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FAK alternative splice mRNA variants expression pattern in colorectal cancer.

ABSTRACT: 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.

SUBMITTER: Devaud C

PROVIDER: S-EPMC6563491 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: CD44 is considered as 'a' metastasis associated gene, despite the fact that it is an umbrella term for a group of molecules produced from a single gene by alternative splicing. However, little consideration is given to the above in the literature of colorectal carcinomas as well as other tumour types, leading to confusion and contradictory results about its possible role in tumour progression. METHODS: We compared the CD44 alternative splice pattern (ASP) of three genetically different human colorectal cancer cell lines (HT25, HT29, HCT116) using a series of PCR reactions and next- generation sequencing method, as well as identified a colorectal adenocarcinoma specific CD44 ASP. This ASP was further investigated in terms of its qualitative and quantitative stability in our experimental iso- and xenograft mouse models for colorectal cancer progression. A complex preclinical experimental set-up was established to separately test the different steps of tumour progression and the role of tumour microenvironment, respectively, focusing on the role of 'CD44' in this process. RESULTS: We managed to present a colorectal cancer-specific CD44 ASP, which remained unchanged from cell lines throughout primary tumour formation and metastatic progression. Furthermore, we report a unique roster of all expressed CD44 variant isoforms characteristic to colorectal cancer. Finally, on quantitative assessment of the variable exons v3 and v6, higher co-expression levels were found to be characteristic to metastatically potent tumour cells. CONCLUSION: Particular CD44 variant isoforms seem to act as "metastasis genes" via tumour microenvironment-driven shifts in v3 and v6 expressions. However, this function may just affect a minority of tumour subclones. This fact and the huge potential number of different CD44 splice variants that can contain v3 and v6 domains can explain incoherence of clinical studies regarding functional asessment of CD44 variants, as well as diminish the chances of using CD44 variants for predictive purpose.

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FAK alternative splice mRNA variants expression pattern in colorectal cancer.

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