Dan A. Dixon

Role of post-transcriptional gene regulation in cancer.

Post-Transcriptional Gene Regulation in Colorectal Cancer

Colorectal cancer (CRC) is a leading cause of cancer incidence and death. Commonly observed in colon tumors is overexpression of many oncogenic and inflammation-associated genes. These factors allow the tumor cell to proliferate, promote angiogenesis, escape apoptosis, and metastasize. In normal cells, post-transcriptional mechanisms involving RNA-binding proteins and microRNAs target oncogenic mRNAs for rapid degradation. However, this critical mechanism is commonly lost in tumor cells allowing for oncogenic gene overexpression. By better understanding these post-transcriptional mechanisms, our goal is to identify new molecular targets for controlling gene expression that can improve on CRC prevention and treatment.

Role of RNA-Binding Proteins in Cancer

A critical point in controlling oncogenic gene expression in normal cells occurs through mechanisms that regulate mRNA decay. The two primary RNA-binding proteins associated with this are the mRNA stability factor HuR and the mRNA decay factor TTP. A common feature observed in many tumor types is the overexpression of the stability factor HuR and loss of the decay factor TTP. These combined defects in tumor cells allow oncogenic mRNA to escape their normal fate being degraded. Current projects involve examining these RNA-binding proteins as therapeutic targets and discovering new ways RNA-binding proteins can influence tumor progression.

Regulation of COX-2 Expression in Cancer

The inducible prostaglandin synthase COX-2 mediates inflammatory responses and plays a pivotal role in the pathogenesis of several cancer types due to its overexpression. Various studies have demonstrated the chemopreventive effects of COX-2 inhibition using non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, however side effects of these drugs have limited their use for chemoprevention. Our research has shown that post-transcriptional regulation is an essential mechanism regulating COX-2 gene expression and loss of this regulation occurs in cancer cells. Using molecular, cellular, and in vivo approaches, we are examining the functional significance post-transcriptional regulation plays in controlling COX-2 expression.