3678

ITGA5

integrin, alpha 5 (fibronectin receptor, alpha polypeptide);ITGA5;integrin, alpha 5 (fibronectin receptor, alpha polypeptide)

CD49 antigen-like family member E|fibronectin receptor subunit alpha|fibronectin receptor, alpha subunit|integrin alpha-5|integrin alpha-F|very late activation protein 5, alpha subunit

12q11-q13

protein-coding

The purpose of this study was to evaluate the association of expression of alpha5beta1-integrin with clinicopathologic features and prognosis in cervical cancer. Levels of alpha5beta1-integrin in normal cervical mucosa and cervical cancer tissue were detected with immunohistochemistry. Survival analysis by the Kaplan-Meier method was performed to assess prognostic significance. alpha5beta1-integrin expression was detected in 84.6% (143/169) cervical cancer samples, significantly different from that in normal cervical mucosa (P < 0.05). Positive expression rates of alpha5beta1-integrin in patients with poor histologic differentiation, lymph node metastasis, and recurrence were elevated. Using Kaplan-Meier analysis, a comparison of survival curves of low versus high expression of alpha5beta1-integrin revealed a highly significant difference in human cervical cancer cases (P < 0.05), suggesting that overexpression of alpha5beta1-integrin is associated with a worse prognosis.The alpha5beta1-integrin promotes angiogenesis and associates with lymph node metastasis, vascular invasion and poor prognosis of cervical cancer. The current study indicated that alpha5beta1-integrin may be an independent prognostic factor for cervical cancer patients.

The purpose of this study was to evaluate the association of expression level of alpha5beta1-integrin and MMP-14 with clinicopathologic features and prognosis in colorectal cancer (CRC). The expressions of alpha5beta1-integrin and MMP-14 in normal colorectal mucosa and CRC tissue were detected with immunohistochemistry. We estimated the five-year survival rate by the Kaplan-Meier method. The positive expressions rates of alpha5beta1-integrin and MMP-14 in CRC tissue were 60.6% and 63.3% respectively, and there were significant differences on their positive expression rates between in CRC tissue and in normal colorectal mucosa(P<0.05). The expression rates of alpha5beta1-integrin and MMP-14 in patients with poor histological differentiation, lymph node metastasis and high clinical staging were heightened. There was a significant difference (P<0.05) on the five-year survival rate for alpha5beta1-integrin expression, which was 44.6% in positive groups and 75.5% in negative groups. And there was a significant difference (P<0.05) on the five-year survival rate for MMP-14 expression, which was 48.2% in positive group and 73.1% in negative group. The expression of alpha5beta1-integrin and MMP-14 is correlated with the progression and metastasis of CRC, and alpha5beta1-integrin and MMP-14 may be used as prognostic markers in CRC.

Colorectal cancer (CRC) displays a predilection for metastasis to liver. Although stromal cell-derived factor-1 (SDF-1)/CXCR4 plays an important role in the liver metastasis, the molecular mechanism still remains obscure. We previously reported that integrin alphavbeta6 was implicated in the progression of CRC. However, no data are currently available on the cross talk between CXCR4 and alphavbeta6. In the present study, we first demonstrated the cross talk between CXCR4 and alphavbeta6 and their role in liver metastasis of CRC. We analyzed 159 human CRC samples and found that expression of CXCR4 and alphavbeta6 was significantly associated with liver metastasis, and interestingly expression of alphavbeta6 significantly correlated with expression of CXCR4. Both CXCR4 and alphavbeta6 were highly expressed in metastatic CRC cell lines HT-29 and WiDr, whereas both of them were exiguous in non-metastatic cell line Caco-2. Furthermore, inhibition of alphavbeta6 significantly decreased SDF-1alpha-induced cell migration in vitro. SDF-1/CXCR4 could upregulate alphavbeta6 expression through phosphorylation of ERK and activation of Ets-1 transcription factor. In conclusion, we demonstrate that SDF-1/CXCR4 induces directional migration and liver metastasis of CRC cells by upregulating alphavbeta6 through ERK/Ets-1 pathway. These data support combined inhibition of CXCR4 and alphavbeta6 to prevent development of liver metastasis of CRC.

Detachment from the extracellular matrix induces a form of programmed cell death termed anoikis. Resistance to anoikis permits cancer cells to survive in systemic circulation and facilitates their metastasis to distant organs. It is well known that S100A4 is overexpressed in many tumors and involved in tumor metastasis, but the mechanisms of the metastasis-promoting function of S100A4 are not fully understood. We hypothesized that S100A4 might play a role in anoikis of gastric cancer cells and further affects their metastasis. To test this hypothesis, we changed the expression of S100A4 by means of RNA interference or experimental overexpression and investigated the effect on anoikis. We found that knockdown of S100A4 by RNA interference led to significantly increased anoikis, whereas overexpression of S100A4 resulted in inhibition of anoikis. Furthermore, we provide evidence that inhibition of S100A4 resulted in the downregulation of alpha5 and alphav integrin expression. These findings suggest that S100A4 protects gastric cancer cells from anoikis by regulation of alphav and alpha5 integrin expression, which sheds a novel light for the role of S100A4 in cancer metastasis.

OBJECTIVE: The study was to evaluate the association of expression level of alpha5beta1-integrin with clinicopathologic features and prognosis in gastric cancer (GC). METHODS: The expression of alpha5beta1-integrin in normal gastric mucosa and GC tissue was detected with immunohistochemistry. The level of alpha5 and beta1 mRNA in GC tissues and non-neoplastic tissues was evaluated in 48 paired cases by quantitative real-time polymerase chain reaction (qRT-PCR). Survival analysis by the Kaplan-Meier method was performed to assess prognostic significance. RESULTS: The alpha5beta1-integrin expression was detected in 68.3 % (127/186) GC samples, and there was a significant difference on their positive expression rate between GC tissue and normal gastric mucosa (P < 0.001). The positive expression rate of alpha5beta1-integrin in patients with poor histologic differentiation (P = 0.001), lymph node metastasis (P < 0.001), and recurrence (P < 0.001) group was heightened. Using Kaplan-Meier analysis, a comparison of survival curves of low versus high expresser of alpha5beta1-integrin revealed a highly significant difference in human GC tissue (P = 0.002), which suggested that overexpression of alpha5beta1-integrin is associated with a worse prognosis. Multivariate analyses showed that alpha5beta1-integrin expression was independent risk factor predicting overall survival [Hazard ratio (HR) 1.594, 95 % confidence interval (CI) 1.236-2.408, P = 0.006] and disease-free survival [HR 3.952, 95 %

Survivin is an apoptotic and mitotic regulator that is overexpressed in melanoma and a poor prognostic marker in patients with metastatic disease. We recently showed that Survivin enhances melanoma cell motility through Akt-dependent upregulation of alpha5 integrin. However, the functional role of Survivin in melanoma metastasis is not clearly understood. We found that overexpression of Survivin in LOX and YUSAC2 human melanoma cells increased colony formation in soft agar, and this effect was abrogated by knockdown of alpha5 integrin by RNA interference. We employed melanoma cell xenografts to determine the in vivo effect of Survivin overexpression on melanoma metastasis. Although Survivin overexpression did not affect primary tumor growth of YUSAC2 or LOX subcutaneous tumors, or indices of proliferation or apoptosis, it significantly increased expression of alpha5 integrin in the primary tumors and formation of metastatic colonies in the lungs. Additionally, Survivin overexpression resulted in enhanced lung colony formation following intravenous (i.v.) injection of tumor cells in vivo and increased adherence to fibronectin-coated plastic in vitro. Importantly, in vivo inhibition of alpha5 integrin via intraperitoneal injection of an alpha5beta1 integrin-blocking antibody significantly slowed tumor growth and reduced Survivin-enhanced pulmonary metastasis. Knockdown of alpha5 integrin in cells prior to i.v. injection also blocked Survivin-enhanced lung colony formation. These findings support a direct role for Survivin in melanoma metastasis, which requires alpha5 integrin and suggest that inhibitors of alpha5 integrin may be useful in combating this process.

BACKGROUND: TMPRSS4 is a membrane-anchored protease involved in cell migration and invasion in different cancer types including lung cancer. TMPRSS4 expression is increased in NSCLC and its inhibition through shRNA reduces lung metastasis. However, molecular mechanisms leading to the protumorigenic regulation of TMPRSS4 in lung cancer are unknown. METHODS: miR-205 was identified as an overexpressed gene upon TMPRSS4 downregulation through microarray analysis. Cell migration and invasion assays and in vivo lung primary tumour and metastasis models were used for functional analysis of miR-205 overexpression in H2170 and H441 cell lines. Luciferase assays were used to identify a new miR-205 direct target in NSCLC. RESULTS: miR-205 overexpression promoted an epithelial phenotype with increased E-cadherin and reduced fibronectin. Furthermore, miR-205 expression caused a G0/G1 cell cycle arrest and inhibition of cell growth, migration, attachment to fibronectin, primary tumour growth and metastasis formation in vivo. Integrin alpha5 (a proinvasive protein) was identified as a new miR-205 direct target in NSCLC. Integrin alpha5 downregulation in lung cancer cells resulted in complete abrogation of cell migration, a decreased capacity to adhere to fibronectin and reduced in vivo tumour growth, compared with control cells. TMPRSS4 silencing resulted in a concomitant reduction of integrin alpha5 levels. CONCLUSION: We have demonstrated for the first time a new molecular pathway that connects TMPRSS4 and integrin alpha5 through miR-205 to regulate cancer cell invasion and metastasis. Our results will help designing new therapeutic strategies to inhibit this novel pathway in NSCLC.

BACKGROUND: Integrins are cell-surface adhesion molecules, regulate normal cellular interactions, and which are consisting of alpha and beta subunits and facilitate signal transduction in a bidirectional manner. tumor cells have been found to express a wide variety of integrins, overexpression of integrin alphav has been detected in a growing number of human malignancy types, However, the reports obout expression of integrin alphav in nasopharyngeal carcinoma (NPC) are very rare. OBJECTIVE: This study aims to detect the expression of integrin alphav in NPC, and to evaluate the correlation between integrin alphav expression and clinicopathological factors. METHODS: Real-time polymerase chain reaction (real-time PCR) assay and immunohistochemical staining were performed to detect the expression of integrin alphav in NPC tissue samples. The correlation between the integrin alphav expression and clinicopathological factors was evaluated. RESULTS: In NPC tissues, the expression levels of integrin alphav mRNA was significantly higher than those in the nasopharyngeal inflammation tissues (P< 0.05), and the expression level were significantly correlated with T, N and clinical stage (all P < 0.05). Moreover, the expression rates of integrin alphav protein in NPC tissues was 76.92%, significantly higher than that of nasopharyngeal inflammation tissues (6.25%, P< 0.05). We also observed that the protein expression of integrin alphav was significantly related to T, N and clinical stage (all P< 0.05). CONCLUSIONS: All these findings suggest that overexpression of integrin alphav is closely associated with metastasis and progression of NPC. Therefore, we can speculate that integrin alphav could be effective prognostic markers in the future for individualized treatment of patients with NPC.

The tumor microenvironment can enhance the invasive capacity of tumor cells. We showed that expression of angiopoietin-like protein 2 (ANGPTL2) in osteosarcoma (OS) cell lines increased and the methylation of its promoter decreased with time when grown as xenografts in mice compared with culture. Compared with cells grown in normal culture conditions, the expression of genes encoding DNA demethylation-related enzymes increased in tumor cells implanted into mice or grown in hypoxic, serum-starved culture conditions. ANGPTL2 expression in OS cell lines correlated with increased tumor metastasis and decreased animal survival by promoting tumor cell intravasation mediated by the integrin alpha5beta1, p38 mitogen-activated protein kinase, and matrix metalloproteinases. The tolloid-like 1 (TLL1) protease cleaved ANGPTL2 into fragments in vitro that did not enhance tumor progression when overexpressed in xenografts. expression of TLL1 was weak in OS patient tumors, suggesting that ANGPTL2 may not be efficiently cleaved upon secretion from OS cells. These findings demonstrate that preventing ANGPTL2 signaling stimulated by the tumor microenvironment could inhibit tumor cell migration and metastasis.

PURPOSE: To investigate the expression and significance of the proteins and mRNA of metastasis suppressor gene Me491/cd63 and integrin alpha5 in ovarian cancer tissues. METHODS: RT-PCR and in situ hybridization were used to detect the expression of the proteins and mRNA of ME491/CD63 and integrin alpha5 in normal ovarian tissues (Group I), ovarian benign tumor tissues (Group II), ovarian borderline tumor tissues (Group III) and ovarian cancer tissues (Group IV), and the correlation between the expression and the age of patient, degree of differentiation, lymphatic metastasis, stage and pathological type was analyzed. RESULTS: There was a significant change in gene expression between the well and moderately differentiated tumors and poorly differentiated tumors. Gene expression in Groups III and IV was significantly weak, and significantly different from that in Group II and the early-stages of Groups III and IV. There was a significant difference in gene expression between each group. CONCLUSION: There is low expression of the proteins and mRNA of ME491/CD63 and integrin alpha5 in ovarian cancer. The lower the pathological differentiation is, the more significant the loss of expression is and the more likely metastasis is.

The role of the fibronectin receptor, alpha(5)beta(1)-integrin, as an adhesion receptor and in angiogenesis is well established. However, its role in cancer cell invasion and metastasis is less clear. We describe a novel mechanism by which fibronectin regulates ovarian cancer cell signaling and promotes metastasis. Fibronectin binding to alpha(5)beta(1)-integrin led to a direct association of alpha(5)-integrin with the receptor tyrosine kinase, c-Met, activating it in a hepatocyte growth factor/scatter factor (HGF/SF) independent manner. Subsequently, c-Met associated with Src, and activated Src and focal adhesion kinase (FAK). Inhibition of alpha(5)beta(1)-integrin decreased the phosphorylation of c-Met, FAK and Src, both in vitro and in vivo. Independent activation of c-Met by its native ligand, HGF/SF, or overexpression of a constitutively active FAK in HeyA8 cells could overcome the effect of alpha(5)beta(1)-integrin inhibition on tumor cell invasion, indicating that alpha(5)beta(1)-integrin is upstream of c-Met, Src and FAK. Inhibition of alpha(5)beta(1)-integrin on cancer cells in two xenograft models of ovarian cancer metastasis resulted in a significant decrease of tumor burden, which was independent of the effect of alpha(5)beta(1)-integrin on angiogenesis. These data suggest that fibronectin promotes ovarian cancer invasion and metastasis through an alpha(5)beta(1)-integrin/c-Met/FAK/Src-dependent signaling pathway, transducing signals through c-Met in an HGF/SF-independent manner.

Human pancreatic ductal adenocarcinoma (PDAC) is characterized by early systemic dissemination. Although RhoC has been implicated in cancer cell migration, the relevant underlying molecular mechanisms remain unknown. RhoC has been implicated in the enhancement of cancer cell migration and invasion, with actions which are distinct from RhoA (84% homology), and are possibly attributed to the divergent C-terminus domain. Here, we confirm that RhoC significantly enhances the migratory and invasive properties of pancreatic carcinoma cells. In addition, we show that RhoC over-expression decreases cancer cell adhesion and, in turn, accelerates cellular body movement and focal adhesion turnover, especially, on fibronectin-coated surfaces. Whilst RhoC over-expression did not alter integrin expression patterns, we show that it enhanced integrin alpha5beta1 internalization and re-cycling (trafficking), an effect that was dependent specifically on the C-terminus (180-193 amino acids) of RhoC protein. We also report that RhoC and integrin alpha5beta1 co-localize within the peri-nuclear region of pancreatic tumor cells, and by masking the CAAX motif at the C-terminal of RhoC protein, we were able to abolish this interaction in vitro and in vivo. Co-localization of integrin alpha5beta1 and RhoC was demonstrable in invading cancer cells in 3D-organotypic cultures, and further mimicked in vivo analyses of, spontaneous human, (two distinct sources: operated patients and rapid autopsy programme) and transgenic murine (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre), pancreatic cancers. In both cases, co-localization of integrin alpha5beta1 and RhoC correlated with poor differentiation status and metastatic potential. We propose that RhoC facilitates tumor cell invasion and promotes subsequent metastasis, in part, by enhancing integrin alpha5beta1 trafficking. Thus, RhoC may serve as a biomarker and a therapeutic target.

Mechanisms of metastasis, the major complication of prostate cancer, are poorly understood. In this study, we define molecular mechanisms that may contribute to the highly invasive potential of prostate cancer cells. Vascular endothelial growth factor (VEGF), its receptors (VEGFRs), and alpha5beta1 integrin were expressed by prostate cancer cells in vitro and by prostate tumors in vivo, and their expression was elevated at sites of bone metastasis compared to original prostate tumor. VEGF, through interaction with its receptors, regulated adhesive and migratory properties of the cancer cells. Specifically, the highly metastatic prostate cancer cell subline LNCaP-C4-2 showed a decreased adhesive but an enhanced migratory response to fibronectin, a ligand for alpha5beta1 integrin, compared to its nonmetastatic counterpart. A similar pattern was also observed when bone sialoprotein was used as a ligand in migration assays. Increased migration of metastatic prostate cancer cells to fibronectin and bone sialoprotein was regulated by VEGF via VEGFR-2. tumor suppressor PTEN was involved in control of VEGF/VEGFR-2 stimulated prostate cancer cell adhesion as well as proliferation.