with extra-follicular dermal melanocytes located at the dermal/epidermal junction. UVB induces melanoma, independent of melanin pigmentation, but UVA-induced and spontaneous melanomas are dependent on black eumelanin. We crossed these mice with yellow C57BL/6-Mc1re/e animals which have a non-functional Mc1r and produce predominantly yellow phaeomelanin. Yellow C57BL/6-Mc1re/e-HGF mice produced no melanoma in response to UVR or spontaneously even though the HGF transgene and its receptor Met were expressed. Total melanin was less than in C57BL/6-Mc1r+/+-HGF mice, hyperpigmentation was not observed and there were few extra-follicular melanocytes. Thus, functional Mc1r was required for expression of the transgenic HGF phenotype. Heterozygous C57BL/6-Mc1re/+-HGF mice were black and hyperpigmented and, although extra-follicular melanocytes and skin melanin content were similar to C57BL/6-Mc1r+/+-HGF animals, they developed UV-induced and spontaneous melanomas with significantly less efficiency by all criteria. Thus, heterozygosity for Mc1r was sufficient to restore the transgenic HGF phenotype but insufficient to fully restore melanoma. We conclude that a previously unsuspected melanin-independent interaction between Mc1r and Met signaling pathways is required for HGF-dependent melanoma and postulate that this pathway is involved in human melanoma.

Burnett AS, Bailey J, Oliver JB, et al.
Sensitivity of alternative testing for pancreaticobiliary cancer: a 10-y review of the literature.
J Surg Res. 2014; 190(2):535-47 [PubMed] Related Publications
BACKGROUND: Biliary strictures present a diagnostic challenge to differentiate benign disease from hepatopancreaticobiliary (HPB) malignancies. Endoscopic retrograde cholangiopancreatography cytology is commonly performed in these patients; however, its sensitivity for diagnosis of HPB malignancy is poor (41.6%). Many adjunctive tests have been investigated to improve the sensitivity of HPB biopsies. To determine the best tests available, however, we reviewed the literature and performed a comparative analysis of all recently investigated tests and their sensitivities.
METHODS: A PubMed search identified articles published between 2003 and 2014, describing alternate methods for diagnosing HPB malignancies, reported sensitivity, final pathology, and had data available online. Meta-analysis was conducted for tests with multiple articles. Tests with the highest sensitivity and specificities were reported.
RESULTS: A total of 77 studies were identified. Meta-analysis was performed on the sensitivity of EUS-FNA (74.2%), fluorescence in situ hybridization (54.2%), immunostain of insulin-like growth factor 2 mRNA-binding Protein 3 (IMP3; 80.4%), IMP3 + cytology (86.4%), K homology domain containing protein overexpressed in cancer (KOC; 85.9%), S100P (77.8%), serum CA19-9 (69.3%), and K-ras mutations (47.0%) to detect malignancy. Ultimately, 12 tests were identified with superior sensitivity (85.3%-100%) and specificities (81.6%-100%) including stricture scrapping, brush sectioning, IMP3 stain + cytology, IMP3+S100A4, bile carcinoembryonic cell adhesion molecule 6 protein (±CA19-9), bile micro RNA (miRNA)-135b, serum miRNA-RNU2-1f, serum miRNA-21 (+CA19-9), peripheral blood mononuclear cells miRNA-27a-3p (+CA19-9), serum miRNA-16 + miRNA-196a (+CA19-9), peripheral blood mononuclear cells mRNAs h-TERT + CK20 + CEA + C-MET.
CONCLUSIONS: We recommend immunostaining with a panel of IMP3+KOC + S100A4 + cytology to achieve maximum sensitivity and specificity from HPB biopsies. One biliary protein (carcinoembryonic cell adhesion molecule 6) and several RNAs (bile and blood) offer exceptional sensitivity and specificity and should be tested prospectively in larger populations. Overall, this review identifies several tests to improve the sensitivity of diagnostic algorithms to identify HPB malignancies.

Sun Y, Li Z, Xu Z
[Association of expression of HGF and its receptor c-Met to primary colorectal cancers with synchronous liver metastasis].
Zhonghua Wei Chang Wai Ke Za Zhi. 2014; 17(6):598-601 [PubMed] Related Publications
OBJECTIVE: To investigate the association between expression of hepatocyte growth factor(HGF) and its receptor c-Met and primary colorectal cancers with synchronous liver metastases.
METHODS: A total of 30 colorectal cancer patients with synchronous liver metastasis underwent radical resection of primary cancer and liver cancer in our hospital from June 2001 to June 2010. According to lymphatic metastasis, patients were divided into group A(T1~T4N1~N2M1, n=21) and group B(T1~T4N0M1, n=9). Twenty-one matched T1~T4N1~N2M0 and 21 T1~T4N0M0 patients were used as the controls of group A. Nine matched T1~T4N0M0 patients were used as the controls of group B. Expressions of HGF and c-Met in tissues of primary loci, liver loci and metastatic loci were detected by immunohistochemistry.
RESULTS: In primary loci of group A, the positive rate of HGF was significantly higher than that of T1~T4N1~N2M0 and T1~T4N0M0 controls [71%(15/21) vs. 43%(9/21), 19%(4/21), all P<0.05]. The positive rate of c-MET[90%(19/21)] was significantly higher compared to T1~T4N0M0 control[43%(9/21), P<0.05], while not significantly different compared to T1~T4N1~N2M0 control[86%(18/21)]. In primary loci of group B, positive rates of HGF and c-MET were not significantly different as compared to T1~T4N0M0 control[6/9 vs. 5/9, P>0.05; 8/9 vs. 6/9, P>0.05]. Concordance of HGF and c-MET expression in group A among primary loci, lymphatic metastatic loci and hepatic metastatic loci was 81%(17/21) and 76%(16/21).
CONCLUSION: HGF-c-Met may play a role in colorectal cancer patients with synchronous liver metastasis who have regional lymphatic metastasis, and may have few effect on colorectal cancer with synchronous liver metastasis without corresponding lymphatic metastasis.

Bowles DW, McDermott JD, Jimeno A
Novel treatments for head and neck squamous cell carcinoma: preclinical identification and clinical investigation.
Future Oncol. 2014; 10(6):1065-80 [PubMed] Related Publications
Head and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide. Classically, it is a disease related to tobacco and alcohol use; an increasing number of patients are being diagnosed with HNSCC caused by infection with the human papillomavirus. New deep-sequencing techniques have confirmed the importance of p53 and EGF receptor in HNSCC development, and have identified pathways of critical importance, such as PI3K/mTOR and NOTCH. Increasing knowledge of key molecular features has lead to new therapeutic avenues for HNSCC. Novel therapies under investigation in HNSCC include antibody and small molecule inhibitors of EGF receptor and its family members, PI3K inhibitors, antiangiogenic agents, immunotherapies and agents interacting with early developmental pathways such as Hedgehog.

Hack SP, Bruey JM, Koeppen H
HGF/MET-directed therapeutics in gastroesophageal cancer: a review of clinical and biomarker development.
Oncotarget. 2014; 5(10):2866-80 [PubMed] Article available free on PMC after 15/02/2016 Related Publications
Aberrant activation of the HGF/MET signaling axis has been strongly implicated in the malignant transformation and progression of gastroesophageal cancer (GEC). MET receptor overexpression in tumor samples from GEC patients has been consistently correlated with an aggressive metastatic phenotype and poor prognosis. In preclinical GEC models, abrogation of HGF/MET signaling has been shown to induce tumor regression as well as inhibition of metastatic dissemination. Promising clinical results in patient subsets in which MET is overexpressed have spurned several randomized studies of HGF/MET-directed agents, including two pivotal global Phase III trials. Available data highlight the need for predictive biomarkers in order to select patients most likely to benefit from HGF/MET inhibition. In this review, we discuss the current knowledge of mechanisms of MET activation in GEC, the current status of the clinical evaluation of MET-targeted therapies in GEC, characteristics of ongoing randomized GEC trials and the associated efforts to identify and validate biomarkers. We also discuss the considerations and challenges for HGF/MET inhibitor drug development in the GEC setting.

Guo B, Cen H, Tan X, et al.
Prognostic value of MET gene copy number and protein expression in patients with surgically resected non-small cell lung cancer: a meta-analysis of published literatures.
PLoS One. 2014; 9(6):e99399 [PubMed] Article available free on PMC after 15/02/2016 Related Publications
BACKGROUND: The prognostic value of the copy number (GCN) and protein expression of the mesenchymal-epithelial transition (MET) gene for survival of patients with non-small cell lung cancer (NSCLC) remains controversial. This study aims to comprehensively and quantitatively asses the suitability of MET GCN and protein expression to predict patients' survival.
METHODS: PubMed, Embase, Web of Science and Google Scholar were searched for articles comparing overall survival in patients with high MET GCN or protein expression with those with low level. Pooled hazard ratio (HR) and 95% confidence intervals (CIs) were calculated using the random and the fixed-effects models. Subgroup and sensitivity analyses were also performed.
RESULTS: Eighteen eligible studies enrolling 5,516 patients were identified. Pooled analyses revealed that high MET GCN or protein expression was associated with poor overall survival (OS) (GCN: HR = 1.90, 95% CI 1.35-2.68, p<0.001; protein expression: HR = 1.52, 95% CI 1.08-2.15, p = 0.017). In Asian populations (GCN: HR = 2.22, 95% CI 1.46-3.38, p<0.001; protein expression: HR = 1.89, 95% CI 1.34-2.68, p<0.001), but not in the non-Asian subset. For adenocarcinoma, high MET GCN or protein expression indicated decreased OS (GCN: HR = 1.49, 95% CI 1.05-2.10, p = 0.025; protein expression: HR = 1.69, 95% CI 1.31-2.19, p<0.001). Results were similar for multivariate analysis (GCN: HR = 1.61, 95% CI 1.15-2.25, p = 0.005; protein expression: HR = 2.18, 95% CI 1.60-2.97, p<0.001). The results of the sensitivity analysis were not materially altered and did not draw different conclusions.
CONCLUSIONS: Increased MET GCN or protein expression was significantly associated with poorer survival in patients with surgically resected NSCLC; this information could potentially further stratify patients in clinical treatment.

Liu H, Qian C, Shen Z
Anti-tumor activity of oridonin on SNU-5 subcutaneous xenograft model via regulation of c-Met pathway.
Tumour Biol. 2014; 35(9):9139-46 [PubMed] Related Publications
Gastric cancer is the leading cause of cancer death worldwide. Oridonin, a diterpenoid isolated from Rabdosia rubescens, has attracted considerable attention as a potential treatment for gastric cancer based on its anti-tumor effects in many tumor cell lines. However, detailed anti-tumor mechanisms of oridonin remain a matter of speculation. In the present study, a gastric carcinoma cell line harboring c-Met gene amplification SNU-5 was used to investigate the underlying mechanisms. The results showed that in vitro, oridonin potently inhibited c-Met phosphorylation and c-Met-dependent cell proliferation (IC50 value, 36.8 μM), meanwhile down-regulated the expression of the downstream signaling molecules including phospho-c-Raf, phospho-Erk, and phospho-Akt. In vivo, oridonin showed efficacy at well-tolerated doses, including marked cytoreductive anti-tumor activity in SNU-5 subcutaneous xenograft model. The anti-tumor efficacy of oridonin was dose-dependent and showed strong inhibition of c-Met phosphorylation. Additional mechanism of action studies showed dose-dependent inhibition of c-Met-dependent signal transduction, tumor cell proliferation (Ki67), and reduction of microvessel density (CD31). These results suggested that the anti-tumor activity of oridonin may be mediated by direct effects on tumor cell growth or survival as well as anti-angiogenic mechanisms. In summary, the results indicated that oridonin exerted anti-tumor growth on human gastric cancer SNU-5 in vitro and in vivo by direct regulation of c-Met signaling pathway and the anti-tumor effects was mainly based on its anti-proliferation and anti-angiogenesis.

Ping Y, Zhang H, Deng Y, et al.
IndividualizedPath: identifying genetic alterations contributing to the dysfunctional pathways in glioblastoma individuals.
Mol Biosyst. 2014; 10(8):2031-42 [PubMed] Related Publications
Due to the extensive complexity and high genetic heterogeneity of genetic alterations in cancer, comprehensively depicting the molecular mechanisms of cancer remains difficult. Characterizing personalized pathogenesis in cancer individuals can help to reveal new details of the complex mechanisms. In this study, we proposed an integrative method called IndividualizedPath to identify genetic alterations and their downstream risk pathways from the perspective of individuals through combining the DNA copy number, gene expression data and topological structures of biological pathways. By applying the method to TCGA glioblastoma multiforme (GBM) samples, we identified 394 gene-pathway pairs in 252 GBM individuals. We found that genes with copy number alterations showed high heterogeneity across GBM individuals, whereas they affected relatively consistent biological pathways. A global landscape of gene-pathway pairs showed that EGFR linked with multiple cancer-related biological pathways confers the highest risk of GBM. GBM individuals with MET-pathway pairs showed significantly shorter survival times than those with only MET amplification. Importantly, we found that the same risk pathways were affected by different genes in distinct groups of GBM individuals with a significant pattern of mutual exclusivity. Similarly, GBM subtype analysis revealed some subtype-specific gene-pathway pairs. In addition, we found that some rare copy number alterations had a large effect on contribution to numerous cancer-related pathways. In summary, our method offers the possibility to identify personalized cancer mechanisms, which can be applied to other types of cancer through the web server (http://bioinfo.hrbmu.edu.cn/IndividualizedPath/).

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. MET gene, Cancer Genetics Web: http://www.cancer-genetics.org/MET.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 27 February, 2015     Cancer Genetics Web, Established 1999