Gene Summary

Gene:MET; MET proto-oncogene, receptor tyrosine kinase
Aliases: HGFR, AUTS9, RCCP2, c-Met, DFNB97
Summary:This gene encodes a member of the receptor tyrosine kinase family of proteins and the product of the proto-oncogene MET. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that are linked via disulfide bonds to form the mature receptor. Further processing of the beta subunit results in the formation of the M10 peptide, which has been shown to reduce lung fibrosis. Binding of its ligand, hepatocyte growth factor, induces dimerization and activation of the receptor, which plays a role in cellular survival, embryogenesis, and cellular migration and invasion. Mutations in this gene are associated with papillary renal cell carcinoma, hepatocellular carcinoma, and various head and neck cancers. Amplification and overexpression of this gene are also associated with multiple human cancers. [provided by RefSeq, May 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:hepatocyte growth factor receptor
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 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 31 August, 2019 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)

Zhang X, Liu N, Zhou M, et al.
DNA Nanorobot Delivers Antisense Oligonucleotides Silencing c-Met Gene Expression for Cancer Therapy.
J Biomed Nanotechnol. 2019; 15(9):1948-1959 [PubMed] Related Publications
Antisense oligonucleotides are considered to be a promising strategy for cancer therapy because of their high specificity and minimal side effects. They can bind specifically to mRNA silencing the expression of target genes. However, ssDNA cannot enter cells in large quantities, which limits its applications. Tetrahedral framework nucleic acids (tFNA) are considered to be optimal nanoscopic drug carriers because of their editability and biocompatibility. Most importantly, they can be modified with functional molecules. The over-expression of c-Met is associated with a wide variety of tumor occurrences, developments, drug resistance and prognoses. Activation of HGF/c-Met signaling pathways can promote cell migration and invasion in cancer. Therefore, blocking the expression of c-Met is a valid technique for cancer therapy. In this study, we used tFNA as carriers to deliver antisense oligonucleotides, which can bind to c-Met mRNA with high specificity and affinity, into cells resulting in the inhibition of c-Met expression for cancer therapy.

van Seijen M, Brcic L, Gonzales AN, et al.
Impact of delayed and prolonged fixation on the evaluation of immunohistochemical staining on lung carcinoma resection specimen.
Virchows Arch. 2019; 475(2):191-199 [PubMed] Free Access to Full Article Related Publications
Pre-analytical factors, such as fixation time, influence morphology of diagnostic and predictive immunohistochemical staining, which are increasingly used in the evaluation of lung cancer. Our aim was to investigate if variations in fixation time influence the outcome of immunohistochemical staining in lung cancer. From lung resections, specimen with tumor size bigger than 4 cm, 10 samples were obtained: 2 were put through the standard fixation protocol, 5 through the delayed, and 3 through the prolonged fixation protocol. After paraffin embedding, tissue microarrays (TMAs) were made. They were stained with 20 antibodies and scored for quality and intensity of staining. Samples with delay in fixation showed loss of TMA cores on glass slides and deterioration of tissue quality leading to reduction in the expression of CK 7, Keratin MNF116, CAM 5.2, CK 5/6, TTF-1, C-MET, Napsin A, D2-40, and PD-L1. Prolonged fixation had no influence on the performance of immunohistochemical stains. Delay of fixation negatively affects the expression of different immunohistochemical markers, influencing diagnostic (cytokeratins) and predictive (PD-L1) testing. These results emphasize the need for adequate fixation of resection specimen.

Peters GJ
From 'Targeted Therapy' to Targeted Therapy.
Anticancer Res. 2019; 39(7):3341-3345 [PubMed] Related Publications
In early 2000, the term 'targeted therapy' became popular and was used to indicate all types of tyrosine kinase inhibitors (TKI). However, the term targeted therapy had been used much earlier. Targeting tumor metabolism was already considered as targeted therapy, with methotrexate and 5-fluorouracil as the most successful examples. Hormone therapy is another successful type of targeted therapy. Imatinib was the first TKI for the fusion protein BCR-ABL and represented a breakthrough in the treatment of chronic myeloid leukemia. Many other TKIs have been introduced into the clinic, but most were less specific and had multiple targets, and therefore, by definition, not targeted. However, with the introduction of TKIs developed specifically against mutations in the active site of a TK, more truly targeted TKI have been approved, such as new anaplastic lymphoma kinase - echinoderm microtubule-associated protein-like 4 (ALK-EML4) inhibitors and the epidermal growth factor-T790M-targeted osimertinib. This article summarizes the content of the Burger-Kelland award lecture given by the Author in February 2019 during the 40th EORTC-PAMM Group meeting in Verona, Italy and reviews the development of various targeted agents.

Tong H, Zhu Y, Liu Y
Incidence and risk of fatigue in cancer patients treated with MET inhibitors: A systematic review and meta-analysis.
Medicine (Baltimore). 2019; 98(22):e15522 [PubMed] Related Publications
BACKGROUND: The N-methyl-N'-nitroso-guanidine human osteosarcoma transforming gene (MET) inhibitors show a surprising survival benefit in the treatment of numerous tumors especially in MET-high tumor. Besides their impressive efficacy, fatigue reduced by MET inhibitors is still the safety issue during treatment. Thus, an understanding of this risk in the context of expanding MET-inhibitors use is an important cost and patient safety issue.
METHODS: We searched PubMed, Embase, and the Cochrane Library databases for relevant studies up to October 2017. Eligibility criteria included phase II/III trials of MET inhibitors that reported adequate safety profiles of fatigue. The principal summary measures were incidence and relative risk (RR) of all-grade (grade 1-4) and high-grade (grade 3-4) fatigue, respectively. Random-effects model was applied to consider within-study and between-study variation.
RESULTS: A total of 5028 patients from 17 clinical trials were identified. The results revealed that the incidences of MET inhibitors-associated all-grade and high-grade fatigue were 41.9% and 9.6%, respectively. The RR of high-grade fatigue was (RR = 1.37; 95% confidence interval, 1.14-1.66; P = .0009), whereas the RR of all-grade fatigue was (RR = 1.02; 95% confidence interval, 0.91-1.15; P = .71).
CONCLUSION: Our meta-analysis has demonstrated that MET inhibitors-based treatment is associated with an increased risk of high-grade fatigue compared with control.

Wu P, Cai J, Chen Q, et al.
Lnc-TALC promotes O
Nat Commun. 2019; 10(1):2045 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules implicated in diverse biological processes, including therapeutic resistance. However, the mechanisms underlying lncRNA-mediated temozolomide (TMZ) resistance in glioblastoma (GBM) remain largely unknown. To illustrate the role of lncRNA in TMZ resistance, we induce TMZ-resistant GBM cells, perform a lncRNA microarray of the parental and TMZ-resistant cells, and find an unreported lncRNA in GBM, lnc-TALC (temozolomide-associated lncRNA in glioblastoma recurrence), correlated with TMZ resistance via competitively binding miR-20b-3p to facilitate c-Met expression. A phosphorylated AKT/FOXO3 axis regulated lnc-TALC expression in TMZ-resistant GBM cells. Furthermore, lnc-TALC increased MGMT expression by mediating the acetylation of H3K9, H3K27 and H3K36 in MGMT promoter regions through the c-Met/Stat3/p300 axis. In clinical patients, lnc-TALC is required for TMZ resistance and GBM recurrence. Our results reveal that lnc-TALC in GBM could serve as a therapeutic target to overcome TMZ resistance, enhancing the clinical benefits of TMZ chemotherapy.

Del Re M, Rofi E, Cappelli C, et al.
The increase in activating EGFR mutation in plasma is an early biomarker to monitor response to osimertinib: a case report.
BMC Cancer. 2019; 19(1):410 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Systemic treatment of advanced non-small cell lung cancer (NSCLC) has changed dramatically since the introduction of targeted therapies. The analysis of circulating tumor DNA (ctDNA) is a valuable approach to monitor the clonal evolution of tumors during treatment with EGFR-tyrosine kinase inhibitors (TKIs) and to detect resistance mutations.
CASE PRESENTATION: A NSCLC patient with exon 19 deletion (ex19del) of EGFR was treated with osimertinib after multiple lines of treatment and obtained a partial response that lasted over 26 months. Blood was collected at each visit and ctDNA was extracted to monitor ex19del by digital droplet PCR. Within a few weeks from the beginning of osimertinib, ex19del disappeared from plasma but appeared again and steadily increased a few months later anticipating tumor progression. Interestingly, the change in ex19del was much more pronounced than other mutations, since T790M appeared 3 months after the increase of ex19del, and C797S was detectable a few weeks before clinical disease progression. Then the patient received cytotoxic chemotherapy, which was associated with a decrease in ex19del and disappearance of T790M and C797S; however, at disease progression, all EGFR mutations increased again in plasma together with MET amplification which was detected by NGS.
CONCLUSIONS: The measurement of ex19del changes in ctDNA is a simple and sensitive approach to monitor clinical outcome to osimertinib and, potentially, to other therapeutic interventions.

Pang HH, Huang CY, Chou YW, et al.
Bioengineering fluorescent virus-like particle/RNAi nanocomplexes act synergistically with temozolomide to eradicate brain tumors.
Nanoscale. 2019; 11(17):8102-8109 [PubMed] Related Publications
The proof-of-concept strategy in this study based on biodegradable and biocompatible self-assembling fluorescent virus-like particle/RNAi nanocomplexes (VLP/RNAi) produced in Escherichia coli (E. coli) followed by surface modification with a cell-penetrating peptide (CPP) and an apolipoprotein E peptide (ApoEP) (dP@VLP/RNAi), which can cross the blood-brain barrier (BBB) to inhibit the DNA repair mechanism and act synergistically with temozolomide (TMZ) for promoting clinical chemotherapy has achieved good therapeutic effects towards malignant brain tumors. The synergistic value of this study's design was verified in intracranial mouse models of glioblastomas (GBMs). Intravenous administration of this formulation enhanced the curative efficacy of TMZ by downregulating the hepatocyte growth factor receptor (c-MET) gene in GBM U87 cells. Furthermore, upon gene-chemotherapy, the methylated DNA in GBM U87 cells was significantly enhanced by inhibiting the DNA repair mechanism, leading to significant brain tumor suppression. The results of this study could be critical for the design of RNAi-based genetic therapeutics for promoting chemotherapy against brain tumors.

Cao H, Xu Z, Wang J, et al.
Functional role of SGK3 in PI3K/Pten driven liver tumor development.
BMC Cancer. 2019; 19(1):343 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer related deaths worldwide. The PI3K cascade is one of the major signaling pathways underlying HCC development and progression. Activating mutations of PI3K catalytic subunit alpha (PIK3CA) and/or loss of Pten often occur in human HCCs. Serum and glucocorticoid kinase 3 (SGK3) belongs to the SGK family of AGK kinases and functions in parallel to AKT downstream of PI3K. Previous studies have shown that SGK3 may be the major kinase responsible for the oncogenic potential of PIK3CA helical domain mutants, such as PIK3CA(E545K), but not kinase domain mutants, such as PIK3CA(H1047R).
METHODS: We investigated the functional contribution of SGK3 in mediating activated PIK3CA mutant or loss of Pten induced HCC development using Sgk3 knockout mice.
RESULTS: We found that ablation of Sgk3 does not affect PIK3CA(H1047R) or PIK3CA(E545K) induced lipogenesis in the liver. Using PIK3CA(H1047R)/c-Met, PIK3CA(E545K)/c-Met, and sgPten/c-Met murine HCC models, we also demonstrated that deletion of Sgk3 moderately delays PIK3CA(E545K)/c-Met driven HCC, while not affecting PIK3CA(H1047R)/c-Met or sgPten/c-Met HCC formation in mice. Similarly, in human HCC cell lines, silencing of SGK3 reduced PIK3CA(E545K) -but not PIK3CA(H1047R)- induced accelerated tumor cell proliferation.
CONCLUSION: Altogether, our data suggest that SGK3 plays a role in transducing helical domain mutant PIK3CA signaling during liver tumor development.

Liu G, Li B
Role of miRNA in transformation from normal tissue to colorectal adenoma and cancer.
J Cancer Res Ther. 2019; 15(2):278-285 [PubMed] Related Publications
Although many modalities can be used to prolong the remission of colorectal cancer (CRC), early diagnosis is essential to improve the therapeutic outcomes. The conventional ways of diagnosing and monitoring the progresses from adenoma to CRC are colonoscopy and fecal occult blood test (FOBT). However, colonoscopy is expensive and invasive; while the FOBT is not sensitive. miRNAs may be a new modality to monitor the transition from adenoma to CRC. We reviewed publications of miRNA profile differences from colorectal normal mucosa (NM) to adenoma, and to CRC and tried to find the roles of miRNA in these transitions. This review also highlighted the possibility of serum miRNAs as markers for monitoring these transitions. The miRNA profiles are different from normal colorectal mucosa to adenoma and to CRC. The miRNAs may have pro- or anti-CRC effects through oncogenes such as c-Met and KRAS. Others may interfere with the immune system. More interestingly, some miRNAs are continuously increased from NM to adenoma and to CRC; others, such as miRNA-30b, are consequently decreased. The literature shows that miRNAs are involved in the whole process of the colorectal carcinogenesis. The miRNAs may be the biomarkers in monitoring the transition from adenoma to CRC.

Kim SS, Eun JW, Cho HJ, et al.
Effect of Fibroblast Growth Factor-2 and its Receptor Gene Polymorphisms on the Survival of Patients With Hepatitis B Virus-associated Hepatocellular Carcinoma.
Anticancer Res. 2019; 39(4):2217-2226 [PubMed] Related Publications
BACKGROUND/AIM: Fibroblast growth factor (FGF), vascular endothelial growth factor, and hepatocyte growth factor play a critical role in the pathogenesis of hepatocellular carcinoma (HCC).
MATERIALS AND METHODS: We assessed nine single nucleotide polymorphisms (SNPs) in the FGF1, FGF2, FGF receptor (FGFR)-2, Flt-1, and c-MET genes in 245 HCC patients and 483 chronic hepatitis B virus (HBV) carriers without HCC.
RESULTS: Kaplan-Meier analysis showed that patients with the FGF2 rs308447 TT genotype had shorter overall survival than patients with the CC or CT genotype (p=0.016) and that FGF2 rs308379 A allele carriers had shorter overall survival than patients with the TT genotype (p=0.020).
CONCLUSION: Multivariate Cox proportional analysis revealed that the FGF2 rs308379 A allele (hazard ratio(HR)=1.663, p=0.004) and advanced tumor stage (HR=3.430, p<0.001) were independent prognostic factors for overall survival in patients with HCC.

Franses JW, Zhu AX
Has PD-1 MET Its Match in Hepatocellular Carcinoma?
Gastroenterology. 2019; 156(6):1563-1565 [PubMed] Related Publications

Casaletto JB, Geddie ML, Abu-Yousif AO, et al.
MM-131, a bispecific anti-Met/EpCAM mAb, inhibits HGF-dependent and HGF-independent Met signaling through concurrent binding to EpCAM.
Proc Natl Acad Sci U S A. 2019; 116(15):7533-7542 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as

Yu G, Wang Z, Zeng S, et al.
Paeoniflorin Inhibits Hepatocyte Growth Factor- (HGF-) Induced Migration and Invasion and Actin Rearrangement via Suppression of c-Met-Mediated RhoA/ROCK Signaling in Glioblastoma.
Biomed Res Int. 2019; 2019:9053295 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
Paeoniflorin (PF), as one of the important valid natural compounds of the total glucosides of peony, has displayed a potential effect in cancer prevention and treatment. Aggressive migration and invasion, as an important process, can contribute to tumor progression through infiltrating the surround normal tissue. Actin cytoskeleton rearrangement plays a key role in cells migration and invasion, involving multiple signal pathways. HGF/c-Met signal, as an important couple of oncoprotein, has been demonstrated to regulate actin cytoskeleton rearrangement. In our study, we aim to explore whether paeoniflorin can inhibit migration and invasion and actin cytoskeleton rearrangement via regulation of HGF/c-Met/RhoA/ROCK signal. Various approaches were applied to demonstrate the mechanism of paeoniflorin-mediated anticancer effect, including cell wound healing assay, invasion assay, immunofluorescence staining and transfection, and western blotting. We observed that paeoniflorin inhibited HGF-induced migration and invasion and actin cytoskeleton rearrangement in glioblastoma cells. Furthermore, the inhibition of HGF-induced migration and invasion and actin cytoskeleton rearrangement involved c-Met-mediated RhoA/ROCK signaling in glioblastoma. Thus, our study proved that paeoniflorin could inhibit migration and invasion and actin cytoskeleton rearrangement through inhibition of HGF/c-Met/RhoA/ROCK signaling in glioblastoma, suggesting that paeoniflorin might be a candidate compound to treat glioblastoma.

Luo T, Zhang SG, Zhu LF, et al.
A selective c-Met and Trks inhibitor Indo5 suppresses hepatocellular carcinoma growth.
J Exp Clin Cancer Res. 2019; 38(1):130 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
BACKGROUND: Human hepatocellular carcinoma (HCC) lacks effective curative therapy and there is an urgent need to develop a novel molecular-targeted therapy for HCC. Selective tyrosine kinase inhibitors have shown promise in treating cancers including HCC. Tyrosine kinases c-Met and Trks are potential therapeutic targets of HCC and strategies to interrupt c-Met and Trks cross-signaling may result in increased effects on HCC inhibition.
METHODS: The effects of Indo5 on c-Met and Trks activity were determined with in vitro kinase activity assay, cell-based signaling pathway activation, and kinases-driven cell transformation. The in vivo anti-tumor activity was determined with xenograft mice and liver orthotopic mice models. The co-expression of c-Met and TrkB in 180 pairs of HCC and adjacent normal tissues were detected using immunohistochemical staining.
RESULTS: Indo5, a novel lead compound displayed biochemical potency against both c-Met and Trks with selectivity over 13 human kinases. Indo5 abrogated HGF-induced c-Met signaling activation and BDNF/NGF-induced Trks signal activation, c-Met or TrkB-mediated cell transformation and migration. Furthermore, Indo5 significantly decreased the growth of HCC cells in xenograft mice and improved the survival of mice with liver orthotopic tumors. In addition, co-expression of c-Met and TrkB in HCC patients was a predictor of poor prognosis, and combined inhibition of c-Met and TrkB exerted a synergistic suppressive effect on HCC.
CONCLUSIONS: These findings indicate that Indo5 is associated with marked suppression of c-Met and Trks co-expressing HCC, supporting its clinical development as an antitumor treatment for HCC patients with co-active c-Met and Trks signaling.

Wang Y, Jiang Z, Xu C, et al.
Increased MET gene copy number negatively affects the survival of esophageal squamous cell carcinoma patients.
BMC Cancer. 2019; 19(1):240 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
BACKGROUNDS: Since Mesenchymal epithelial transition (MET) amplification has been regarded as a potential treatment target, the knowledge of its prevalence and prognostic importance is crucial. However, its clinical pathologic characteristics are not well known in esophageal squamous cell carcinoma (ESCC).
METHODS: We investigated MET gene status with fluorescence in situ hybridization (FISH) assay in 495 ESCC cases using tissue microarrays. Prognostic significance as well as correlations with various clinicopathological parameters was evaluated.
RESULTS: Among 495 patients, 28 (5.7%) cases were MET FISH positive, including 5 cases (1%) with true gene amplification. There were no statistically significant associations between MET FISH-positivity and clinicopathologic characteristics. A significantly poorer prognosis was observed in 28 patients with MET FISH-positivity (disease free survival/DFS, P < 0.001 and overall survival/OS, P = 0.001). Multivariate analysis revealed MET FISH-positivity was an independent prognostic factor for DFS (hazard ratio/HR, 1.953; 95% confidence interval/CI, 1.271-2.999; P = 0.002) and OS (HR, 1.926; 95% CI, 1.243-2.983; P = 0.003). MET FISH-positivity was associated with DFS (P = 0.022 and 0.020) and OS (P = 0.046 and 0.024) both in stage I-II ESCC and in stage III-IVa ESCC. No statistical significance (DFS, P = 0.492 and OS, P = 0.344) was detected between stage I-II ESCC with MET FISH-positivity and stage III-IVa ESCC with FISH-negativity.
CONCLUSIONS: Increased MET gene copy number is an independent prognostic factor in ESCC, and ESCC might have potentially been up-staged by increased MET gene copy number. The results indicate that increased MET gene copy number is a very promising parameter, in clinical therapy and follow-up plans.

Liu Z, Jiang L, Li Y, et al.
Cyclosporine A sensitizes lung cancer cells to crizotinib through inhibition of the Ca2
EBioMedicine. 2019; 42:326-339 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
BACKGROUND: Crizotinib has potent anti-tumor activity in patients with advanced MET-amplified non-small cell lung cancer (NSCLC). However, the therapeutic effect is still not satisfying. Thus, developing approaches that improve the efficacy of crizotinib remains a significant challenge.
METHODS: MET-amplified NSCLC cell lines were treated with crizotinib and cyclosporine A (CsA). Cell viability was determined by MTS assay. The changes of apoptosis, cell cycle and calcineurin-Erk pathways were assessed by western blot. Xenograft mouse model, primary human NSCLC cells and hollow fiber assays were utilized to confirm the effects of CsA.
FINDINGS: We demonstrated that CsA significantly increased the anti-tumor effect of crizotinib on multiple MET-amplified NSCLC cells in vitro and in vivo. Mechanistically, crizotinib treatment led to the activation of Ca
INTERPRETATION: This study provides preclinical evidences that combination therapy of CsA and crizotinib is a promising approach for targeted treatment of MET-amplified lung cancer patients. FUND: This work was supported by the National Natural Science Foundation of China, the Key Projects of Natural Foundation of Zhejiang Province, the Ten thousand plan youth talent support program of Zhejiang Province, the Zhejiang Natural Sciences Foundation Grant, and the Zhejiang medical innovative discipline construction project-2016.

Sohn SH, Kim B, Sul HJ, et al.
INC280 inhibits Wnt/β-catenin and EMT signaling pathways and its induce apoptosis in diffuse gastric cancer positive for c-MET amplification.
BMC Res Notes. 2019; 12(1):125 [PubMed] Article available free on PMC after 21/09/2019 Related Publications
OBJECTIVE: Gastric cancer is more open related to genetic predisposition. In our RNA sequencing study on gastric cancer patients, Runt-related transcription factor-3 (RUNX3) expression was significantly down-regulated in gastric cancer. We showed that decreased levels of RUNX3 are significantly associated with c-MET (r = - 0.4216, P = 0.0130). In addition, c-MET expression is a candidate for targeted therapy in gastric cancer. Therefore, in the present study, the anti-cancer effects of the c-MET inhibitor on gastric cancer cells from positive or negative for c-MET amplification were evaluated.
RESULTS: INC280 treatment inhibits growth of a c-MET-amplified MKN45 (RUNX3-positive) and SNU620 (RUNX3-negative) diffuse type cells. Then, INC280 showed the highest inhibition and apoptotic rates with the lowest IC

Liu F, Cox CD, Chowdhury R, et al.
SPINT2 is hypermethylated in both IDH1 mutated and wild-type glioblastomas, and exerts tumor suppression via reduction of c-Met activation.
J Neurooncol. 2019; 142(3):423-434 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
PURPOSE: Both IDH1-mutated and wild-type gliomas abundantly display aberrant CpG island hypermethylation. However, the potential role of hypermethylation in promoting gliomas, especially the most aggressive form, glioblastoma (GBM), remains poorly understood.
METHODS: We analyzed RRBS-generated methylation profiles for 11 IDH1
RESULTS: We identified SPINT2 as a candidate tumor-suppressor gene within a group of CpG islands (designated G
CONCLUSIONS: We defined a previously under-recognized group of coordinately methylated CpG islands common to both IDH1

Kinslechner K, Schütz B, Pistek M, et al.
Loss of SR-BI Down-Regulates MITF and Suppresses Extracellular Vesicle Release in Human Melanoma.
Int J Mol Sci. 2019; 20(5) [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Melanoma is a skin tumor with a high tendency for metastasis and thus is one of the deadliest cancers worldwide. Here, we investigated the expression of the scavenger receptor class B type 1 (SR-BI), a high-density lipoprotein (HDL) receptor, and tested for its role in melanoma pigmentation as well as extracellular vesicle release. We first analyzed the expression of

Labib PL, Goodchild G, Pereira SP
Molecular Pathogenesis of Cholangiocarcinoma.
BMC Cancer. 2019; 19(1):185 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Cholangiocarcinomas are a heterogeneous group of malignancies arising from a number of cells of origin along the biliary tree. Although most cases in Western countries are sporadic, large population-based studies have identified a number of risk factors. This review summarises the evidence behind reported risk factors and current understanding of the molecular pathogenesis of cholangiocarcinoma, with a focus on inflammation and cholestasis as the driving forces in cholangiocarcinoma development.
RISK FACTORS FOR CHOLANGIOCARCINOGENESIS: Cholestatic liver diseases (e.g. primary sclerosing cholangitis and fibropolycystic liver diseases), liver cirrhosis, and biliary stone disease all increase the risk of cholangiocarcinoma. Certain bacterial, viral or parasitic infections such as hepatitis B and C and liver flukes also increase cholangiocarcinoma risk. Other risk factors include inflammatory disorders (such as inflammatory bowel disease and chronic pancreatitis), toxins (e.g. alcohol and tobacco), metabolic conditions (diabetes, obesity and non-alcoholic fatty liver disease) and a number of genetic disorders.
MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA: Regardless of aetiology, most risk factors cause chronic inflammation or cholestasis. Chronic inflammation leads to increased exposure of cholangiocytes to the inflammatory mediators interleukin-6, Tumour Necrosis Factor-ɑ, Cyclo-oxygenase-2 and Wnt, resulting in progressive mutations in tumour suppressor genes, proto-oncogenes and DNA mismatch-repair genes. Accumulating bile acids from cholestasis lead to reduced pH, increased apoptosis and activation of ERK1/2, Akt and NF-κB pathways that encourage cell proliferation, migration and survival. Other mediators upregulated in cholangiocarcinoma include Transforming Growth Factor-β, Vascular Endothelial Growth Factor, Hepatocyte Growth Factor and several microRNAs. Increased expression of the cell surface receptor c-Met, the glucose transporter GLUT-1 and the sodium iodide symporter lead to tumour growth, angiogenesis and cell migration. Stromal changes are also observed, resulting in alterations to the extracellular matrix composition and recruitment of fibroblasts and macrophages that create a microenvironment promoting cell survival, invasion and metastasis.
CONCLUSION: Regardless of aetiology, most risk factors for cholangiocarcinoma cause chronic inflammation and/or cholestasis, leading to the activation of common intracellular pathways that result in reactive cell proliferation, genetic/epigenetic mutations and cholangiocarcinogenesis. An understanding of the molecular pathogenesis of cholangiocarcinoma is vital when developing new diagnostic biomarkers and targeted therapies for this disease.

Wang Y, Tai Q, Zhang J, et al.
MiRNA-206 inhibits hepatocellular carcinoma cell proliferation and migration but promotes apoptosis by modulating cMET expression.
Acta Biochim Biophys Sin (Shanghai). 2019; 51(3):243-253 [PubMed] Related Publications
A close relationship between cancer progression and microRNAs (miRNAs) regulation has been demonstrated. Abnormal microRNA-206 (miR-206) expression has been shown to be related to the development of malignancies. However, the role of miR-206 in hepatocellular carcinoma (HCC) remains unclear. Here, we evaluated the function of miR-206 in HCC. Results showed that miR-206 expression was decreased in 27 human HCC tissues compared with that of adjacent normal tissues. Conversely, cMET was up-regulated in human HCC cancer tissues, and cMET levels were shown to be negatively correlated with miR-206 expression. Abnormally increased miR-206 expression in three HCC cell lines (SMMC-7721, HepG2, and Huh7) attenuated cell viability, migration, and invasion. Increased apoptosis was also observed in these miR-206 expressing cells. Furthermore, we identified that miR-206 targets the 3'-UTR of the cMET gene for silencing, and restoration of cMET expression reversed the inhibitory effect of miR-206 on HCC. Tumor cells expressing miR-206 also showed delayed growth in the in vivo experiments compared with the controls. Altogether, our findings provide new insights into the molecular mechanisms of HCC oncogenesis.

Sun Z, Zhang T, Chen B
Long Non-Coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) Promotes Proliferation and Metastasis of Osteosarcoma Cells by Targeting c-Met and SOX4 via miR-34a/c-5p and miR-449a/b.
Med Sci Monit. 2019; 25:1410-1422 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a functional long non-coding RNA involved in many biologic processes. The study was aimed to explore the functional roles of MALAT1 in osteosarcoma progression. MATERIAL AND METHODS A total of 76 osteosarcoma tissues and paired adjacent non-tumor tissues were collected from surgical resection. MALAT1, miRNAs, and genes mRNA expression levels were detected using quantitative real-time PCR (qRT-PCR). Protein expression level, cell proliferation, migration, and invasion were assessed using western blot, Cell Counting Kit-8 (CCK-8), wound-healing assay, and Matrigel invasion assay respectively. The target relationships among miRNAs, MALAT1, and mRNA were detected via dual-luciferase reporter assay. RESULTS We found that MALAT1 was frequently upregulated in osteosarcoma samples and cell lines and a high level of MALAT1 predicted poor overall survival in osteosarcoma patients. Knockdown of MALAT1 inhibited proliferation, migration, and invasion of osteosarcoma cells. Further study showed a positive correlation between MALAT1 and c-Met or SOX4 expression. Mechanistic investigations demonstrated that MALAT1, as a competing endogenous RNA (ceRNA), regulated osteosarcoma proliferation and metastasis through competitively binding to miR-34a/c-5p and miR-449a/b. CONCLUSIONS Taken together, our study illustrates a new regulatory mechanism for MALAT1 and may provide a novel therapeutic strategy for the treatment of osteosarcoma.

Huang WC, Jang TH, Tung SL, et al.
A novel miR-365-3p/EHF/keratin 16 axis promotes oral squamous cell carcinoma metastasis, cancer stemness and drug resistance via enhancing β5-integrin/c-met signaling pathway.
J Exp Clin Cancer Res. 2019; 38(1):89 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Targeting the c-Met signaling pathway has become a therapeutic strategy in multiple types of cancer. We unveiled a novel c-Met regulating mechanism that could be applied as a modality for oral squamous cell carcinoma (OSCC) therapy.
METHODS: Upregulation of keratin 16 (KRT16) was found by comparing isogenic pairs of low and high invasive human OSCC lines via microarray analysis. OSCC cells with ectopic expression or silencing of KRT16 were used to scrutinize functional roles and associated molecular mechanisms.
RESULTS: We observed that high KRT16 expression significantly correlated with poorer pathological differentiation, advanced stages, increased lymph nodes metastasis, and decreased survival rate from several Taiwanese OSCC patient cohorts. We further revealed that miR-365-3p could target ETS homologous factor (EHF), a KRT16 transcription factor, to decrease migration, invasion, metastasis and chemoresistance in OSCC cells via inhibition of KRT16. Under confocal microscopic examination, c-Met was found possibly partially associates with KRT16 through β5-integrin. Colocalization of these three proteins may facilitate c-Met and β5-integrin-mediated signaling in OSCC cells. Depletion of KRT16 led to increased protein degradation of β5-integrin and c-Met through a lysosomal pathway leading to inhibition of their downstream Src/STAT3/FAK/ERK signaling in OSCC cells. Knockdown of KRT16 enhanced chemosensitivity of OSCC towards 5-fluorouracil (5-FU). Various combination of c-Met inhibitor (foretinib), protein tyrosine kinase inhibitor (genistein), β5-integrin antibody, and 5-FU markedly augmented cytotoxic effects in OSCC cells as well as tumor killing effects in vitro and in vivo.
CONCLUSIONS: Our data indicate that targeting a novel miR-365-3p/EHF/KRT16/β5-integrin/c-Met signaling pathway could improve treatment efficacy in OSCC.

Siddique AB, Ebrahim HY, Akl MR, et al.
(-)-Oleocanthal Combined with Lapatinib Treatment Synergized against HER-2 Positive Breast Cancer In Vitro and In Vivo.
Nutrients. 2019; 11(2) [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Dysregulation of epidermal growth factor receptor (EGFR)/human epidermal growth factor-2 (HER2) family is a hallmark of aggressive breast cancer. Small-molecule tyrosine kinase inhibitors are among the most effective cancer targeted treatments. (-)-Oleocanthal (OC) is a naturally occurring phenolic secoiridoid lead from extra-virgin olive oil with documented anti-cancer activities via targeting mesenchymal epithelial transition factor (c-Met). Dysregulation of c-Met promotes aggressiveness to breast cancer-targeted therapies. Lapatinib (LP) is an FDA-approved dual EGFR/HER2 inhibitor for HER2-amplified breast cancer. HER2-Positive tumor cells can escape targeted therapies like LP effects by overexpressing c-Met. Combined OC-LP treatment is hypothesized to be mechanistically synergistic against HER2-overexpressing breast cancer. Combined sub-effective treatments of OC-LP resulted in synergistic anti-proliferative effects against the HER2-positive BT-474 and SK-BR-3 breast cancer cell lines, compared to OC or LP monotherapy. Antibody array and Western blot analysis showed that combined OC-LP treatment significantly inhibited EGFR, HER2, and c-Met receptor activation, as well as multiple downstream signaling proteins, compared to individual OC or LP treatment. OC-LP Combination significantly inhibited invasion and migration of breast cancer cells through reduced activation of focal adhesion kinase (FAK) and paxillin. Combined treatment of OC-10 mg/kg with LP-12.5 mg/kg suppressed more than 90% of BT-474 tumor cells growth in a nude mouse xenograft model, compared to individual OC or LP treatment. Activated c-Met, EGFR, HER2, and protein kinase B (AKT) were significantly suppressed in combination-treated mice tumors, compared to OC or LP monotherapy. This study reveals the OC future potential as combination therapy to sensitize HER2-overexpressing breast cancers and significantly reduce required doses of targeted HER family therapeutics.

(Not Giving Up) The Marathon Race of MET Targeting Therapy: Are We There Yet?
Clin Cancer Res. 2019; 25(8):2375-2378 [PubMed] Article available free on PMC after 15/04/2020 Related Publications
Among the various

Athauda A, Chau I
Do investigational MET inhibitors have potential for the treatment of gastric cancer?
Expert Opin Investig Drugs. 2019; 28(4):299-302 [PubMed] Related Publications

Teufel M, Seidel H, Köchert K, et al.
Biomarkers Associated With Response to Regorafenib in Patients With Hepatocellular Carcinoma.
Gastroenterology. 2019; 156(6):1731-1741 [PubMed] Related Publications
BACKGROUND & AIMS: In a phase 3 trial (RESORCE), regorafenib increased overall survival compared with placebo in patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. In an exploratory study, we analyzed plasma and tumor samples from study participants to identify genetic, microRNA (miRNA), and protein biomarkers associated with response to regorafenib.
METHODS: We obtained archived tumor tissues and baseline plasma samples from patients with HCC given regorafenib in the RESORCE trial. Baseline plasma samples from 499 patients were analyzed for expression of 294 proteins (DiscoveryMAP) and plasma samples from 349 patients were analyzed for levels of 750 miRNAs (miRCURY miRNA PCR). Tumor tissues from 7 responders and 10 patients who did not respond (progressors) were analyzed by next-generation sequencing (FoundationOne). Forty-six tumor tissues were analyzed for expression patterns of 770 genes involved in oncogenic and inflammatory pathways (PanCancer Immune Profiling). Associations between plasma levels of proteins and miRNAs and response to treatment (overall survival and time to progression) were evaluated using a Cox proportional hazards model.
RESULTS: Decreased baseline plasma concentrations of 5 of 266 evaluable proteins (angiopoietin 1, cystatin B, the latency-associated peptide of transforming growth factor beta 1, oxidized low-density lipoprotein receptor 1, and C-C motif chemokine ligand 3; adjusted P ≤ .05) were significantly associated with increased overall survival time after regorafenib treatment. Levels of these 5 proteins, which have roles in inflammation and/or HCC pathogenesis, were not associated with survival independently of treatment. Only 20 of 499 patients had high levels and a reduced survival time. Plasma levels of α-fetoprotein and c-MET were associated with poor outcome (overall survival) independently of regorafenib treatment only. We identified 9 plasma miRNAs (MIR30A, MIR122, MIR125B, MIR200A, MIR374B, MIR15B, MIR107, MIR320, and MIR645) whose levels significantly associated with overall survival time with regorafenib (adjusted P ≤ .05). Functional analyses of these miRNAs indicated that their expression level associated with increased overall survival of patients with tumors of the Hoshida S3 subtype. Next-generation sequencing analyses of tumor tissues revealed 49 variants in 27 oncogenes or tumor suppressor genes. Mutations in CTNNB1 were detected in 3 of 10 progressors and VEGFA amplification in 1 of 7 responders.
CONCLUSION: We identified expression patterns of plasma proteins and miRNAs that associated with increased overall survival times of patients with HCC following treatment with regorafenib in the RESORCE trial. Levels of these circulating biomarkers and genetic features of tumors might be used to identify patients with HCC most likely to respond to regorafenib. number NCT01774344. NCBI GEO accession numbers: mRNA data (NanoString): GSE119220; miRNA data (Exiqon): GSE119221.

Furuse M, Nonoguchi N, Yamada K, et al.
Radiological diagnosis of brain radiation necrosis after cranial irradiation for brain tumor: a systematic review.
Radiat Oncol. 2019; 14(1):28 [PubMed] Article available free on PMC after 15/04/2020 Related Publications
INTRODUCTION: This systematic review aims to elucidate the diagnostic accuracy of radiological examinations to distinguish between brain radiation necrosis (BRN) and tumor progression (TP).
METHODS: We divided diagnostic approaches into two categories as follows-conventional radiological imaging [computed tomography (CT) and magnetic resonance imaging (MRI): review question (RQ) 1] and nuclear medicine studies [single photon emission CT (SPECT) and positron emission tomography (PET): RQ2]-and queried. Our librarians conducted a comprehensive systematic search on PubMed, the Cochrane Library, and the Japan Medical Abstracts Society up to March 2015. We estimated summary statistics using the bivariate random effects model and performed subanalysis by dividing into tumor types-gliomas and metastatic brain tumors.
RESULTS: Of 188 and 239 records extracted from the database, we included 20 and 26 studies in the analysis for RQ1 and RQ2, respectively. In RQ1, we used gadolinium (Gd)-enhanced MRI, diffusion-weighted image, MR spectroscopy, and perfusion CT/MRI to diagnose BRN in RQ1. In RQ2,
CONCLUSIONS: Differentiating BRN from TP using Gd-enhanced MRI and

Hoffman RM
Is the Hoffman Effect for Methionine Overuse Analogous to the Warburg Effect for Glucose Overuse in Cancer?
Methods Mol Biol. 2019; 1866:273-278 [PubMed] Related Publications
The general cancer-specific metabolic defect of methionine (MET) dependence is due to MET overuse for aberrant transmethylation reactions. The excess use of MET for aberrant transmethylation reactions apparently diverts methyl groups from DNA. The resulting global DNA hypomethylation is also a general phenomenon in cancer and leads to unstable genomes and aneuploid karyotypes. The excessive and aberrant use of MET in cancer is readily observed in [

Hoffman RM
Methods Mol Biol. 2019; 1866:267-271 [PubMed] Related Publications
Methionine (MET) dependence is a cancer-specific metabolic abnormality that is due to MET overuse for aberrant transmethylation reactions. [

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