FAK alternative splice mRNA variants expression pattern in colorectal cancer

• Published in: International journal of cancer Vol. 145; no. 2; pp. 494 - 502
• Main Authors: Devaud, Christel, Tilkin‐Mariamé, Anne‐Françoise, Vignolle‐Vidoni, Alix, Souleres, Philippine, Denadai‐Souza, Alexandre, Rolland, Corinne, Duthoit, Christine, Blanpied, Catherine, Chabot, Sophie, Bouillé, Pascale, Lluel, Philippe, Vergnolle, Nathalie, Racaud‐Sultan, Claire, Ferrand, Audrey
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 15-07-2019; Wiley Subscription Services, Inc; Wiley
• Subjects: Alternative Splicing; Animal models; Animals; Biochemistry, Molecular Biology; Biomarkers, Tumor - genetics; Cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; FAK; Female; Focal adhesion kinase; Focal Adhesion Kinase 1 - genetics; Gene expression; Gene Expression Regulation, Neoplastic; Genomics; HCT116 Cells; HT29 Cells; Humans; Invasiveness; Isoforms; Kinases; Life Sciences; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver Neoplasms - secondary; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Lungs; Medical research; Metastases; Metastasis; Mice; Molecular Cancer Biology; mRNA; Neoplasm Invasiveness; Neoplasm Transplantation; RNA Isoforms - genetics; Therapeutic applications; Tumors; Up-Regulation; FAK; metastases; colorectal cancer; alternative splicing
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.32120

The Focal adhesion kinase (FAK) is a ubiquitous cytoplasmic tyrosine‐kinase promoting tumor progression and metastasis processes by acting in cancer cells and their tumor microenvironment partners. FAK overexpression in primary colon tumors and their metastasis is associated to poor colorectal cancer (CRC) patients’ outcome. Eight FAK mRNA alternative splice variants have been described and contribute to additional level of FAK activity regulation, some of them corresponding to overactivated FAK isoforms. To date, FAK mRNA alternative splice variants expression and implication in CRC processes remain unknown. Here, using different human CRC cells lines displaying differential invasive capacities in an in vivo murine model recapitulating the different steps of CRC development from primary tumors to liver and lung metastasis, we identified three out of the eight mRNA variants (namely FAK0, FAK28 and FAK6) differentially expressed along the CRC process and the tumor sites. Our results highlight an association between FAK0 and FAK6 expressions and the metastatic potential of the most aggressive cell lines HT29 and HCT116, suggesting that FAK0 and FAK6 could represent aggressiveness markers in CRC. Our findings also suggest a more specific role for FAK28 in the interactions between the tumors cells and their microenvironment. In conclusion, targeting FAK0, the common form of FAK, might not be a good strategy based on the numerous roles of this kinase in physiological processes. In contrast, FAK6 or FAK28 splice variants, or their corresponding protein isoforms, may putatively represent future therapeutic target candidates in the development of CRC primary tumors and metastasis.
What's new?
Overexpression of the focal adhesion kinase (FAK) is associated with poor outcome in patients with colorectal cancer but the role of the eight splice variants of FAK remains unknown. Here the authors correlated FAK splice variant expression in colorectal tumor cell lines with invasiveness in mouse models. FAK0 and FAK6 splice variant expression was associated with higher aggressiveness and metastatic potential, underscoring that distinct FAK splice variants may represent new targets in the development of drugs against colorectal cancer and associated metastasis.