Integrin α6β4 requires plectin and vimentin for adhesion complex distribution and invasive growth

Integrin α6β4 binds plectin to associate with vimentin; however, the biological function remains unclear. Here, we utilized various integrin β4 mutants and CRISPR-Cas9 editing to investigate this association. Upon laminin binding, integrin α6β4 distinctly distributed peripherally, and centrally proximal to the nucleus. Upon fibronectin addition, integrin α6β4 was centrally recruited to large focal adhesions (FAs) and enhanced Fak phosphorylation. Integrin β4 plectin-binding mutants or genetic deletion of plectin inhibited β4 recruitment to FAs and integrin α6β4-enhanced cell spreading, migration and three-dimensional invasive growth. Loss of the β4 signaling domain (but retains plectin binding) blocked migration and invasiveness but not cell spreading, recruitment to FAs or colony growth. Immunostaining revealed that integrin α6β4 redistributed vimentin perinuclearly where it colocalized with plectin and FAs. Depletion of vimentin completely blocked integrin β4-enhanced invasive growth, Fak phosphorylation and proliferation in three-dimensions but not two-dimensions. In summary, we demonstrate the essential roles of plectin and vimentin in promoting an invasive phenotype downstream of integrin α6β4.

Integrin β4 as a Potential Diagnostic and Therapeutic Tumor Marker

Integrin β4 (ITGβ4) is a class of transmembrane adhesion molecules composed of hemidesmosomes (HDs). Its unique long intracellular domain provides intricate signal transduction functions. These signal transduction effects are especially prominent in tumors. Many recent studies have shown that integrin β4 is differentially expressed in various tumors, and it plays a vital role in tumor invasion, proliferation, epithelial–mesenchymal transition, and angiogenesis. Therefore, we categorize the research related to integrin β4, starting from its structure and function in tumor tissues, and provide a basic description. Based on its structure and function, we believe that integrin β4 can be used as a tumor marker. In clinical practice, it is described as a diagnostic marker for the targeted treatment of cancer and will be helpful in the clinical diagnosis and treatment of tumors.

Localization of Integrin Beta-4 Subunit at Soft Tissue–Titanium or Zirconia Interface

Currently, along with titanium (Ti), zirconia is widely used as an abutment material for dental implants because it makes it possible to avoid gingival discoloration; however, the epithelial sealing capability of zirconia remains unknown. The purpose of the present study is to elucidate the localization of integrin β4 subunit (Inβ4), one of the main proteins in the attachment structure between gingival junctional epithelial (JE) cells and substrata. Maxillary first molars were extracted from rats, and implants were placed with Ti or zirconia transgingival parts; then, the localization of Inβ4 was observed. Morphological and functional changes in rat oral epithelial cells (OECs) cultured on a culture dish (Dish) and Ti and zirconia plates were also evaluated with Inβ4 immunofluorescence histochemistry and Western blotting. After four weeks of implant placement, the morphology of the peri-implant epithelium (PIE) and the localization of Inβ4 around the Ti and zirconia transgingival parts were similar. However, both exhibited markedly shorter Inβ4-positive bands in the PIE than in the JE around natural teeth. Decreased expression levels of Inβ4 were observed in OECs cultured on Ti and zirconia plates compared with those cultured on Dish. In conclusion, although inferior to natural teeth, zirconia implants are thought to have epithelial sealing properties comparable to those of titanium.

Cancer Exosome-derived Integrin α6 and Integrin β4 Promote Lung Metastasis of Colorectal Cancer

Background: Colorectal cancer (CRC) metastasis remains the major cause of the CRC mortality, while the underlying mechanisms remain to be fully understood. In this study we investigated the role of cancer exosomes in CRC lung metastasis in vivo and in vitro. Methods: Expressions of Integrinα6 and Integrin β4 were examined in CRC cells as well as released exosomes. Co-culture assay with vascular endothelial cells was also analyzed.Results: We found that Integrin α6 and Integrin β4 are overexpressed in highly tumorigenic and metastatic CRC cell lines HCT116 and SW620 and their secreted exosomes, compared to the low tumorigenic and non-metastatic CRC cell lines. Disruption of ITGA6 and ITGB4 expression in CRC decreased the proliferation and tubulogenic capacities of vascular endothelial cells significantly, while ectopic expression of ITGA6 and ITGB4 gave rise to opposite effects. Further more, we demonstrated that exosomal ITGA6 and ITGB4 promoted the lung metastasis of CRCs in vivo.Conclusions: Our study provides new insight into the molecular mechanism of CRC metastasis by which CRC-derived exosomal ITGA6 and ITGB4 induce organotropism to the lung, leading to increased tubulogenic capacity and metastasis. It also reveals a biomarker-based prediction for CRC metastasis and a novel potential therapeutic targets for CRC.