No abstract

The proto-oncogene c-Src is a non-receptor tyrosine kinase playing a key role in many cellular pathways, including cell survival, migration and proliferation. c-Src de-regulation has been observed in several cancer types, making it an appealing target for drug discovery efforts. Recent evidence emphasizes its crucial role not only in promoting oncogenic traits, but also in the acquisition and maintenance of cancer resistance to various chemotherapeutic or molecular target drugs. c-Src modulates epidermal growth factor receptor (EGFR) activation and amplifies its downstream oncogenic signals. In this review, we report several studies supporting c-Src kinase role in the intricate mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs). We further highlighted pre- and clinical progresses of combined treatment strategies made in recent years. Several pre-clinical data have encouraged the use of c-Src inhibitors in combination with EGFR inhibitors. However, clinical trials provided controversial outcomes in some cancer types. Despite c-Src inhibitors showed good tolerability in cancer patients, no incontrovertible and consistent clinical responses were recorded, supporting the idea that a better selection of patients is needed to improve clinical outcome. Currently, the identification of biological markers predictive of therapy response and the accurate molecular screening of cancer patients aimed to gain most clinical benefits become decisive and mandatory.

No abstract

RET rearrangements as well as BRAF and RAS mutations drive differential pathway activation in papillary thyroid carcinomas, leading to different tumor phenotypes and prognoses. Although The Cancer Genome Atlas Consortium has identified tumor subgroups based on protein-coding gene signatures, neither expression of long noncoding RNAs (lncRNA) nor their correlation with specific tumor-driving mutations and rearrangements have been systematically assessed. Here, we reanalyzed our RNA-sequencing data using a de novo discovery approach to identify lncRNAs and define tumor subtype-specific signatures of annotated lncRNAs. Among them, we identified COMET (Correlated-to-MET), a natural antisense transcript that was highly expressed in carcinomas harboring BRAF V600E mutation or RET gene rearrangements (i.e., BRAF-like tumors) and induced the downstream MAPK pathway. In papillary thyroid carcinomas, COMET was part of a coexpression network including different oncogenes belonging to the MAPK pathway, and its expression highly correlated with MET expression. Depletion of COMET resulted in reduced expression of genes within this network, including the MET oncogene. COMET repression inhibited viability and proliferation of tumor cells harboring BRAF V600E somatic mutation or RET oncogene rearrangement and dramatically reduced motility and invasiveness of tumor cells. Moreover, silencing COMET markedly increased sensitivity to vemurafenib, a common inhibitor of mutated B-raf. Collectively, our results suggest COMET as a new target to improve drug-based cancer therapies, especially in BRAF-mutated and METaddicted papillary thyroid carcinomas.Significance: These results highlight the oncogenic role of lncRNA COMET in thyroid and indicate it as a potential new target to overcome vemurafenib resistance in BRAF-mutated and MET-addicted carcinomas.

We show that ptma, a single copy gene found in all organisms investigated so far, is duplicated in zebrafish. The two genes, ptmaa and ptmab, are individually controlled as indicated by their different expression patterns during embryonic development. Only the ptmab transcript is observed at 4 and 8 hpf of development in all embryonic cells, whereas both genes are expressed at later stages as revealed by in situ hybridization studies. In most cases, the two genes are expressed in the same territories, but only the ptmaa transcript was found in the trigeminal ganglion and in endodermal pouches. In the eye, at 72 hpf, the ptmaa and ptmab transcripts were found in amacrine cells, whereas only the ptmab transcript appeared in horizontal cells. The existence of two prothymosin genes indicates that their function in cell proliferation and differentiation is more complex in fishes than in mammals.

No abstract

Diagnosing a complex genetic syndrome and correctly assigning the concomitant phenotypic traits to a well-defined clinical form is often a medical challenge. In this work, we report the analysis of a family with complex phenotypes, including microcephaly, intellectual disability, dysmorphic features, and polydactyly in the proband, with the aim of adding new aspects for obtaining a clear diagnosis. We performed array-comparative genomic hybridization and quantitative reverse transcriptase PCR (qRT-PCR) analyses. We identified a deletion of chromosome 20p12.1 involving the macrodomain containing 2/mono-ADP ribosylhydrolase 2 gene (MACROD2) in several members of the family. This gene is actually not associated with a specific syndrome but with congenital anomalies of multiple organs. qRT-PCR showed higher levels of a MACROD2 mRNA isoform in the individuals carrying the deletion. Our results, together with other data reported in the literature, support the hypothesis that the deletion in MACROD2 can affect correct embryonic development and that the presence of another associated event, such as epigenetic modifications at the MACROD2 locus, can influence the level of severity of the pathology.

Cutaneous melanoma is considered a rare tumor, although it is one of the most common cancers in young adults and its incidence has risen in the last decades. Targeted therapy, with BRAF and MEK inhibitors, and immunotherapy revolutionized the treatment of metastatic melanoma but there is still a considerable percentage of patients with primary or acquired resistance to these therapies. Recently, oncology researchers directed their attention at the role of long non-coding RNAs (lncRNAs) in different types of cancers, including melanoma. lncRNAs are RNA transcripts, initially considered “junk sequences”, that have been proven to have a crucial role in the fine regulation of physiological and pathological processes of different tissues. Furthermore, they are more expressed in tumors than protein-coding genes, constituting perfect candidates either as biomarkers (diagnostic, prognostic, predictive) or as therapeutic targets. In this work, we reviewed all the literature available for lncRNA in melanoma, elucidating all the potential roles in this tumor.