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Exploring post-translational regulation of angiogenic and inflammatory-related processes during colorectal cancer progession and differential recurrence

20th national competition for scientific and technical research

Intercellular Dialogue and Interactome: Pathological Implications

Senior Researcher : Petronila Penela Márquez

Research Centre or Institution : Centro de Biología Molecular Severo Ochoa. CSIC - UAM

Abstract

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.

During this initial period, we have characterized the protein dosage of GRK2 in a first panel of 12 cell lines modeling different tumor stages and Cetuximab resistance. Among CRC cell lines with A-B or D-C Duke´s classification, we can distinguish cells displaying both up-regulation and down-regulation of GRK2 levels without clear correlations with their mutational status at KRAS/BRAF genes. However, independently of the cell line staging, increased GRK2 levels seems to correlate with Cetuximab resistance of CRC cells. Moreover, in cells that became resistant to 5-Fluorouracil with the continuous exposure to increasing concentrations of this chemotherapeutic agent, GRK2 levels were notably upregulated compared to isogenic sensitive cells. These results suggest that GRK2 could drive a strong pro-survival advantage which mechanism of action, through upregulation of the mRNA-binding protein HuR and the COX2/PGE2/EP axis, is being addressed. In addition, we are undertaking functional correlations of GRK2 with tumor-enabling processes such as angiogenesis or inflammation in CRC samples which could help identify possible therapeutic strategies.

 

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