Research projects

Colorectal cancer (CRC) is the third most commonly diagnosed tumoral disease and rates of recurrence and metastasis are still high, even in early stages of the disease. The interplay of transformed epithelial cells with a pro-tumoral microenvironment, comprising angiogenic vasculature and pro-inflammatory signals, is key in tumor progression. Post-translational regulation of signal transduction by non-genetically altered kinases emerges also as an important driving process in cancer. Based on the available evidence and preliminary data, we proposed that kinase GRK2 might be a prognostic marker of CRC recurrence that influences CRC tumor development and therapy resistance in a stage-dependent manner. Our aim is to investigate GRK2 alterations in CRC patients and cellular and animal models of CRC progression, by exploring its impact on several pro-inflammatory and angiogenic signaling axes linked to proliferation and survival of intestinal epithelial cells. In this period, the levels of GRK2 and relevant partners such as HuR were analyzed in response to the pro-inflammatory cytokine PGE2, a key factor in the progression of CRC. Based on the basal expression in a panel of CCR lines, those with differential expression of GRK2 in early stage (high level, Caco2 versus low level, SW480) and late stage (high level SW620, versus low level, HCT116) were selected. HuR expression profiles vary in response to PGE2 differentially depending on cell type. The potency of HuR induction by PGE2 seems to be positively correlated with similar changes in GRK2 levels, which could be compatible with positive feedback between both proteins, excepting in the HCT116 line wherein changes run in opposite ways. We are addressing the type of interrelation between both proteins, and extending the study to other interactors as endoglin, whose results will help to reveal new mechanisms of action of PGE2 in colon cancer.