Cancer, Caveolin-1, and Non-Coding RNAs: Novel Insights into Tumor Biology.

摘要

Cancer may be thought of as the manifestation of a number of dysregulated biochemical processes that ultimately lead to a population of cells demonstrating uncontrolled proliferation, limitless replicative potential, resistance to programmed death, loss of differentiated phenotypes, and capacity for invasion into surrounding tissues. Given their heterogeneous nature, the oncogenic steps towards the development of these attributes are highly variable and often unique to specific cancers and tissue types. This work aims to characterize the roles of two different cellular factors with emerging relevance to cancer onset and progression. Specifically, the role of caveolin-1, a transmembrane scaffolding protein, is explored in the context of malignant glioma, and further, the role of microRNAs (miRNAs) are characterized in relation to the ability to post-transcriptionally regulate DNA repair pathways as well as miRNA regulatory networks in an in vitro model of pancreatic cancer. The findings presented here suggest that caveolin-1 acts as an endogenous tumor suppressor in glioma by silencing a number of a number of oncogenic signaling mechanisms related to MAP-kinase and PI3K/AKT pathways both in vitro and in vivo through the use of microarray and protein expression profiling methods. Additionally, forced upregulation of caveolin-1 in a cell line model of glioma results in increased sensitivity to treatment with the commonly used chemotherapeutic agent, temozolomide. Separately, computational approaches towards the identification of non-standard miRNA interactions yielded a novel target site for the miR-15/107 family of miRNAs on the BRCA1 transcript, a critical factor in DNA repair machinery commonly dysregulated in familial cancers. Lastly, argonaute CLIP-seq performed in cell line models of both normal and cancerous pancreatic epithelium demonstrates a highly dynamic repertoire of miRNA targets originating from many non-coding genomic loci. Together, these results highlight novel avenues for further exploration as it relates to the molecular mechanisms of oncogenesis in brain, pancreatic, and other cancers.