4170

MCL1

BCL2L3|EAT|MCL1-ES|MCL1L|MCL1S|Mcl-1|TM|bcl2-L-3|mcl1/EAT;myeloid cell leukemia sequence 1 (BCL2-related);MCL1;myeloid cell leukemia sequence 1 (BCL2-related)

bcl-2-like protein 3|bcl-2-related protein EAT/mcl1|induced myeloid leukemia cell differentiation protein Mcl-1|myeloid cell leukemia ES

1q21

protein-coding

Rhabdomyosarcoma, the most common soft tissue sarcoma in childhood, belongs to the small round cell tumor family and is classified according to its histopathological features as embryonal, alveolar and pleomorphic. In this studywe propose to explore genetic alterations involved in rhabdomyosarcoma tumorigenesis and assess the level of mRNA gene expression of controlling survival signalling pathways. For genetic and molecular analysis, array-based comparative genomic hybridization, combined with Real Time PCR using the comparative method, was performed on 14 primary well-characterized human primaryrhabdomyosarcomas. Multiple changes affecting chromosome arms were detected in ALL cases, including gain or loss of specific regions harbouring cancer progression-associated genes. Evaluation of mRNA levels showed in the majority of cases overexpression of MCL1 and MAP2K4 genes, both involved in cell viability regulation. Our findings on rhabdomyosarcoma samples showed multiple copy numberalterations in chromosome regions implicated in malignancy progression and indicated a strong expression of MAP2K4 and MCL1 genes, both involved in different biological functions of complicated signalling pathways.

Osteosarcoma is the most common type of bone cancer, with a peak incidence in the early childhood. The relationship between microRNAs (miRNAs) and cancer development attracted more and more attention over the last few years. Members of the miRNA-29 family, including miRNA-29a, miRNA-29b, and miRNA-29c were shown toparticipate in the development of rhabdomyosarcoma and hepatocarcinogenesis. Here, it has been demonstrated miRNA-29a and miRNA-29b expression levels to be downregulated in most of the osteosarcoma tissues (23 from 30). Besides, miRNA-29a displayed ability to induce apoptosis in both U2OS and SAOS-2 osteoblastic cells. While miRNA-29 members induced apoptosis through p53 gene activation, the effect of miRNA-29a on osteoblastic cells was independent on p53expression level. Moreover, Bcl-2 and Mcl-1 were earlier demonstrated to be the direct targets of miRNA-29 in many types of cancer tissues and cancers. In both U2OS and SAOS-2 osteoblastic cell types, overexpression of miRNA-29a also downregulated Bcl-2 and Mcl-1, while silencing of miRNA-29a increased their expression. In addition, enhanced expression of miRNA-29a increased the expression of two tumor suppressor genes, E2F1 and E2F3. In summary, data obtained highlight the role of miRNA-29a in the regulation of osteoblastic cell apoptosis by silencing Bcl-2 and Mcl-1 and inducing E2F1 and E2F3 expression.

Genetically engineered mouse models (GEMMs) of human cancer are important for advancing our understanding of tumor initiation and progression as well as for testing novel therapeutics. Retinoblastoma is a childhood cancer of the developing retina that initiates with biallelic inactivation of the RB1 gene. GEMMs faithfully recapitulate the histopathology, molecular, cellular, morphometric, neuroanatomical and neurochemical features of human retinoblastoma. In this study, we analyzed the genomic and epigenomic landscape of murine retinoblastoma and compared them to human retinoblastomas to gain insight into shared mechanisms of tumor progression across species. Similar to human retinoblastoma, mouse tumors have low rates of single nucleotide variations. However, mouse retinoblastomas have higher rates of aneuploidy and regional and focal copy number changes that vary depending on the genetic lesions that initiate tumorigenesis in the developing murine retina. Furthermore, the epigenetic landscape in mouse retinoblastoma was significantly different from human tumors and some pathways that are candidates for molecular targeted therapy for human retinoblastoma such as SYK or MCL1 are not deregulated in GEMMs. Takentogether, these data suggest there are important differences between mouse and human retinoblastomas with respect to the mechanism of tumor progression and those differences can have significant implications for translational research to test the efficacy of novel therapies for this devastating childhood cancer.