Repression of 4F2hc impairs tumorigenicity


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Angélica Santiago-Gómez (1), Javier Turnay (1), Emilio Lecona (1), Nieves Olmo (1), Hans Burghardt (2), Manuel Palacín (2), Mª Antonia Lizarbe (1)
Dept. Biochemistry and Molecular Biology I, Faculty of Chemistry, Complutense University of Madrid, Madrid, Spain (1), Institute for Research in Biomedicine (IRB), Barcelona, Spain (2)

Background

4F2hc (heavy chain) is over-expressed in hepatoma, breast and colon cancer. 4F2hc has been proposed as a potential tumour marker of poor prognosis in patients who have suffered larynx, breast, renal or lung cancer. Moreover, a direct correlation between in vitro over-expression of the protein and malignant transformation of NIH3T3 cells has been shown, and its deletion markedly impaired the ability of embryonic stem cells to form teratocarcinomas in mice. This multifunctional protein associates with beta1-integrin (modulating integrin signalling events) and with different light chains (being the guide towards the membrane and enabling heteromeric amino acid transport). The aim of this study is to analyze the role of 4F2hc in tumorigenesis.

Method

We have used colon adenocarcinoma cells lines with different tumorigenic capacity to check the relation of 4F2hc with tumorigenicity. Additionally, we have silenced 4F2hc expression in HeLa cells by miRNA using a HIV-derived lentiviral system for cell transduction.

Results

After assessing the expression of 4F2hc in colon adenocarcinoma cells with different tumorigenic capacity and differentiation degree, a clear correlation was not clearly evident. In vivo experiments showed a reduction of 39% in the weight of tumours derived from 4F2hc silenced-HeLa cells compared with control ones. Furthermore, a delay in the tumour growth lag phase indicates a relevant role of 4F2hc in tumour initial growth. We did not find significant differences in the in vitro response of silenced-HeLa cells regarding adhesion and spreading on several extracellular matrix proteins. However, mitogenic activity in response to serum or PMA as well as the Akt signalling pathway are impaired in silenced cells.

Conclusion

A silenced 4F2hc cell line has been obtained showing an impaired ability to form tumours in athymic nude mice which is not related with alterations in adhesion and spreading processes, but impaires mitogenic response to serum or PMA and Akt signalling.

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