Integrin α6β4 in Colorectal Cancer: Expression, Regulation, Functional Alterations and Use as a Biomarker

Abstract

Integrin α6β4 is one of the main laminin receptors and is primarily expressed by epithelial cells as an active component of hemidesmosomes. In this article, after a brief summary about integrins in the gut epithelium in general, I review the knowledge and clinical potential of this receptor in human colorectal cancer (CRC) cells. Most CRC cells overexpress both α6 and β4 subunits, in situ in primary tumours as well as in established CRC cell lines. The mechanisms that lead to overexpression have not yet been elucidated but clearly involve specific transcription factors such as MYC. From a functional point of view, one key element affecting CRC cell behaviour is the relocalization of α6β4 to the actin cytoskeleton, favouring a more migratory and anoikis-resistant phenotype. Another major element is its expression under various molecular forms that have the distinct ability to interact with ligands (α6β4 ± ctd) or to promote pro- or anti-proliferative properties (α6Aβ4 vs. α6Bβ4). The integrin α6β4 is thus involved in most steps susceptible to participation with CRC progression. The potential clinical significance of this integrin has begun to be investigated and recent studies have shown that ITGA6 and ITGB4 can be useful biomarkers for CRC early detection in a non-invasive assay and as a prognostic factor, respectively.

Proteomic characterization of GSK3β knockout shows altered cell adhesion and metabolic pathway utilisation in colorectal cancer cells.

“…This multi-protein complex is anchored by integrin α6β4, and both α6 and β4 showed significant and substantial decreases in HCT116-GSK3β-KO cells. Integrins α6 and β4 were the only integrins identified in our study as significantly differentially expressed, consistent with the observation that in epithelial cells β4 only dimerizes with α6 subunit in an exclusive association (23). We investigated the strength of cell-cell adhesion and found that HCT116-GSK3β-KO were significantly less adherent than HCT116-GSK3β-WT cell films consistent with the proteomic data indicating major hemidesmosome disruption.…”

Bladder Cancer Metastasis Induced by Chronic Everolimus Application Can Be Counteracted by Sulforaphane In Vitro

“…Prevention of αV, α6, and β1 up-regulation by SFN or the SFN-everolimus combination could, therefore, immobilize tumor cells to impede cancer progression. Down-regulation of β4 by SFN and, even more so by SFN combined with everolimus, indicates that β4, which mediates pro-migratory and pro-proliferative properties [ 31 , 32 ], could serve as a potential therapeutic target [ 33 ]. Since the combination with everolimus was superior to SFN alone, SFN may re-sensitize tumor cells to everolimus, similar to it re-sensitizing tumor cells to tamoxifen or lapatinib [ 34 , 35 ].…”

An autophagy-related prognostic signature associated with immune microenvironment features of uveal melanoma

“…It was reported that BNIP1 could restrain cervical cancer cell proliferation, migration and invasion by inhibit mTOR signaling pathway, although it seemed to be a risky factor in UM patients [ 26 ]. Integrin subunit α 6 (ITGA6), a member of the integrin α chain family of proteins, is an efficient early-detection biomarker and prognostic factor for colorectal cancer patients [ 27 ]. FKBP1A belongs to immunophilin protein family and mediate the immunosuppressive and antitumor effects of rapamycin [ 28 ].…”