Integrin β4 promotes cell invasion and epithelial-mesenchymal transition through the modulation of Slug expression in hepatocellular carcinoma

Abstract

Integrin β4 (ITGB4) is a transmembrane receptor involved in tumorigenesis and the invasiveness of many cancers. However, its role in hepatocellular carcinoma (HCC), one of the most prevalent human cancers worldwide, remains unclear. Here, we examined the involvement of ITGB4 in HCC and explored the underlying mechanisms. Real-time PCR and immunohistochemical analyses of tissues from 82 patients with HCC and four HCC cell lines showed higher ITGB4 levels in tumor than in adjacent non-tumor tissues and in HCC than in normal hepatic cells. Silencing of ITGB4 repressed cell proliferation, colony forming ability and cell invasiveness, whereas ectopic expression of ITGB4 promoted the proliferation and invasion of HCC cells and induced epithelial to mesenchymal transition (EMT) in parallel with the upregulation of Slug, as shown by transwell assays, WB and immunocytochemistry. Knockdown of Slug reduced cell viability inhibited invasion and reversed the effects of ITBG4 overexpression on promoting EMT, and AKT/Sox2-Nanog may also be involved. In a xenograft tumor model induced by injection of ITGB4-overexpressing cells into nude mice, ITGB4 promoted tumor growth and metastasis to the lungs. Taken together, our results indicate that ITGB4 plays a tumorigenic and pro-metastatic role mediated by Slug and suggest IGTB4 could be a prognostic indicator or a therapeutic target in patients with HCC.

Identification of prognostic and bone metastatic alternative splicing signatures in bladder cancer

“…Phosphoinositide 3-kinase (PI3K) and RhoA small gtpase were activated by integrin alpha 6 beta 4 bound to laminin. In addition, the interaction between integrin alpha6 beta4 and growth factor receptors included activation signaling pathways of the epidermal growth factor receptor family, such as PI3K AKT, and MAPK signaling was involved in tumorigenesis and metastasis [44]. Therefore, similar to our hypothesis, ITGB4 was associated with bone metastasis of bladder cancer and could be used as a prognostic marker in bladder cancer.…”

Cullin7 promotes epithelial‑mesenchymal transition of esophageal carcinoma via the ERK‑SNAI2 signaling pathway

“…On the basis of the associations between CUL7 expression and invasion depth, lymph node involvement and advanced clinical stage, CUL7 may promote EMT in EC cells. SNAI2 is a transcription factor that has been reported to be upregulated in various types of tumors and is associated with decreased expression of the epithelial marker E-cadherin and increased expression of the mesenchymal marker Vimentin, and may thus serve important roles in the regulation of EMT (18). In the present study, results from IHC and cell culture experiments suggested that CUL7 may enhance the expression levels of SNAI2 and Vimentin, and inhibit E-cadherin expression, and increase cell migration.…”

Peer Review #1 of "Expression and prognostic analyses of ITGA11, ITGB4 and ITGB8 in human non-small cell lung cancer (v0.1)"

“…Manuscript to be reviewed migration, epithelial-mesenchymal transition, invasion, and metastasis in different cancers (Gan et al 2018;Huang et al 2017;Kitajiri et al 2002;Li et al 2017). The aberrant expression of ITGA11, ITGB4, and ITGB8 have been reported in many cancers (Grossman et al 2000;Mertens-Walker et al 2015;Parajuli et al 2017;Tagliabue et al 1998).…”

“…Moreover, higher ITGB4 expression level was detected in tumor than adjacent non-tumor tissues in patients with hepatocellular carcinoma (HCC). Silencing of ITGB4 could repress cell proliferation, colony forming ability and cell invasiveness (Li et al 2017). Integrin β8, paired with αv subunit, is encoded by ITGB8.…”