Expression Of ITGA11 Research Articles

Association of ITGA 11 and ITGAV upregulation with outcomes in gastric cancer.

332 Background: Gastric cancer (GC) is a common cancer worldwide. The integrin α (ITGA) family members play essential roles in various cancers and variants of ITGA are involved in metastatic process in gastric cancer. Thus, this study was conducted to explore the roles of ITGA family members in stomach adenocarcinoma (STAD). Methods: RNA-sequencing FPKM data and corresponding clinical information of 375 STAD tumor tissues and 32 normal tissues were retrieved from The Cancer Genome Atlas (TCGA). The ‘limma’ package was used to compare the expression differences between the normal and cancer tissues using Wilcoxon rank-sum test. Analysis of overall survival (OS) was conducted by Kaplan–Meier (K–M) method via ‘survminer’ package. Univariate Cox hazard regression analysis was applied to seven clinicopathological variables from T stage, N stage, M stage, pathologic stage, histologic grade, gender, age, and expression level of selected ITGA family members, by using ‘survival’ package. Furthermore, a nomogram was also visualized by the R ‘rms’ package and ‘survival’ package to predict the 1-, 3-, and 5-year OS and individual predictors. Results: The expression of ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA11, and ITGAV were upregulated in STAD tissues compared with normal tissues (P<0.05), whereas ITGA7, ITGA8, and ITGA9 were downregulated in tumor tissues (P<0.05). In addition, no statistically significant difference was found for TGA1 and ITGA10 between tumor and normal tissues ((P>0.05). Further survival analysis found that higher expression of ITGA 11 (HR=1.46, 95%CI 1.05-2.03, P<0.026) and ITGAV (HR=1.92, 95%CI 1.37-2.70, P<0.001) were associate with worse OS. Univariate Cox hazard regression analysis showed that T3, T4, N1, N3, M1, pathologic stage III and IV, age>65, and high expression level of ITGA11 and ITGAV were associated with worse OS (all P < 0.05). The nomogram based on six clinicopathological variables (T stage, N stage, M stage, pathologic stage, age, and expression levels of ITGA11 and ITGAV) and 1-, 3-, 5-year OS probabilities were developed. The concordance index (C-index) of the nomograms was 0.673(0.647-0.700), indicating that the potential predicting role and sufficient discrimination ability of the nomogram as C-index was more than 0.5. The calibration curves of 1-, 3-, and 5-year indicated the consistency of our results and the predictive values, indicating satisfactory performance for this nomogram. However, 1-, 3-, 5-year AUCs of ITGA11- and ITGAV-based nomogram were 0.687, 0.691, and 0.687, showing a relatively acceptable accuracy as they were great than 0.5. Conclusions: ITGA2, ITGA3, ITGA4, ITGA5, ITGA6, ITGA11, and ITGAV are upregulated, while ITGA7, ITGA8, and ITGA9 are down regulated in STAD tumor samples. High expression levels of ITGA11 and ITGAV are associated with worse OS. The ITGA11- and ITGAV-based monogram developed by this study might be useful in predicting the OS outcome for STAD patients.

P056 Crohn’s Disease associated fibrosis modulates the expression of collagen receptors

Abstract Background Crohn’s Disease (CD) patients often develop stenotic complications as immunomodulatory treatments do not prevent the fibrogenic response in the affected tissues, where a dysregulated activation of stromal cells provokes an excessive deposition of extracellular matrix (ECM). Recent evidences support the notion that local cells can sense the consequent alterations in tissue structure and rigidity through receptors that respond to some ECM components, and this may perpetuate the fibrogenic process even in the absence of inflammation. We aim to analyse the relevance of these signalling pathways in the fibrotic process associated to CD. Methods We obtained fibrotic ileal tissues from CD patients and healthy ileal samples from colon carcinoma patients (control), and analysed the expression (RT-PCR, IHQ) of collagen receptors (integrins, discoidin domain receptors/DDR) and of markers for some stromal cells (fibroblasts, endothelial cells). The relationship between these sets of data was analysed by Pearson’s correlation and the results organized as a correlation matrix. The expression of collagen receptors was also analysed in endothelial cells (HUVEC) treated with TGFβ 2 (1ng/ml, 48h). Results Ileal samples from CD patients present a differential gene expression of collagen receptors (Fig 1), with increased levels of ITGA10, ITGA11 and DDR2, and reduced expression of DDR1. In CD tissues, the expression of ITGA11 and DDR1 showed a significant correlation, positive and negative respectively, with that of endothelial markers (Fig 2). These correlations do not occur in control tissues. Integrin-α11 was detected in endothelial cells of submucosal vessels (IHQ). In HUVEC, TGFβ 2 increased the expression of ITGA11 (8.1±0.7 fold induction, p<0.01) and reduced that of DDR1 (0.74±0.06 fold induction, p<0.01), without affecting that of the other collagen receptors. Conclusion Intestinal tissues from CD patients affected by fibrosis present an altered pattern of expression of collagen receptors, which suggests a regulatory role of the ECM in the fibrotic response, while the correlation analysis and the changes induced by the fibrotic cytokine TGFβ in endothelial cells insinuates a particular relevance of these stromal cells in this process.

Cancer-associated fibroblast migration in non-small cell lung cancers is modulated by increased integrin α11 expression.

Cancer‐associated fibroblasts (CAFs) regulate cancer progression through the modulation of extracellular matrix (ECM) and cancer cell adhesion. While undergoing a series of phenotypic changes, CAFs control cancer–stroma interactions through integrin receptor signaling. Here, we isolated CAFs from patients with non‐small‐cell lung cancer (NSCLC) and examined their gene expression profiles. We identified collagen type XI α1 (COL11A1), integrin α11 (ITGA11), and the ITGA11 major ligand collagen type I α1 (COL1A1) among the 390 genes that were significantly enriched in NSCLC‐associated CAFs. Increased ITGA11 expression in cancer stroma was correlated with a poor clinical outcome in patients with NSCLC. Increased expression of fibronectin and collagen type I induced ITGA11 expression in CAFs. The cellular migration of CAFs toward collagen type I and fibronectin was promoted via ERK1/2 signaling, independently of the fibronectin receptor integrin α5β1. Additionally, ERK1/2 signaling induced ITGA11 and COL11A1 expression in cancer stroma. We, therefore, propose that targeting ITGA11 and COL11A1 expressing CAFs to block cancer–stroma interactions may serve as a novel, promising anti‐tumor strategy.

Long non‑coding RNA FEZF1‑AS1 facilitates non‑small cell lung cancer progression via the ITGA11/miR‑516b‑5p axis.

Long non-coding RNAs (lncRNAs) have emerged as key players in the development and progression of cancer. FEZ family zinc finger 1 antisense RNA 1 (FEZF1-AS1) is a novel lncRNA that is involved in the development of cancer and acts as a potential biomarker for cancer. However, the clinical significance and molecular mechanism of FEZF1-AS1 in non-small cell lung cancer (NSCLC) remains uncertain. In the present study, FEZF1-AS1 was selected using Arraystar Human lncRNA microarray and was identified to be upregulated in NSCLC tissues and negatively associated with the overall survival of patients with NSCLC. Loss-of-function assays revealed that FEZF1-AS1 inhibition decreased cell proliferation and migration, and arrested cells at the G2/M cell cycle phase. Mechanistically, FEZF1-AS1 expression was influenced by N6-methyladenosine (m6A) modification. Since FEZF1-AS1 was mainly located in the cytoplasmic fraction of NSCLC cells, it was hypothesized that it may be involved in competing endogenous RNA regulatory network to impact the prognosis of NSCLC. Via integrating Arraystar Human mRNA microarray data and miRNA bioinformatics analysis, it was revealed that ITGA11 expression was decreased with loss of FEZF1-AS1 and increased with gain of FEZF1-AS1 expression, and microRNA (miR)-516b-5p inhibited the expression levels of both FEZF1-AS and ITGA11. RNA-binding protein immunoprecipitation and RNA pulldown assays further demonstrated that FEZF1-AS1 could bind to miR-516b-5p and that ITGA11 was a direct target of miR-516b-5p by luciferase reporter assay. Overall, the present findings demonstrated that FEZF1-AS1 was upregulated and acted as an oncogene in NSCLC by regulating the ITGA11/miR-516b-5p axis, suggesting that FEZF1-AS1 may be a potential prognostic biomarker and therapeutic target for NSCLC.

Expression and prognostic analyses of ITGA11, ITGB4 and ITGB8 in human non-small cell lung cancer.

BackgroundIntegrins play a crucial role in the regulation process of cell proliferation, migration, differentiation, tumor invasion and metastasis. ITGA11, ITGB4 and ITGB8 are three encoding genes of integrins family. Accumulative evidences have proved that abnormal expression of ITGA11, ITGB4 and ITGB8 are a common phenomenon in different malignances. However, their expression patterns and prognostic roles for patients with non-small cell lung cancer (NSCLC) have not been completely illustrated.MethodsWe investigated the expression patterns and prognostic values of ITGA11, ITGB4 and ITGB8 in patients with NSCLC through using a series of databases and various datasets, including ONCOMINE, GEPIA, HPA, TCGA and GEO datasets.ResultsWe found that the expression levels of ITGA11 and ITGB4 were significantly upregulated in both LUAD and LUSC, while ITGB8 was obviously upregulated in LUSC. Additionally, higher expression level of ITGB4 revealed a worse OS in LUAD.ConclusionOur findings suggested that ITGA11 and ITGB4 might have the potential ability to act as diagnostic biomarkers for both LUAD and LUSC, while ITGB8 might serve as diagnostic biomarker for LUSC. Furthermore, ITGB4 could serve as a potential prognostic biomarker for LUAD.

Integrin α11 in non-small cell lung cancer is associated with tumor progression and postoperative recurrence.

Integrins are transmembrane proteins that mediate cell adhesion to the extracellular matrix. Integrin α11 (ITGA11) is not expressed in normal alveolar epithelial cells and is a known receptor for collagen. While integrin α11β1 overexpression in the tumor stroma has been associated with tumor growth and metastatic potential of non–small cell lung cancer (NSCLC), little is known about the role of ITGA11 in tumor cells. Thus, we examined the RNA expression of ITGA11 by quantitative RT‐PCR in 80 samples collected from NSCLC patients who had undergone surgical resection and analyzed the clinical outcomes. We found that high expression of ITGA11 was associated with lower recurrence‐free survival in all NSCLC patients (P = 0.043) and in stage I NSCLC patients (P = 0.049). These results were consistent with in silico analyses of the Cancer Genome Atlas database. We also analyzed cell proliferation, migration and invasion capacity in lung cancer cell lines after overexpression of ITGA11. Overexpression of ITGA11 in lung cancer cell lines had little effect on cell proliferation but resulted in increased migration and invasion capacity. Our findings suggest that ITGA11 plays a significant role in cancer migration and invasion, leading to higher recurrence. ITGA11 expression may be a predictor of poor prognosis in patients with surgically resected NSCLC.

Integrin α11 in pancreatic stellate cells regulates tumor stroma interaction in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest tumor due to its highly abundant tumor stroma. Pancreatic stellate cells (PSCs) are considered precursor cells of cancer-associated fibroblasts (CAFs), which induce tumor progression, invasion, and metastasis. In this study, we investigated the role of integrin subunit α (ITGA) 11, the receptor for collagen type I, in tumor stroma interaction. Clinical sample analysis showed that ITGA11 was overexpressed by CAFs in PDAC stroma, as shown with colocalization immunostaining with α-smooth muscle actin. In contrast, there was no expression in healthy pancreas. Public transcriptomic data confirmed a reduced expression of ITGA11 in healthy pancreas and adjacent nontumoral tissues compared with human tumor tissues. Primary human PSCs (hPSCs) activated with either TGF-β or pancreatic cancer cell (PANC-1)-conditioned medium (CM) resulted in the significant up-regulation of ITGA11 and various CAF markers. Furthermore, short hairpin RNA (shRNA)-mediated stable ITGA11 knockdown (shITGA11) in hPSCs significantly inhibited TGF-β- and PANC-1 CM-mediated activation at both gene and protein levels of extracellular matrix, cytokines, and adhesion molecules. Additionally, shITGA11 hPSCs had a reduced migration and contractility compared with shRNA control (shCTR) PSCs. Furthermore, we investigated the effect of ITGA11 on the paracrine effects of hPSCs. Interestingly, the CM from shITGA11 hPSCs, activated with either TGF-β or PANC-1 CM, caused tumor cells to migrate and invade lesser compared with their counterpart, activated shCTR PSCs. In summary, this study presents ITGA11 as an interesting stromal therapeutic target that plays a crucial role in the regulation of the differentiation of PSCs into CAFs and paracrine effects.-Schnittert, J., Bansal, R., Mardhian, D. F., van Baarlen, J., Östman, A., Prakash, J. Integrin α11 in pancreatic stellate cells regulates tumor stroma interaction in pancreatic cancer.

FGF2 Overrides TGFβ1-Driven Integrin ITGA11 Expression in Human Dermal Fibroblasts.

Deposition of collagen-based extracellular matrix by fibroblasts during wound healing leads to scar formation--a typical outcome of the healing process in soft tissue wounds. The process can, however, be skewed in favor of tissue regeneration by manipulation of wound environment. Low oxygen conditions and supplementation with FGF2 provide extracellular cues that drive wound fibroblasts towards a pro-regenerative phenotype. Under these conditions, fibroblasts dramatically alter expression of many genes among which the most significantly deregulated are extracellular matrix and adhesion molecules. Here we investigate the mechanism of a collagen I binding integrin α11 (ITGA11) deregulation in response to low oxygen-mediated FGF2 effects in dermal fibroblasts. Using RT-PCR, qRT-PCR, Western blotting, and immunocytochemistry, we describe significant down-regulation of ITGA11. Decrease in ITGA11 is associated with its loss from focal adhesions. We show that loss of ITGA11 requires FGF2 induced ERK1/2 activity and in the presence of FGF2, ITGA11 expression cannot be rescued by TGFβ1, a potent activator of ITGA11. Our results indicate that FGF2 may be redirecting fibroblasts towards an anti-fibrotic phenotype by overriding TGFβ1 mediated ITGA11 expression.

SAT0563 Integrin α11β1 is Induced in Synovial Fibroblasts of Arthritic Htnftg Mice

BackgroundCell-matrix interactions of synovial fibroblasts (SF) with cartilage components via β1 integrins are of importance not only for cartilage degradation, but also for the persistence of synovial inflammation during rheumatoid...

Progesterone Modulates Integrin α2 (ITGA2) and α11 (ITGA11) in the Pregnant Cervix

Fibrillar collagen in the cervical extracellular matrix (ECM) is the predominant component providing mechanical support. Cellular integrins contribute to structural integrity by cross-linking ECM components. We investigated the expression of collagen-binding integrins in the normal rat gestation and after treatment with mifepristone to determine whether integrin modulation is involved in changes in tissue resistance. Cervical tissue was harvested from nonpregnant and timed pregnant Sprague-Dawley rats. Normal gestational expression was evaluated in nonpregnant and timed pregnant tissue on days 12, 16, 18, 20, 21 and 22. Progesterone inhibition was induced with 3 mg mifepristone administered on day 15. Primary rat cervical stromal (RCS) cell cultures were generated from nonpregnant rats using tissue explants. The effects of progesterone environment on RCS cells were evaluated in the presence and absence of various inhibitors. Protein expression and signaling pathways were evaluated by Western blot. Integrin α2 (ITGA2) expression increased over gestation, peaking at the end of gestation (analysis of variance [ANOVA] P < .01). Integrin α11 (ITGA11) expression increased through mid-gestation, peaking on day 18 and decreasing through day 22 (ANOVA P < .001). Progesterone increased the expression of ITGA11 and phosphorylated focal adhesion kinase ([pFAK] P < .002). Mifepristone blocked these effects in vitro. Mifepristone increased ITGA2 and phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) in vivo and in vitro. Mifepristone-induced upregulation of ITGA2 was abrogated by inhibition of ERK1/2. Progesterone/progesterone withdrawal is involved in regulating the expression of collagen-binding integrins. These changes differ among the collagen-binding integrins. Mitogen-activated protein kinase (MAPK) signaling is involved in regulating some of these integrins.