Integrin α1β1 expression is controlled by c-MYC in colorectal cancer cells

Abstract

The α1β1 collagen receptor is only present in a few epithelial cell types. In the intestine, it is specifically expressed in proliferating crypt cells. This integrin has been reported to be involved in various cancers where it mediates the downstream activation of the Ras/ERK proliferative pathway. We have recently shown that integrin α1β1 is present in two-thirds of colon adenocarcinomas, but the mechanism by which ITGA1 expression is regulated is not known. DNA methylation, involved in ITGA1 repression during megakaryocyte differentiation, is not the mechanism of ITGA1 regulation in colorectal cancer cells. Our in silico analysis of the ITGA1 promoter revealed two response elements for MYC, an oncogenic factor known to regulate cancer cell proliferation, invasion and migration. In situ, the expressions of both MYC and ITGA1 are localized in the lower crypt of the normal colon and correlate in 72% of the 65 analyzed colorectal cancers. MYC pharmacological inhibition or downregulation of expression with short hairpin RNA in HT29, T84 and SW480 cells resulted in reduced ITGA1 expression at both the transcript and protein levels. Chromatin immunoprecipitation assays revealed that MYC was bound to the chromatin region of the ITGA1 proximal promoter, whereas MYC overexpression enhanced ITGA1 promoter activity that was reduced with MAD co-transfection or by the disruption of the response elements. We concluded that MYC is a key regulating factor for the control of ITGA1 expression.

The integrin–collagen connection – a glue for tissue repair?

“…Furthermore, the absence of α1 has been found to ameliorate or reduce tumor growth and metastasis in a number of lung cancer models (Chen et al, 2005;Macias-Perez et al, 2008). Careful investigation of the role of α1 in the colon has revealed that it is expressed on both epithelial cells and submucosal myofibroblasts (Boudjadi et al, , 2015. Interestingly, increased levels of α1 in tumors can be found in the majority of colon cancer patients , and it has recently been demonstrated that α1 expression is mediated by the transcription factor Myc, raising the possibility that α1 integrin is important in mediating the effects of Myc in colon cancer and other tumors (Boudjadi et al, 2015).…”

“…Careful investigation of the role of α1 in the colon has revealed that it is expressed on both epithelial cells and submucosal myofibroblasts (Boudjadi et al, , 2015. Interestingly, increased levels of α1 in tumors can be found in the majority of colon cancer patients , and it has recently been demonstrated that α1 expression is mediated by the transcription factor Myc, raising the possibility that α1 integrin is important in mediating the effects of Myc in colon cancer and other tumors (Boudjadi et al, 2015). Only limited information exists with regard to the expression of α1 in the tumor stroma, except for the above-mentioned role in tumor angiogenesis (Pozzi et al, 2000) and the expression of cancer-associated fibroblasts (CAFs) in colon cancer Rodriguez et al, 2009).…”

Sterol regulatory element-binding protein 1 cooperates with c-Myc to promote epithelial-mesenchymal transition in colorectal cancer

“…The proto-oncogene, c-Myc, serves crucial roles in various types of cancer and is known to be highly expressed in the majority of cases of CRCs (12)(13)(14)(21)(22)(23). It has been reported that c-Myc is primarily involved in regulation at the transcriptional and post-transcriptional levels in multiple types of cancer (14,(21)(22)(23).…”

“…Due to the fact that c-Myc is highly expressed in CRC and that SNAIL is one of the crucial targets of c-Myc in EMT (12)(13)(14), the present study investigated whether or not c-Myc is responsible for SREBP1-driven SNAIL expression and EMT in CRC. To begin with, the expression of c-Myc was measured in different CRC cell lines and it was revealed that c-Myc is highly expressed in all these CRC cell lines (Fig.…”

Aqueous extract of Sanguisorba officinalis blocks the Wnt/β-catenin signaling pathway in colorectal cancer cells

“…In fact, HT29 cell is different from the HEK293 cell at gene levels. In HT29 cells, the Wnt/b-catenin signaling pathway has been innately and aberrantly activated by the mutation of APC 27 and Wnt-related oncogenes especially c-Myc 28 and CyclinD1 (ref. 29) are overexpressed.…”