Two-Chains Tissue Plasminogen Activator Unifies Met and NMDA Receptor Signalling to Control Neuronal Survival.

Tissue-type plasminogen activator (tPA) plays roles in the development and the plasticity of the nervous system. Here, we demonstrate in neurons, that by opposition to the single chain form (sc-tPA), the two-chains form of tPA (tc-tPA) activates the MET receptor, leading to the recruitment of N-Methyl-d-Aspartate receptors (NMDARs) and to the endocytosis and proteasome-dependent degradation of NMDARs containing the GluN2B subunit. Accordingly, tc-tPA down-regulated GluN2B-NMDAR-driven signalling, a process prevented by blockers of HGFR/MET and mimicked by its agonists, leading to a modulation of neuronal death. Thus, our present study unmasks a new mechanism of action of tPA, with its two-chains form mediating a crosstalk between MET and the GluN2B subunit of NMDARs to control neuronal survival.

Overcoming resistance to targeted therapy using MET inhibitors in solid cancers: evidence from preclinical and clinical studies.

Targeted therapy is a hallmark of cancer treatment that has changed the landscape of cancer management and enabled a personalized treatment approach. Nevertheless, the development of cancer resistance is a major challenge that is currently threatening the effective utilization of targeted therapies. The hepatocyte growth factor receptor, MET, is a receptor tyrosine kinase known for its oncogenic activity and tumorigenic potential. MET is a well-known driver of cancer resistance. A growing body of evidence revealed a major role of MET in mediating acquired resistance to several classes of targeted therapies. Deregulations of MET commonly associated with the development of cancer resistance include gene amplification, overexpression, autocrine activation, and crosstalk with other signaling pathways. Small-molecule tyrosine kinase inhibitors of MET are currently approved for the treatment of different solid cancers. This review summarizes the current evidence regarding MET-mediated cancer resistance toward targeted therapies. The molecular mechanisms associated with resistance are described along with findings from preclinical and clinical studies on using MET inhibitors to restore the anticancer activity of targeted therapies for the treatment of solid tumors.

Organ-specific cholesterol metabolic aberration fuels liver metastasis of colorectal cancer.

Rationale: Metastasis, the development of secondary malignant growth at a distance from a primary tumor, is the main cause of cancer-associated death. However, little is known about how metastatic cancer cells adapt to and colonize in the new organ environment. Here we sought to investigate the functional mechanism of cholesterol metabolic aberration in colorectal carcinoma (CRC) liver metastasis. Methods: The expression of cholesterol metabolism-related genes in primary colorectal tumors (PT) and paired liver metastases (LM) were examined by RT-PCR. The role of SREBP2-dependent cholesterol biosynthesis pathway in cell growth and CRC liver metastasis were determined by SREBP2 silencing in CRC cell lines and experimental metastasis models including, intra-splenic injection models and liver orthotropic injection model. Growth factors treatment and co-culture experiment were performed to reveal the mechanism underlying the up-regulation of SREBP2 in CRC liver metastases. The in vivo efficacy of inhibition of cholesterol biosynthesis pathway by betulin or simvastatin were evaluated in experimental metastasis models. Results: In the present study, we identify a colorectal cancer (CRC) liver metastasis-specific cholesterol metabolic pathway involving the activation of SREBP2-dependent cholesterol biosynthesis, which is required for the colonization and growth of metastatic CRC cells in the liver. Inhibiting this cholesterol biosynthesis pathway suppresses CRC liver metastasis. Mechanically, hepatocyte growth factor (HGF) from liver environment activates SREBP2-dependent cholesterol biosynthesis pathway by activating c-Met/PI3K/AKT/mTOR axis in CRC cells. Conclusion: Our findings support the notion that CRC liver metastases show a specific cholesterol metabolic aberration. Targeting this cholesterol biosynthesis pathway could be a promising treatment for CRC liver metastasis.

HGF/c-Met regulates p22phox subunit of the NADPH oxidase complex in primary mouse hepatocytes by transcriptional and post-translational mechanisms.

INTRODUCTION AND OBJECTIVES: It is well-known that signaling mediated by the hepatocyte growth factor (HGF) and its receptor c-Met in the liver is involved in the control of cellular redox status and oxidative stress, particularly through its ability to induce hepatoprotective gene expression by activating survival pathways in hepatocytes. It has been reported that HGF can regulate the expression of some members of the NADPH oxidase family in liver cells, particularly the catalytic subunits and p22phox. In the present work we were focused to characterize the mechanism of regulation of p22phox by HGF and its receptor c-Met in primary mouse hepatocytes as a key determinant for cellular redox regulation. MATERIALS AND METHODS: Primary mouse hepatocytes were treated with HGF (50 ng/mL) at different times. cyba expression (gene encoding p22phox) or protein content were addressed by real time RT-PCR, Western blot or immunofluorescence. Protein interactions were explored by immunoprecipitation and FRET analysis. RESULTS: Our results provided mechanistic information supporting the transcriptional repression of cyba induced by HGF in a mechanism dependent of NF-κB activity. We identified a post-translational regulation mechanism directed by p22phox degradation by proteasome 26S, and a second mechanism mediated by p22phox sequestration by c-Met in plasma membrane. CONCLUSION: Our data clearly show that HGF/c-Met exerts regulation of the NADPH oxidase by a wide-range of molecular mechanisms. NADPH oxidase-derived reactive oxygen species regulated by HGF/c-Met represents one of the main mechanisms of signal transduction elicited by this growth factor.

MicroRNA­34b expression enhances chemosensitivity of endometrial cancer cells to paclitaxel.

Aberrant DNA methylation is widely observed in various types of cancer, and expression of microRNAs (miRNAs/miRs) is suppressed by DNA methylation. The present study explored tumor suppressor miRNAs downregulated by DNA methylation in endometrial cancer cells, as the basis of a novel therapeutic approach for endometrial cancer. Among 821 candidate miRNAs, miR­34b was identified as an upregulated miRNA after demethylation treatment in all four endometrial cancer cell lines (HEC­108, SNG­II, Ishikawa and HHUA) examined. miR­34b expression with or without demethylation treatment in cancer cells was confirmed by TaqMan quantitative PCR. MYC and MET, the predicted target genes of miR­34b, were downregulated at both the RNA and protein levels following miR­34b overexpression. Following miR­34b treatment, inhibition of cell growth and invasion, and cell cycle arrest were observed in HEC­108 cells. Sensitivity to paclitaxel was increased in cancer cells with miR­34b overexpression, compared with untreated cancer cells, but this difference was not identified for cisplatin or doxorubicin. In vivo, combination treatment with miR­34b and paclitaxel markedly reduced tumor growth compared with treatment with negative control miRNA and paclitaxel. These data suggest that miR­34b enhances paclitaxel sensitivity in endometrial cancer cells, and that miR­34b and MET are key targets for treatment of endometrial cancer. The present results may contribute to the development of combination treatment with a demethylation agent, miR­34b mimic or MET inhibitor and an anticancer drug.

c-Met/MAPK pathway promotes the malignant progression of residual hepatocellular carcinoma cells after insufficient radiofrequency ablation.

Radiofrequency ablation (RFA) is popularly used in the treatment of hepatocellular carcinoma (HCC). However, the accelerated malignant progression of residual HCC cells after RFA is the main obstacle for the application of this technology in HCC treatment. In the present study, HepG2 cells, an established human HCC cell line, experienced repeatedly with heat treatment, survived cells, HepG2-H cells, were used to simulate residual HCC cells after RFA. The abilities of proliferation, colony formation, and migration were compared between HepG2 and HepG2-H cells. Then, RNA sequencing was used to explore the difference in genes expression between two groups of cells. Subsequently, the level of c-Met, one of membranous receptors of MAPK signal pathway, was measured by RT-qPCR and western blot; the effect of c-Met inhibition on the malignant progression of HepG2-H cells was evaluated. The results showed that HepG2-H cells exhibited higher abilities in the proliferation, colony formation, and migration than that of HepG2 cells. Moreover, differentially expressed genes between two groups of cells were prominently enriched in MAPK signal pathway. The level of c-Met in HepG2-H cells was significantly higher than that in HepG2 cells, and the inhibition in the activity of c-Met could repress the malignant behaviors of HepG2-H cells. These results indicated that the accelerated malignant progression of residual HCC cells after RFA can be partly attributed to the overexpression of c-Met and the activation of MAPK signal pathway. Therefore, we proposed that RFA followed by c-Met inhibitor intake maybe is a better treatment protocol for HCC.

HGF-MET Signaling Shifts M1 Macrophages Toward an M2-Like Phenotype Through PI3K-Mediated Induction of Arginase-1 Expression.

Backgrounds and Aims: Hepatocyte Growth Factor (HGF)-MET signaling is known to promote biological functions such as cell survival, cell motility, and cell proliferation. However, it is unknown if HGF-MET alters the macrophage phenotype. In this study, we aimed to study the effects of HGF-MET signaling on the M1 macrophage phenotype. Methods and Materials: Bone marrow-derived macrophages (BMDMs) isolated from mice were either polarized to an M1 phenotype by IFN-γ and LPS treatment or to an M2 phenotype by IL-4 treatment. Changes in M1 or M2 markers induced by HGF-MET signaling were evaluated. Mechanisms responsible for alternations in the macrophage phenotype and intracellular metabolism were analyzed. Results: c-Met was expressed especially in M1 macrophages polarized by treatment with IFN-γ and LPS. In M1 macrophages, HGF-MET signaling induced the expression of Arg-1 mRNA and secretion of IL-10 and TGF-ß1 and downregulated the mRNA expression of iNOS, TNF-α, and IL-6. In addition, activation of the PI3K pathway and inactivation of NFκB were also observed in M1 macrophages treated with HGF. The increased Arg-1 expression and IL-10 secretion were abrogated by PI3K inhibition, whereas, no changes were observed in TNF-α and IL-6 expression. The inactivation of NFκB was found to be independent of the PI3K pathway. HGF-MET signaling shifted the M1 macrophages to an M2-like phenotype, mainly through PI3K-mediated induction of Arg-1 expression. Finally, HGF-MET signaling also shifted the M1 macrophage intracellular metabolism toward an M2 phenotype, especially with respect to fatty acid metabolism. Conclusion: Our results suggested that HGF treatment not only promotes regeneration in epithelial cells, but also leads to tissue repair by altering M1 macrophages to an M2-like phenotype.

Control of cell death/survival balance by the MET dependence receptor.

Control of cell death/survival balance is an important feature to maintain tissue homeostasis. Dependence receptors are able to induce either survival or cell death in presence or absence of their ligand, respectively. However, their precise mechanism of action and their physiological importance are still elusive for most of them including the MET receptor. We evidence that pro-apoptotic fragment generated by caspase cleavage of MET localizes to the mitochondria-associated membrane region. This fragment triggers a calcium transfer from endoplasmic reticulum to mitochondria, which is instrumental for the apoptotic action of the receptor. Knock-in mice bearing a mutation of MET caspase cleavage site highlighted that p40MET production is important for FAS-driven hepatocyte apoptosis, and demonstrate that MET acts as a dependence receptor in vivo. Our data shed light on new signaling mechanisms for dependence receptors' control of cell survival/death balance, which may offer new clues for the pathophysiology of epithelial structures.

Tivantinib Hampers the Proliferation of Glioblastoma Cells via PI3K/Akt/Mammalian Target of Rapamycin (mTOR) Signaling.

BACKGROUND Glioblastoma, the most common and malignant glial tumor, often has poor prognosis. Tivantinib has shown its potential in treating c-Met-high carcinoma. No studies have explored whether tivantinib inhibits the development of glioblastoma. MATERIAL AND METHODS The correlation between c-Met expression and clinicopathological characteristics of glioblastoma was investigated. U251 and T98MG glioblastoma cells treated with tivantinib, PI3K inhibitor (LY294002), PI3K activator (740 Y-P), and/or mammalian target of rapamycin (mTOR) inhibitor were subjected to MTT assay or colony formation assay to evaluate cell proliferation. The expression of mTOR signaling and caspase-3 in tivantinib-treated glioblastoma cells was differentially measured by western blotting. RESULTS In a group of Chinese patients, expression of c-Met was elevated with the size of glioblastoma, but not with the other clinicopathological characteristics, including gender, age, grade, IDH status, 1p/19q status, and Ki67 status. High dose of tivantinib (1 µmol/L) obviously repressed the proliferation and colony formation of U251 and T98MG glioblastoma cells, but low dose (0.1 µmol/L) of tivantinib failed to retard cell proliferation. Tivantinib blocked PI3K/Akt/mTOR signaling but did not change the expression of cleaved caspase-3. PI3K activator 740 Y-P (20 µmol/L) significantly rescued tivantinib-induced decrease of cell proliferation. Tivantinib (1 µmol/L) in combination with PI3K inhibitor LY294002 (0.5 µmol/L) and mTOR inhibitor rapamycin (0.1 nmol/L) largely inhibited the proliferation of glioblastoma cells. CONCLUSIONS c-MET inhibitor tivantinib blocks PIKE/Akt/mTOR signaling and hampers the proliferation of glioblastoma cells, which endows the drug a therapeutic effect.

The Role of MET in Melanoma and Melanocytic Lesions.

Melanoma is the leading cause of death due to cutaneous malignancy and its incidence is on the rise. Several signaling pathways, including receptor tyrosine kinases, have been recognized to have an etiopathogenetic role in the development and progression of precursor melanocytic lesions and malignant melanoma. Among those, the hepatocyte growth factor/MET (HGF/MET) axis is emerging as a critical player not only in the tumor itself but also in the immune microenvironment in which the tumor grows and advances in its development. Moreover, the activation of this pathway has emerged as a paradigm of tumor resistance to modern targeted therapies, and the assessment of its expression in patients' samples may be a valuable biomarker of tumor progression and response to targeted therapy. Here we summarize our current understanding of this important receptor tyrosine kinase in normal melanocyte proliferation/motility, in tumor progression and metastasis, its genetic alterations in certain subtype of melanocytic lesions, and how its pathway has been explored for the development of selective inhibitors.

A hepatocyte growth factor/MET-induced antiapoptotic pathway protects against radiation-induced salivary gland dysfunction.

OBJECTIVE: Hepatocyte growth factor (HGF) and its receptor MET are expressed in the salivary glands during developmental stages and tumor formation; however, the function of HGF in injured salivary gland tissues remains unclear. The present study investigated the role of HGF in protecting the salivary glands against radiation-induced injury using an organotypic culture method. MATERIALS AND METHODS: Acinar-like organoids were formed by means of a three-dimensional (3D) human parotid tissue-derived spheroids (hPTS) culture method. Radioprotective effects of HGF on irradiated hPTS and signaling pathways on radioprotection were investigated. RESULTS: We detected MET expression in hPTS grown in a 3D culture. Treatment of irradiated hPTS with recombinant human HGF (rhHGF) restored salivary marker expression and secretory function of hPTS. Changes in the phosphorylation levels of apoptosis-related proteins through HGF-MET axis inhibited radiation-induced apoptosis. Treatment with PHA665752, a MET inhibitor, blocked MET-PI3K-AKT pathway, increased apoptosis, and suppressed the radioprotective effect of rhHGF against IR-induced damage of hPTS. CONCLUSIONS: These results suggest that HGF is a key effector of radioprotection and that HGF-MET-PI3K-AKT axis is involved in protecting the salivary glands from radiation-induced apoptosis.

Metabolomics reveals tepotinib-related mitochondrial dysfunction in MET-activating mutations-driven models.

Genetic aberrations in the hepatocyte growth factor receptor tyrosine kinase MET induce oncogenic addiction in various types of human cancers, advocating MET as a viable anticancer target. Here, we report that MET signaling plays an important role in conferring a unique metabolic phenotype to cellular models expressing MET-activating mutated variants that are either sensitive or resistant toward MET small molecule inhibitors. MET phosphorylation downregulated by the specific MET inhibitor tepotinib resulted in markedly decreased viability and increased apoptosis in tepotinib-sensitive cells. Moreover, prior to the induction of MET inhibition-dependent cell death, tepotinib also led to an altered metabolic signature, characterized by a prominent reduction of metabolite ions related to amino sugar metabolism, gluconeogenesis, glycine and serine metabolism, and of numerous TCA cycle-related metabolites such as succinate, malate, and citrate. Functionally, a decrease in oxygen consumption rate, a reduced citrate synthase activity, a drop in membrane potential, and an associated misbalanced mitochondrial function were observed exclusively in MET inhibitor-sensitive cells. These data imply that interference with metabolic state can be considered an early indicator of efficient MET inhibition and particular changes reported here could be explored in the future as markers of efficacy of anti-MET therapies.

Axis inhibition protein 1 (Axin1) Deletion-Induced Hepatocarcinogenesis Requires Intact ß-Catenin but Not Notch Cascade in Mice.

Inactivating mutations of axis inhibition protein 1 (AXIN1), a negative regulator of the Wnt/ß-Catenin cascade, are among the common genetic events in human hepatocellular carcinoma (HCC), affecting approximately 10% of cases. In the present manuscript, we sought to define the genetic crosstalk between Axin1 mutants and Wnt/ß-catenin as well as Notch signaling cascades along hepatocarcinogenesis. We discovered that c-MET activation and AXIN1 mutations occur concomitantly in ~3%-5% of human HCC samples. Subsequently, we generated a murine HCC model by means of CRISPR/Cas9-based gene deletion of Axin1 (sgAxin1) in combination with transposon-based expression of c-Met in the mouse liver (c-Met/sgAxin1). Global gene expression analysis of mouse normal liver, HCCs induced by c-Met/sgAxin1, and HCCs induced by c-Met/∆N90-ß-Catenin revealed activation of the Wnt/ß-Catenin and Notch signaling in c-Met/sgAxin1 HCCs. However, only a few of the canonical Wnt/ß-Catenin target genes were induced in c-Met/sgAxin1 HCC when compared with corresponding lesions from c-Met/∆N90-ß-Catenin mice. To study whether endogenous ß-Catenin is required for c-Met/sgAxin1-driven HCC development, we expressed c-Met/sgAxin1 in liver-specific Ctnnb1 null mice, which completely prevented HCC development. Consistently, in AXIN1 mutant or null human HCC cell lines, silencing of ß-Catenin strongly inhibited cell proliferation. In striking contrast, blocking the Notch cascade through expression of either the dominant negative form of the recombinant signal-binding protein for immunoglobulin kappa J region (RBP-J) or the ablation of Notch2 did not significantly affect c-Met/sgAxin1-driven hepatocarcinogenesis. Conclusion: We demonstrated here that loss of Axin1 cooperates with c-Met to induce HCC in mice, in a ß-Catenin signaling-dependent but Notch cascade-independent way.

Proteolytic cleavages of MET: the divide-and-conquer strategy of a receptor tyrosine kinase.

Membrane-anchored full-length MET stimulated by its ligand HGF/SF induces various biological responses, including survival, growth, and invasion. This panel of responses, referred to invasive growth, is required for embryogenesis and tissue regeneration in adults. On the contrary, MET deregulation is associated with tumorigenesis in many kinds of cancer. In addition to its well-documented ligand-stimulated downstream signaling, the receptor can be cleaved by proteases such as secretases, caspases, and calpains. These cleavages are involved either in MET receptor inactivation or, more interestingly, in generating active fragments that can modify cell fate. For instance, MET fragments can promote cell death or invasion. Given a large number of proteases capable of cleaving MET, this receptor appears as a prototype of proteolytic-cleavage-regulated receptor tyrosine kinase. In this review, we describe and discuss the mechanisms and consequences, both physiological and pathological, of MET proteolytic cleavages. [BMB Reports 2019; 52(4): 239-249].

Paracrine Mechanisms Involved in Mesenchymal Stem Cell Differentiation into Cardiomyocytes.

Cardiovascular Disease (CVD) is one of the world-wide healthcare problem that involves the heart or blood vessels. CVD includes myocardial infarction and coronary artery diseases (CAD). Dysfunctional myocardial cells are leading causes of low cardiac output or ventricular dysfunction after cardiac arrest and may contribute to the progression of CVD which could not generate new cardiomyocytes in human adult heart. The mesenchymal stem cells (MSCs) which are present in adult marrow can self-renew and have the capacity of differentiation into multiple types of cells including cardiomyocytes. Recent biochemical analyses greatly revealed that several regulators of MSCs, such as HGF, PDGF, Wnt, and Notch-1 signaling pathways have been shown to be involved in the proliferation and differentiation into cardiomyocytes. Preclinical studies are paving the way for further applications of MSCs in the repair of myocardial infarction. In this study, we discuss and summarize the paracrine mechanisms involved in MSCs differentiation into cardiomyocytes.

Prognostic Significance of Mesenchymal-Epithelial Transition in Triple-Negative Breast Cancers.

INTRODUCTION: The prognostic value of the mesenchymal-epithelial transition (MET) in triple-negative breast cancers (TNBCs) remains controversial. A meta-analysis of the impact of MET in TNBCs was performed by searching published data. METHODS: PubMed and Embase databases were searched for eligible literature. The principal outcome measures were hazard ratios (HRs) for recurrence-free survival or overall survival according to MET expression. Combined HRs were calculated using fixed- or random-effects models according to heterogeneity. RESULTS: Six studies involving 785 patients met our selection criteria. The meta-analysis results showed that MET overexpression was associated with a 1.29-fold increased risk of recurrence (combined HR 1.29; 95% confidence interval, 1.04-1.60; P = .020) in the TNBCs. Three studies provided the related overall survival data (488 cases). The results showed that MET overexpression was associated with a 1.38-fold increased risk of mortality (HR, 1.38; 95% confidence interval, 1.08-1.76; P = .009). CONCLUSION: MET is an adverse prognostic marker for TNBCs. The results strengthen the rationale for targeted therapy of TNBCs using MET inhibitors in future clinical trials.

Long noncoding RNA lncHand2 promotes liver repopulation via c-Met signaling.

BACKGROUND & AIMS: Long noncoding RNAs (lncRNAs) play important roles in various biological processes, regulating gene expression by diverse mechanisms. However, how lncRNAs regulate liver repopulation is unknown. Herein, we aimed to identify lncRNAs that regulate liver repopulation and elucidate the signaling pathways involved. METHODS: Herein, we performed 70% partial hepatectomy in wild-type and gene knockout mice. We then performed transcriptomic analyses to identify a divergent lncRNA termed lncHand2 that is highly expressed during liver regeneration. RESULTS: LncHand2 is constitutively expressed in the nuclei of pericentral hepatocytes in mouse and human livers. LncHand2 knockout abrogates liver regeneration and repopulation capacity. Mechanistically, lncHand2 recruits the Ino80 remodeling complex to initiate expression of Nkx1-2 in trans, which triggers c-Met (Met) expression in hepatocytes. Finally, knockout of both Nkx1-2 and c-Met causes more severe liver injury and poorer repopulation ability. Thus, lncHand2 promotes liver repopulation via initiating Nkx1-2-induced c-Met signaling. CONCLUSIONS: Our findings reveal that lncHand2 acts as a critical mediator regulating liver repopulation. It does this by inducing Nkx1-2 expression, which in turn triggers c-Met signaling. LAY SUMMARY: Long noncoding RNAs play important roles in various biological processes. While long noncoding RNAs do not directly code proteins, they can regulate gene expression by diverse mechanisms. We identified the long noncoding RNA, termed lncHand2 because of its proximity to the gene Hand2, to be an important determinant of liver regeneration through c-Met signaling.

The Impact of the Epithelial-Mesenchymal Transition Regulator Hepatocyte Growth Factor Receptor/Met on Skin Immunity by Modulating Langerhans Cell Migration.

Langerhans cells (LCs), the epidermal dendritic cell (DC) subset, express the transmembrane tyrosine kinase receptor Met also known as hepatocyte growth factor (HGF) receptor. HGF is the exclusive ligand of Met and upon binding executes mitogenic, morphogenic, and motogenic activities to various cells. HGF exerts anti-inflammatory activities via Met signaling and was found to regulate various functions of immune cells, including differentiation and maturation, cytokine production, cellular migration and adhesion, and T cell effector function. It has only recently become evident that a number of HGF-regulated functions in inflammatory processes and immune responses are imparted via DCs. However, the mechanisms by which Met signaling in DCs conveys its immunoregulatory effects have not yet been fully understood. In this review, we focus on the current knowledge of Met signaling in DCs with particular attention on the morphogenic and motogenic activities. Met signaling was shown to promote DC mobility by regulating matrix metalloproteinase activities and adhesion. This is a striking resemblance to the role of Met in regulating a cell fate program during embryonic development, wound healing, and in tumor invasion known as epithelial-mesenchymal transition (EMT). Hence, we propose the concept that an EMT program is executed by Met signaling in LCs.

Overexpression of ING5 inhibits HGF-induced proliferation, invasion and EMT in thyroid cancer cells via regulation of the c-Met/PI3K/Akt signaling pathway.

The inhibitor of growth 5 (ING5), a novel member of the ING family, is involved in diverse biological processes such as cell growth, apoptosis and DNA repair. Recently, ING5 has been reported to be associated with cancer development. However, its specific role in thyroid cancer has yet to be elucidated. In this study, we found that the expression of ING5 was significantly down-regulated in human thyroid cancer tissues and cell lines. In addition, overexpression of ING5 markedly inhibited hepatocyte growth factor (HGF)-induced proliferation, invasion and epithelial-mesenchymal transition (EMT) of thyroid cancer cells as well as suppressed the tumor growth and metastasis in vivo. Furthermore, our data showed that the c-Met/PI3K/Akt signaling pathway was responsible for the inhibitory effect of ING5 on the thyroid cancer. Taken together, these findings provided an essential basis for the tumor-suppression role of ING5 in thyroid cancer.

Prognostic value of c-MET in head and neck cancer: A systematic review and meta-analysis of aggregate data.

OBJECTIVES: The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-MET) ligand/receptor axis has been implicated in pathogenesis of malignant diseases including squamous cell carcinoma of the head and neck (SCCHN). Overexpression of c-MET has been reported as a common molecular abnormality in SCCHN, although its prognostic and predictive value remains to be validated. METHODS: We systematically searched literature for studies evaluating c-MET expression on immunohistochemistry in newly diagnosed, non-metastatic SCCHN. The c-MET expressing cases were classified into three categories according to predefined cut-off values for positivity. Our aim was to assess the prevalence of c-MET expression and its relationship with selected clinicopathological variables. RESULTS: Twenty-eight studies with 2019 cases were included. Relative frequencies of c-MET expression above cut-off levels I, II, and III were 81.8%, 63.8%, and 46.2%, respectively. Differences between these three values were statistically significant (p<1.0×10-6). Above cut-off level II, c-MET positivity was associated with worse overall survival (p=4.0×10-6), positive nodal status (p=1.0×10-4), higher disease stage (p=7.0×10-4), older age (p=2.1×10-3), disease recurrence (p=2.0×10-2), and primary tumour localization in the oral cavity (p=2.3×10-2). Above cut-off level III, c-MET positivity was associated with worse disease-free or progression-free survival (p=9.0×10-6), p16 negativity (p=2.4×10-4), worse overall survival (p=4.0×10-4), positive epidermal growth factor receptor (EGFR) status (p=7.2×10-4), and larger primary tumours (p=4.6×10-3). CONCLUSION: In SCCHN, immunohistochemical overexpression of c-MET above cut-off levels III and particularly II was associated with inferior survival outcomes and advanced disease. Moreover, it represents a promising predictive biomarker for c-MET targeting, yet the optimal scoring method remains to be defined.