Increase chromosomal aberrations leads to Increase,miRNA levels

The contribution of microRNAs (miR) to the pathogenesis of mantle cell lymphoma (MCL) is not well known. The expression of 86 mature miRs mapped to frequently altered genomic regions in MCL in CD5+ /CD5 normal B cells, reactive lymph nodes, and purified tumor cells of 17 leukemic MCL, 12 nodal MCL, and 8MCL cell lines were investigated. Genomic alterations of the tumors were studied by single nucleotide polymorphism arrays and comparative genomic hybridization. Leukemic and nodal tumors showed a high number of differentially expressed miRs compared with purified normal B cells, but only some of them were commonly deregulated in both tumor types. An unsupervised analysis of miR expression profile in purified leukemic MCL cells revealed two clusters of tumors characterized by different mutational status of the immunoglobulin genes, proliferation signature, and number of genomic alterations. The expression of most miRs was not related to copy number changes in their respective chromosomal loci. Only the levels of miRs included in the miR-17-92 cluster were significantly related to genetic alterations at 13q31. Moreover, overexpression of miR-17-5p/miR-20a from this cluster was associated with high MYC mRNA levels in tumors with a more aggressive behavior. In conclusion, the miR expression pattern of MCL is deregulated in comparison with normal lymphoid cells and distinguishes two subgroups of tumors with different biological features.

Detailed investigation of the 13q14.3 deletions showed that both members of an miRNA cluster, miR-15a and miR-16-1, are deleted or downregulated in approximately 68% of CLL cases as compared with healthy donors (Calin, G.A., et al. 2002). Furthermore, a rare mutation lowering the expression of these genes was identified in two CLL patients including one from a family with individuals having CLL and breast cancer, and was found to be associated with the loss of the normal allele in the leukemic cells (Calin, G.A., et al. 2005). It was shown that the levels of both miR-15 and miR-16 inversely correlate with the BCL-2 protein expression and that BCL-2 repression by these miRNAs induces apoptosis in leukemia cells (Cimmino, A., et al. 2005).

Levels of miR-16 were decreased in NZB lymphoid tissue, and exogenous miR-16 delivered to an NZB malignant B-1 cell line resulted in cell cycle alterations and increased apoptosis. Linkage of the miR-15a/miR-16-1 complex to the development of CLL in this spontaneous mouse model suggests that the altered expression of these genes is the molecular lesion in CLL (Raveche, E.S., et al. 2007).

The only miRNA found to be overexpressed in any type of solid tumor analyzed (breast, colon, lung, prostate, stomach, and endocrine pancreas tumors, glioblastomas, and uterine leiomyomas) is miR-21 (Volinia, S., et al. 2006, Ciafre, S.A., et al. 2005; . Krichevsky et al.,2003; Wang, T., et al. 2007). This gene is located in the 3′UTR of the vacuole membrane protein 1 (VMP1) gene at chromosome 17q23.2, a region frequently found amplified in neuroblastomas and breast, colon, and lung cancers. Knockdown of miR-21 in glioblastoma cell lines induces a caspase-mediated apoptosis, further supporting the oncogenic role of this miRNA (Chan, et al.,2005).

Studies performed in solid cancer cell lines showed that miR-16 negatively regulated cellular growth and cell cycle progression. miR-16–downregulated transcripts were enriched with genes whose silencing by small interfering RNAs causes an accumulation of cells in G0/G1. Simultaneous silencing of these genes was more effective at blocking cell cycle progression than was disruption of the individual genes. Thus, miR-16 coordinately regulates targets that may act in concert to control cell cycle progression (Linsley, P.S., et al. 2007)

Not mentioned.