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Integrins are transmembrane receptors that facilitate cell adhesion to the extracellular matrix and neighboring cells. Aberrant expression of integrins has been associated with tumor progression and metastasis in various cancer types. Integrin alpha‐5 (ITGA5) is an integrin subtype that serves as a receptor for fibronectin, fibrinogen, and fibrillin‐1. The purpose of this study was to elucidate how ITGA5 expression plays a role in human non‐small cell lung cancer (NSCLC). Our clinical data, along with data retrieved from The Cancer Genome Database (TCGA), revealed that high ITGA5 expression in NSCLC patients was associated with a lower recurrence‐free survival and overall survival. In our in vitro functional assays, ITGA5 overexpression in human NSCLC cell lines resulted in increased cell size, adhesion, and migration properties, while knockdown of ITGA5 restored the phenotypes. Correspondingly, knockdown and inhibition of ITGA5 in endogenously high‐expressing NSCLC cell lines resulted in decreased cell size, adhesion, migration, and proliferation. The antiproliferative effect was also confirmed by a reduction in Ki‐67 without discernible changes in apoptosis. Collectively, these findings reveal the significant role of ITGA5 in various functional behaviors in NSCLC, providing a potential therapeutic target for NSCLC patients with high ITGA5 expression. Our overexpression, knockdown, and inhibitor studies showed that ITGA5 may play a significant role in NSCLC by affecting cellular adhesion, migration, and proliferation. These findings imply a potential therapeutic target for NSCLC patients with elevated ITGA5 expression.

Summary Metastasis is the main cause of deaths related to breast cancer. This is particular the case for triple negative breast cancer. No targeted therapies are reported as efficient until now. The extracellular matrix, in particular the fibronectin type I motif IGDQ, plays a major role in regulating cell migration prior metastasis formation. This motif interacts with specific integrins inducing their activation and the migratory signal transduction.Here, we characterized the migratory phenotype of MDA-MB-231 cells, using functionalized IGDQ-exposing surfaces, and compared it to integrin A5 and integrin B3 knock-down cells. A multiomic analysis was developed that highlighted the splicing factor SRSF6 as a putative master regulator of cell migration and of integrin intracellular trafficking. Indacaterol-induced inhibition of SRSF6 provoked: i) the inhibition of collective and IGDQ-mediated cell migration and ii) ITGA5 sequestration into endosomes and lysosomes. Upon further studies, indacaterol may be a potential therapy to prevent cell migration and reduce metastasis formation in breast cancer. 1CRnmBvVXp9LXQy1nJKbUF Video Abstract

Altered integrin expression in carcinomas has been associated with tumor aggressiveness, including survival outcomes. The alpha 5 (α5) integrin is associated with increased proliferation, invasion, migration, and metastasis in various types of cancer, however there is no systematic review on its potential as a prognostic marker for survival outcomes. This systematic review analyzed studies reporting α5 integrin detection by immunohistochemistry and associated survival outcomes, retrieved from PubMed, Embase, Scopus, and the Cochrane Library databases. Fourteen publications met the inclusion criteria including a total of 2,018 patients diagnosed with ovarian, colorectal, liver, cervical, esophageal, pancreatic ductal, tongue or bladder carcinoma. The survival outcomes assessed in these studies included overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS), and percent survival. Eleven studies reported a positive association between elevated α5 integrin expression and poorer OS or percent survival, while two found no association. Reduced PFS was associated with elevated α5 integrin expression in three studies, whereas two studies reported no such association. One study evaluated α5 integrin expression in relation to RFS and found no association. In conclusion, there is evidence that increased α5 integrin expression is associated with poorer overall and progression-free survival in carcinomas. However, these findings should be further validated through additional research to confirm its potential as a prognostic marker.

Background The actin filament-associated protein (AFAP) family genes include AFAP1/AFAP-110, AFAP1L1 and AFAP1L2/XB130. Increasing evidence indicates these three AFAP family members participate in tumor progression, but their clinical significance and molecular mechanisms in gastric cancer (GC) remain unclear. Methods We first analyzed expression of AFAP family genes using public datasets and verified the results. The clinical significance of AFAP family genes in GC patients was also analyzed. In vitro and in vivo experiments were applied to explore the function of AFAP1L1. Enrichment analysis was used to explore potential molecular mechanisms. We then performed additional experiments, such as cell adhesion assay, co-immunoprecipitation and so on to confirm the downstream molecular mechanisms of AFAP1L1. Results Public data analyses and our verification both showed AFAP1L1 was the only AFAP family members that was significantly upregulated in GC compared with normal gastric tissues. Besides, only AFAP1L1 could predict poor prognosis and act as an independent risk factor for GC patients. In addition, AFAP1L1 promotes GC cells proliferation, migration, invasion in vitro and tumor growth, metastasis in vivo by inducing epithelial-to-mesenchymal transition (EMT). In terms of mechanism, AFAP1L1 interacts with VAV guanine nucleotide exchange factor 2 (VAV2) to activate Rho family GTPases CDC42, which finally promotes expression of integrin subunit alpha 5 (ITGA5) and activation of integrin signaling pathway. Conclusion AFAP1L1 promotes GC progression by inducing EMT through VAV2-mediated activation of CDC42 and ITGA5 signaling pathway, indicating AFAP1L1 may be a promising prognostic biomarker and therapeutic target for GC patients.

Diabetic retinopathy is a retinal damage, which causes vision impairment and blindness. Integrin Subunit Alpha 5 (ITGA5) regulates angiogenic response, but its roles in diabetic retinopathy remain unclear. In this work, diabetes mellitus was induced in rats by streptozotocin. ITGA5 interference was achieved by intravitreal delivery of adeno-associated virus. Upregulation of ITGA5 was found in diabetic rat retinal tissues. ITGA5 knockdown decreased the neovascularization, acellular capillary formation, and pericytes. The protein expression of vascular endothelial growth factor (VEGFA), vascular adhesion molecule-1(VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) was reduced after ITGA5 interference. Besides, ITGA5 knockdown decreased the phosphorylation level of FAK, TAK-1, and p65. In vitro, rat retinal microvascular endothelial cells (RRMECs) were cultured under high glucose condition to stimulate diabetic environment. ITGA5 knockdown inhibited VEGFA secretion, tube formation, cell invasion, and migration. Upregulation of VCAM-1 and ICAM-1 that induced by high glucose was reversed by ITGA5 silencing. ITGA5 knockdown blocked the activation of TAK-1/NF-kB pathway in RRMECs. Additionally, in oxygen-induced retinopathy model, ITGA5 interference inhibited pathological neovascularization. These results demonstrate that ITGA5 contributes to the angiogenesis in diabetic retinopathy by activating TAK-1/NF-kB pathway.

Hepatocellular carcinoma (HCC) constitutes a formidable global health challenge. Lenvatinib, a multi-targeted tyrosine kinase inhibitor (TKI), has gradually become a cornerstone therapeutic agent for advanced HCC; however, the emergence of drug resistance severely compromises its clinical efficacy and remains a major obstacle to improving patient outcomes. In this study, we identified key genes associated with lenvatinib resistance, among which regulator of nuclear pre-mRNA domain-containing protein 1A (RPRD1A) emerged as a prominent candidate. Functional assays demonstrated that RPRD1A overexpression significantly reduces the sensitivity of HCC to lenvatinib, whereas its knockdown restores drug responsiveness. Mechanistically, RPRD1A competes with RNA polymerase II-associated protein 2 (RPAP2) for binding to RNA polymerase II (RNA Pol II), thereby derepressing integrin subunit alpha 5 (ITGA5) transcription via a c-JUN-dependent pathway. Upregulated ITGA5 subsequently activates focal adhesion kinase (FAK) signaling, which critically drives lenvatinib resistance. Notably, combined treatment with lenvatinib and either the ITGA5 inhibitor volociximab or the FAK inhibitor defactinib effectively reversed lenvatinib resistance in preclinical models. Furthermore, clinical analyses revealed that elevated expression of RPRD1A and ITGA5 correlates with poor response to lenvatinib in HCC patients, reinforcing their potential as predictive biomarkers for therapeutic resistance. Collectively, our results demonstrate that co-targeting the RPRD1A-ITGA5-FAK signaling axis in combination with lenvatinib represents a promising strategy to improve therapeutic efficacy in HCC.

MicroRNA27b-3p (miR-27b) has been reported to be dysregulated in multiple types of human cancer. However, the expression levels, biological roles, and underlying mechanism of miR-27b in tongue squamous cell carcinoma (TSCC) remain to be elucidated. Bioinformatics analyses and quantitative real-time PCR (qRT-PCR) were used to determine miR-27b expression in TSCC tissues and cell lines. The influence of miR-27b overexpression or inhibition on TSCC cell proliferation, migration, and invasion in vitro, and on tumor growth in vivo, was explored via CCK8, colony formation, wound healing, and transwell assays, and in xenograft tumors in nude mice, respectively. Luciferase reporter assays, qRT-PCR, and Western blotting were performed to clarify the potential mechanisms involving miR-27b in TSCC cells. miR-27b was significantly downregulated in TSCC tissues and cell lines, and its expression was correlated with cancer status. Overexpression of miR-27b led to diminished proliferation, migration, and invasion, and notably reduced tumor growth in vivo. Bioinformatics analysis followed by luciferase reporter assays demonstrated that miR-27b expression was inversely correlated with that of integrin subunit α5 (ITGA5)and that miR-27b directly bound to the 3'-untranslated region of ITGA5 in TSCC cells. The bioinformatics analysis also indicated that ITGA5 was upregulated in TSCC and that its expression was correlated with epithelial-mesenchymal transition (EMT) and poor prognosis. Moreover, we found that miRNA-27b could reverse ITGA5-induced promotion of TSCC cell proliferation and migration. Finally, we demonstrated that regulation of miR-27b expression in TSCC may result in alterations in the expression of ITGA5 and EMT-related marker genes at the mRNA and protein levels. These results indicate that miR-27b hampers TSCC proliferation and migration via suppressing the EMT process by targeting ITGA5. These findings support consideration of miR-27b/ITGA5 as a valuable marker for the metastatic potential of TSCC, or as a therapeutic target for the treatment of TSCC.

The node and notochord (and their equivalents in other species) are essential signaling centers, positioned along the plane of bilateral symmetry in developing vertebrate embryos. However, genes and mechanisms regulating morphogenesis of these structures and their placement along the embryonic midline are not well understood. In this work, we provide the first evidence that the position of the node and the notochord along the bilateral plane of symmetry are under genetic control and are regulated by integrin α5β1 and fibronectin in mice. We found that the shape of the node is often inverted in integrin α5-null and fibronectin-null mutants, and that the positioning of node and the notochord is often skewed away from the perceived plane of embryonic bilateral of symmetry. Our studies also show that the shape and position of the notochord are dependent on the shape and embryonic placement of the node. Our studies suggest that fibronectin regulates the shape of the node by affecting apico-basal polarity of the nodal cells. Taken together, our data indicate that cell–extracellular matrix interactions mediated by integrin α5β1 and fibronectin regulate the geometry of the node as well as the placement of the node and notochord along the plane of bilateral symmetry in the mammalian embryo.

Objective. This study aimed to screen potential crucial lncRNAs and genes involved in aging. Methods. The data of 9 peripheral white adipocytes, respectively, taken from male C57BL/6J mice (6 months, 14 months, and 18 months of age) in GSE25905 were used in this study. Differentially time series expressed lncRNA genes (DE-lncRNAs) and mRNA genes (DEGs) were identified. After cluster analysis of lncRNAs expression pattern, target genes of DE-lncRNAs were predicted from the DEGs, and functional analysis for target genes was conducted. Results. A total of 8301 time series-related DEGs and 43 time series-related DE-lncRNAs were identified. Among them, 41 DE-lncRNAs targeted 1880 DEGs. The DEGs positively regulated by DE-lncRNAs were mainly related to the development of blood vessel and the pathways of cholesterol biosynthesis and elastic fibre formation. Furthermore, the DEGs negatively regulated by DE-lncRNAs were correlated with protein metabolism. Conclusion. These DE-lncRNAs and DEGs are potentially involved in the process of aging.

We recently demonstrated that cell spreading on surface-adsorbed fibronectin activates the Na/H antiporter and that inhibition of this chemical-signaling pathway suppresses growth. We now show that insoluble fibronectin activates the Na/H antiporter by clustering and immobilizing integrin alpha sub(5) beta sub(1), independent of effects on cell shape. The results show that an extracellular matrix receptor can behave similarly to a growth factor receptor to activate a signaling pathway implicated in growth control.