Involvement of the Integrin α1β1 in the Progression of Colorectal Cancer.

Salah Boudjadi,Blanche Sénicourt,Jean-François Beaulieu,Gérald Bernatchez,Marco Beauséjour,Pierre Vachon,Julie Carrier

doi:10.3390/cancers9080096

Abstract

Integrins are a family of heterodimeric glycoproteins involved in bidirectional cell signaling that participate in the regulation of cell shape, adhesion, migration, survival and proliferation. The integrin α1β1 is known to be involved in RAS/ERK proliferative pathway activation and plays an important role in fibroblast proliferation. In the small intestine, the integrin α1 subunit is present in the crypt proliferative compartment and absent in the villus. We have recently shown that the integrin α1 protein and transcript (ITGA1) are present in a large proportion of colorectal cancers (CRC) and that their expression is controlled by the MYC oncogenic factor. Considering that α1 subunit/ITGA1 expression is correlated with MYC in more than 70% of colon adenocarcinomas, we postulated that the integrin α1β1 has a pro-tumoral contribution to CRC. In HT29, T84 and SW480 CRC cells, α1 subunit/ITGA1 knockdown resulted in a reduction of cell proliferation associated with an impaired resistance to anoikis and an altered cell migration in HT29 and T84 cells. Moreover, tumor development in xenografts was reduced in HT29 and T84 sh-ITGA1 cells, associated with extensive necrosis, a low mitotic index and a reduced number of blood vessels. Our results show that α1β1 is involved in tumor cell proliferation, survival and migration. This finding suggests that α1β1 contributes to CRC progression.

Highlights

As a unique family of heterodimeric transmembrane glycoproteins, integrins are characterized by their involvement in bidirectional cell signaling that participates in the regulation of cell shape, adhesion, migration, survival and proliferation
We have previously shown that the integrin α1 subunit/ITGA1 is present in the crypt proliferative compartment and normally absent in the villus of the small intestine and in the surface epithelium of the colon [11], while in colorectal cancers (CRC), it is present in 65% of tumors where its expression appears to be regulated by the oncogenic MYC transcription factor [12], suggesting that the integrin α1β1 is involved in colorectal neoplasia
Since integrin α1β1 was shown to be involved in the proliferation of different cell types including endothelial cells [14], fibroblasts [15] and pulmonary carcinomatous cells [16], we first tested whether this integrin is important for the proliferation of CRC cells

Summary

Introduction

As a unique family of heterodimeric transmembrane glycoproteins, integrins are characterized by their involvement in bidirectional cell signaling that participates in the regulation of cell shape, adhesion, migration, survival and proliferation. The integrin α1β1 is known to be involved in the mitogen-activated protein kinase (MEK [MAPK] kinase)/extracellular regulated kinase (ERK). Proliferative pathway activation through the recruitment of caveolin-1 and the Src homology 2 domain containing transforming protein 1 (Shc) by the integrin α1 subunit [1,2,3]. It was demonstrated that the integrin α1β1 regulates different pathways and functions through specific amino acids in the cytoplasmic tail of the integrin α6 subunit [6]. These characteristics reflect the reported involvement of the integrin α1β1 in the proliferation of fibroblasts, endothelial cells and in mammary carcinoma

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Results

Conclusion