Increased Expression of Integrin Alpha 6 in Nucleus Pulposus Cells in Response to High Oxygen Tension Protects against Intervertebral Disc Degeneration

The destruction of the low oxygen microenvironment in nucleus pulposus (NP) cells played a critical role in the pathogenesis of intervertebral disc degeneration (IVDD). The purpose of this study was to determine the potential role of integrin alpha 6 (ITG α6) in NP cells in response to high oxygen tension (HOT) in IVDD. Immunofluorescence staining and western blot analysis showed that the levels of ITG α6 expression were increased in the NP tissue from IVDD patients and the IVDD rat model with mild degeneration, which were reduced as the degree of degeneration increases in severity. In NP cells, the treatment of HOT resulted in upregulation of ITG α6 expression, which could be alleviated by blocking the PI3K/AKT signaling pathway. Further studies found that ITG α6 could protect NP cells against HOT-induced apoptosis and oxidative stress and protect NP cells from HOT-inhibited ECM protein synthesis. Upregulation of ITG α6 expression by HOT contributed to maintaining NP tissue homeostasis through the interaction with hypoxia-inducible factor-1α (HIF-1α). Furthermore, silencing of ITG α6 in vivo could obviously accelerate puncture-induced IVDD. Taken together, these results revealed that the increase of ITG α6 expression by HOT in NP cells might be a protective factor in IVD degeneration as well as restore NP cell function.

Dual Role of Integrin Alpha-6 in Glioblastoma: Supporting Stemness in Proneural Stem-Like Cells While Inducing Radioresistance in Mesenchymal Stem-Like Cells

Therapeutic resistance after multimodal therapy is the most relevant cause of glioblastoma (GBM) recurrence. Extensive cellular heterogeneity, mainly driven by the presence of GBM stem-like cells (GSCs), strongly correlates with patients’ prognosis and limited response to therapies. Defining the mechanisms that drive stemness and control responsiveness to therapy in a GSC-specific manner is therefore essential. Here we investigated the role of integrin a6 (ITGA6) in controlling stemness and resistance to radiotherapy in proneural and mesenchymal GSCs subtypes. Using cell sorting, gene silencing, RNA-Seq, and in vitro assays, we verified that ITGA6 expression seems crucial for proliferation and stemness of proneural GSCs, while it appears not to be relevant in mesenchymal GSCs under basal conditions. However, when challenged with a fractionated protocol of radiation therapy, comparable to that used in the clinical setting, mesenchymal GSCs were dependent on integrin a6 for survival. Specifically, GSCs with reduced levels of ITGA6 displayed a clear reduction of DNA damage response and perturbation of cell cycle pathways. These data indicate that ITGA6 inhibition is able to overcome the radioresistance of mesenchymal GSCs, while it reduces proliferation and stemness in proneural GSCs. Therefore, integrin a6 controls crucial characteristics across GBM subtypes in GBM heterogeneous biology and thus may represent a promising target to improve patient outcomes.

Inhibited Long Non-Coding RNA OIP5-AS1 Elevated microRNA-92a to Suppress Proliferation and Metastasis of Ovarian Cancer Cells by Silencing ITGA6

Objective: Over the years, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been identified as essential biomarkers during the development of malignancies. This study was performed to verify the roles of lncRNA opa-interacting protein 5 antisense transcript 1 (OIP5-AS1) and miR-92a in ovarian cancer (OC).Methods: OIP5-AS1, miR-92a and ITGA6 expression in tissues and cells was assessed. The screened OC cells were respectively with integrin alpha 6 (ITGA6)/OIP5-AS1 silenced vector, miR-92a mimic/inhibitor or their negative controls. The viability, migration, invasion and apoptosis of the cells were determined and the levels of epithelial-mesenchymal transition (EMT)-related proteins were also measured. The interactions between OIP5-AS1 and miR-92a, and between miR-92a and ITGA6 were confirmed by dual luciferase report gene assay and/or RNA pull-down assay.Results: OIP5-AS1 and ITGA6 were upregulated while miR-92a was downregulated in OC tissues versus the adjacent normal tissues. Inhibited OIP5-AS1 or elevated miR-92a repressed EMT, viability, migration and invasion of OC cells, and promoted OC cell apoptosis. These effects that induced by silenced OIP5-AS1 could be reversed by miR-92a inhibitor. The reduction of ITGA6 restricted EMT in OC cells. MiR-92a was a target of OIP5-AS1 and ITGA6 was targeted by miR-92a.Conclusion: OIP5-AS1 silencing promoted miR-92a to repress proliferation and metastasis of OC cells through inhibiting ITGA6. This research may provide potential biomarkers for OC.

Integrin-alpha-6+ Candidate stem cells are responsible for whole body regeneration in the invertebrate chordate Botrylloides diegensis

Colonial ascidians are the only chordates able to undergo whole body regeneration (WBR), during which entire new bodies can be regenerated from small fragments of blood vessels. Here, we show that during the early stages of WBR in Botrylloides diegensis, proliferation occurs only in small, blood-borne cells that express integrin-alpha-6 (IA6), pou3 and vasa. WBR cannot proceed when proliferating IA6+ cells are ablated with Mitomycin C, and injection of a single IA6+ Candidate stem cell can rescue WBR after ablation. Lineage tracing using EdU-labeling demonstrates that donor-derived IA6+ Candidate stem cells directly give rise to regenerating tissues. Inhibitors of either Notch or canonical Wnt signaling block WBR and reduce proliferation of IA6+ Candidate stem cells, indicating that these two pathways regulate their activation. In conclusion, we show that IA6+ Candidate stem cells are responsible for whole body regeneration and give rise to regenerating tissues.

MicroRNA-363-3p suppresses anoikis resistance in human papillary thyroid carcinoma via targeting integrin alpha 6

MicroRNAs are highly conserved endogenous small noncoding RNAs and demonstrated to play important roles in the metastatic cascade of papillary thyroid carcinoma (PTC), including the process of anoikis resistance. In this study, the correlation between miRNA-363-3p (miR-363-3p) expression and PTC metastasis was analyzed based on clinical data, and the effect and related mechanism of miR-363-3p on anoikis resistance in B-CPAP cells were further investigated. First, miR-363-3p was found to be down-regulated in PTC tissue, which was correlated with the advanced clinical stage and lymph node (LN) metastasis. Then, functional study revealed that miR-363-3p was also down-regulated in B-CPAP cells compared with that in thyroid epithelial Nthy-ori3-1 cells, and miR-363-3p transfection could suppress anoikis resistance of B-CPAP cells. Finally, integrin alpha 6 (ITGA6) was validated as the target gene of miR-363-3p, and restoration of ITGA6 expression attenuated miR-363-3p’s inhibitory effect on anoikis resistance in B-CPAP cells. These findings contribute to understand the role of miR-363-3p in the metastatic cascade of PTC and suggest the potential clinical value of miR-363-3p for the prevention of PTC metastasis.