Papel de las proteínas unidoras de rna sf2/asf y hnrnpa1 en cáncer de pulmón

Abstract

Lung cancer is the primary cause of cancer deaths in the world. New approaches are necessary to understand the mechanisms that guide lung carcinogenesis, in order to identify biomarkers and develop improved molecular-targeted therapies. Recent data have shown that the regulation of mRNA metabolism contributes more relevantly than previously suspected to the genesis of a great variety of diseases, including cancer. Modifications in the levels of mRNA processing proteins can elicit global changes in the profile of mRNA expression, affecting a number of cancer-associated genes. An mRNA processing protein, SF2/ASF, has been recently described as an oncoprotein, what has focused the interest on the study of this factor in cancer. Another RNA binding protein, hnRNP A1, is an antagonistic factor of SF2/ASF in the regulation of alternative splicing, and an altered relative expression of these factors has been related to the presence of metastasis-associated alternative splicing isoforms of CD44 in mouse lung carcinogenesis. These factors also play other multiple roles in the regulation of RNA metabolism. In the present work, we aimed to clarify the role of the oncoprotein SF2/ASF and its antagonistic factor hnRNP A1 in non-small cell lung cancer. We describe an over-expression of SF2/ASF and hnRNP A1 in human NSCLC specimens. In order to determine the role of their overexpression, we performed RNA interference experiments. We demonstrate a role of SF2/ASF in the maintenance of the transformed phenotype by controlling the expression of survivin, an anti-apoptotic protein widely up-regulated in cancer, through the activation of the mTOR pathway. Moreover, we demonstrate a significant correlation between SF2/ASF and survivin expression both in human lung cancer cell lines and primary tumors, suggesting that SF2/ASF regulates the expression of survivin in lung cancer in vivo. In the case of hnRNP A1, RNA inhibition does not affect anchorage-dependent proliferation but strongly enhances cell growth in anchorage-independent conditions, suggesting hnRNP A1 can play a role in the resistance to stress and anoikis. Lowering hnRNP A1 in lung cancer cells promotes STAT3 expression and activation in anchorage-independent conditions. High levels of STAT3 have already been related to invasion, metastasis and resistance to anoikis, suggesting that this factor could mediate the effects observed after hnRNP A1 inhibition. Nevertheless, no correlation has been found between activated STAT3 and hnRNP A1 in human lung cancer primary tumors. CLIP technique has shown that hnRNP A1 binds a wide variety of mRNAs which have roles in invasion, and resistance to anoikis. Future studies will determine the role of these factors in hnRNP A1-dependent regulation of anchorage-independent growth.