Research
In the last 3 years, our main focus of research has been centered on the molecular and cellular events determining the initiation and progression of human cancer with special emphasis in chronic lymphocytic leukemia. Ongoing work deal with three main research areas:
Role of microRNAs in the initiation and progression of chronic lymphocytic leukemia
Recently, a novel class of small noncoding RNAs dubbed microRNAs has been identified in plants and animals. Mature microRNAs are 19-22 nt in length and regulate target gene expression post-transcriptionally through base pairing with the 3’ untranslated regions of the target messenger RNA inducing either degradation or translation inhibition. They participate in the regulation of developmental timing, cell death, cell proliferation and differentiation, fat metabolism and haematopoiesis. The finding that more than half of the known human microRNAs are located at cancer-associated regions of the genome suggests that microRNAs might play a broad role in cancer pathogenesis. In order to gain insight into the role of microRNAs in the initiation and progression of Chronic Lymphocytic Leukemia we have recently performed a cloning-based analysis of small RNAs in leukemic B cells from affected patients. Our results showed an almost complete loss of expression levels of several relevant microRNAs associated to the finding of new microRNAs candidates associated to the malignant phenotype. Currently we analyze the role of several cancer associated microRNAs in the malignant phenotype of leukemic B cells with eukaryotic expression vectors specially designed to express microRNAs. This project can afford emerging and relevant new mechanisms in cancer biology with a great potential in actual knowledge of B-CLL biology.
Redox imbalance and pathogenesis of chronic lymphocytic leukemia
B-chronic lymphocytic leukemia (B-CLL) is the commonest leukemia in the Western world and is a significant cause of morbidity and mortality in the older adult population. In spite of recent advances in cancer biology, the cellular and molecular processes underlying B-CLL are poorly known. In contrast to most leukemic processes there are not typical genetic alterations in B-CLL. In light of recent data from our and other labs and the recent advances in the chemistry and biology of biological relevant reactive species as RNS, ROS and RSS, new and relevant questions emerge with a great potential in the actual knowledgement of B-CLL biology. B-CLL cells are prone to a state of oxidant stress and have a clear vulnerability to pro-oxidants. Additionally, prognosis and therapy responses are highly linked to cellular redox status. The unusual vulnerability to oxidant stress observed in CLL cells can be explained by a quanti or qualitative defects in the biological pathways integrated by peroxyredoxins and their regenerating/regulating enzymes, which in turn could affect BCR-mediated signaling and cell survival. We speculate that these defects could explain the typical evolution, prognosis and response to therapy characteristics of LLC. The characterization of the prx system, including sulfiredoxins and sestrins, will show the relevance of the different components of this system in B-CLL cells, and which of them are responsible for the establishment and persistence of the disease. Because the biological importance of this antioxidant system in other cellular systems as mentioned above work in these directions seems to be relevant in order to elucidate the role of ROS, RNS or RSS in the pathogenesis of CLL.
MicroRNA-dependent chromohelicases as a novel tumorigenic pathway in human cancer
In previous work, we succeeded to identify five novel microRNAs. In this proposal we intend to identify a novel tumorigenic pathway in human cancer in which these microRNAs appear to play an important role. In silico predictions showed that a significant proportion of mRNA targets of these novel microRNA mapped within a small region in the short arm of human chromosome 1 (1p31–1p36) which is frequently deleted in neuroblastoma and other neural-related malignancies. We speculate that these novel miRNAs could use as an effector arm the p19Arf/Mdm2/p53 pathway. The link between both molecular circuitries is represented by the recently identified Chromohelicase 5 (CHD5) which was demonstrated to act as a tumor suppressor via transcriptional activation of the INK4a-ARF locus. Surprisingly, CHD5 is a target shared by three out of these 5 novel oncogenic microRNA reported in this proposal. The validation of this tumorigenic pathway could provide new insights into the molecular mechanisms predisposing to human cancer and the identification of new therapeutic targets. We aim to identify a novel tumorigenic pathway which could be activated through a microRNA-induced deficiency of the chromatin-remodeling protein CHD5 expression. This could predispose to malignancy by crippling tumor suppressive pathways involving p16lnk4a, p19Arf and p53. We will try to establish an unrecognized role of hCHD5 in both facilitating transcriptional programs providing tumor suppression and as an alternative regulating pathway for the p19Arf/Mdm2/p53 axis.