Abstract. Hepatocyte Growth Factor (HGF, also known as Scatter Factor) is a powerful mitogen or motility factor in different cells, acting through the tyrosine kinase receptor encoded by the MET protooncogene. Endothelial cells express the MET gene and expose at the cell surface the mature protein (p190 MEt) made of a 50 kD (o0 subunit disulfide linked to a 145-kD (~) subunit. HGF binding to endothelial ceils identifies two sites with different affinities. The higher affinity binding site (Kd = 0.35 nM) corresponds to the p190 MET receptor. Sub-nanomolar concentrations of HGF, but not of a recombinant inactive precursor, stimulate the receptor kinase activity, cell proliferation and motility. HGF induces repairs of a wound in endothelial cell monolayer. HGF stimulates the scatter of endothelial cells grown on three-dimensional collagen gels, inducing an elongated phenotype. In the rabbit cornea, highly purified HGF promotes neovascularization at sub-nanomolar concentrations. HGF lacks activities related to hemostasis-thrombosis, inflammation and endothelial cells accessory functions. These data show that HGF is an in vivo potent angiogenic factor and in vitro induces endothelial cells to proliferate and migrate.

A metastatic cancer develops by accumulation of mutations in genes that control growth, survival and spreading. The latter genes have not yet been identi®ed. In lymph node metastases of head and neck squamous cell carcinomas (HNSCC), we found mutations in the MET oncogene, which encodes the tyrosine kinase receptor for Scatter Factor, a cytokine that stimulates epithelial cell motility and invasiveness during embryogenesis and tissue remodeling. We identi®ed two somatic mutations: the Y1230C, known as a MET germline mutation which predisposes to hereditary renal cell carcinoma, and the Y1235D that is novel and changes a critical tyrosine, known to regulate MET kinase activity. The mutated MET receptors are constitutively active and confer an invasive phenotype to transfected cells. Interestingly, cells carrying the MET mutations are selected during metastatic spread: transcripts of the mutant alleles are highly represented in metastases, but barely detectable in primary tumors. These data indicate that cells expressing mutant MET undergo clonal expansion during HNSCC progression and suggest that MET might be one of the long sought oncogenes controlling progression of primary cancers to metastasis. Oncogene (2000) 19, 1547 ± 1555.

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The MET oncogene encodes the receptor for Hepatocyte Growth Factor/Scatter Factor, a unique growth factor that induces not only proliferation of epithelial cells, but also cell motility and invasiveness. DNA level and expression of the Met/HGF receptor gene were examined with Southern- and Western-blot analyses, respectively, in human ovary, benign ovarian tumors and epithelial ovarian carcinomas. The Met/HGF receptor was detectable in the surface epithelium of normal ovary. The level of expression was unchanged in benign ovarian tumors of various origins. Fourteen out of 67 malignant carcinomas (20%) showed a 3- to 10-fold increase in expression. In 5 additional cases the Met/HGF protein was overexpressed over 50-fold. This represents a total of 28% of cases. Overexpression was not associated with MET gene amplification. Overexpressing tumors belonged to different histotypic variants, but showed a well-differentiated phenotype. Clinically, overexpression was associated with disease at any pathologic stage, but was significantly correlated with premenopausal status of patients. These data suggest that expression of the Met/HGF receptor may add a selective growth advantage to a narrow subset of differentiated ovarian cancers in premenopausal patients.

RON is a tyrosine kinase receptor that triggers scattering of normal cells and invasive growth of cancer cells on ligand binding. We identified a short RON mRNA, which is expressed in human lung, ovary, tissues of the gastrointestinal tract, and also in several human cancers, including ovarian carcinomas and cell lines from pancreatic carcinomas and leukemias. This transcript encodes a truncated protein (short-form RON; sf-RON), lacking most of the RON receptor extracellular domain but retaining the whole transmembrane and intracellular domains. Sf-RON shows strong intrinsic tyrosine kinase activity and is constitutively phosphorylated. Epithelial cells transduced with sf-RON display an aggressive phenotype; they shift to a nonepithelial morphology, are unable to form aggregates, grow faster in monolayer cultures, show anchorage-independent growth, and become motile. We show that in these cells, E-cadherin expression is lost through a dominant transcriptional repression pathway likely mediated by the transcriptional factor SLUG. Altogether, these data show that expression of a naturally occurring, constitutively active truncated RON kinase results in loss of epithelial phenotype and aggressive behavior and, thus, it might contribute to tumor progression.

The MET oncogene was causally involved in the pathogenesis of a rare tumor, i.e., the papillary renal cell carcinoma, in which activating mutations, either germline or somatic, were identified. MET activating mutations are rarely found in other human tumors, whereas at higher frequencies, MET is amplified and/or overexpressed in sporadic tumors of specific histotypes, including osteosarcoma. In this work, we provide experimental evidence that overexpression of the MET oncogene causes and sustains the full-blown transformation of osteoblasts. Overexpression of MET, obtained by lentiviral vector-mediated gene transfer, resulted in the conversion of primary human osteoblasts into osteosarcoma cells, displaying the transformed phenotype in vitro and the distinguishing features of human osteosarcomas in vivo. These included atypical nuclei, aberrant mitoses, production of alkaline phosphatase, secretion of osteoid extracellular matrix, and striking neovascularization. Although with a lower tumorigenicity, this phenotype was superimposable to that observed after transfer of the MET gene activated by mutation. Both transformation and tumorigenesis were fully abrogated when MET expression was quenched by short-hairpin RNA or when signaling was impaired by a dominant-negative MET receptor. These data show that MET overexpression is oncogenic and that it is essential for the maintenance of the cancer phenotype. (Cancer Res 2006; 66(9): 4750-7)

Summary Hepatocyte growth factor/scatter factor (HGF/SF) stimulates the invasive growth of epithelial cells via the c-MET oncogene-encoded receptor. In normal lung, both the receptor and the ligand are detected, and the latter is known to be a mitogenic and a motogenic factor for both cultured bronchial epithelial cells and non-small-cell carcinoma lines. Here, ligand and receptor expression was examined in 42 samples of primary human non-small-cell lung carcinoma of different histotype. Each carcinoma sample was compared with adjacent normal lung tissue. The MetlHGF receptor was found to be 2 to 10-fold increased in 25% of carcinoma samples (P=0.0113). The ligand, HGF/SF, was found to be 10 to 100-fold overexpressed in carcinoma samples (P<0.0001). Notably, while HGF/SF was occasionally detectable and found exclusively as a single-chain inactive precursor in normal tissues, it was constantly in the biologically-active heterodimeric form in carcinomas. Immunohistochemical staining showed homogeneous expression of both the receptor and the ligand in carcinoma samples, whereas staining was barely detectable in their normal counterparts. These data show that HGF/SF is overexpressed and consistently activated in non-small-cell lung carcinomas and may contribute to the invasive growth of lung cancer.

Alteration in RNA metabolism, concerning both coding and long non-coding RNAs (lncRNAs), may play an important role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. In this work, we performed a whole transcriptome RNA-seq analysis to investigate the regulation of non-coding and coding RNAs in Sporadic ALS patients (SALS), mutated ALS patients (FUS, TARDBP and SOD1) and matched controls in Peripheral Blood Mononuclear Cells (PBMC). Selected transcripts were validated in spinal cord tissues. A total of 293 differentially expressed (DE) lncRNAs was found in SALS patients, whereas a limited amount of lncRNAs was deregulated in mutated patients. A total of 87 mRNAs was differentially expressed in SALS patients; affected genes showed an association with transcription regulation, immunity and apoptosis pathways. Taken together our data highlighted the importance of extending the knowledge on transcriptomic molecular alterations and on the significance of regulatory lncRNAs classes in the understanding of ALS disease. Our data brought the light on the importance of lncRNAs and mRNAs regulation in central and peripheral systems, offering starting points for new investigations about pathogenic mechanism involved in ALS disease.