Gene Summary

Gene:ITGB1; integrin subunit beta 1
Summary:Integrins are heterodimeric proteins made up of alpha and beta subunits. At least 18 alpha and 8 beta subunits have been described in mammals. Integrin family members are membrane receptors involved in cell adhesion and recognition in a variety of processes including embryogenesis, hemostasis, tissue repair, immune response and metastatic diffusion of tumor cells. This gene encodes a beta subunit. Multiple alternatively spliced transcript variants which encode different protein isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:integrin beta-1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ITGB1 (cancer-related)

An T, Zhang Z, Li Y, et al.
Integrin β1-Mediated Cell⁻Cell Adhesion Augments Metformin-Induced Anoikis.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Cell⁻cell adhesion plays an important role in regulation of cell proliferation, migration, survival, and drug sensitivity. Metformin, a first line drug for type 2 diabetes, has been shown to possess anti-cancer activities. However, whether cell⁻cell adhesion affects metformin anti-cancer activity is unknown. In this study, Microscopic and FACS analyses showed that metformin induced cancer cell⁻cell adhesion exemplified by cell aggregation and anoikis under glucose restriction. Furthermore, western blot and QPCR analyses revealed that metformin dramatically upregulated integrin β1 expression. Silencing of integrin β1 significantly disrupted cell aggregation and reduced anoikis induced by metformin. Moreover, we showed that p53 family member ΔNp63α transcriptionally suppressed integrin β1 expression and is responsible for metformin-mediated upregulation of integrin β1. In summary, this study reveals a novel mechanism for metformin anticancer activity and demonstrates that cell⁻cell adhesion mediated by integrin β1 plays a critical role in metformin-induced anoikis.

Wang J, Zhou P, Wang X, et al.
Rab25 promotes erlotinib resistance by activating the β1 integrin/AKT/β-catenin pathway in NSCLC.
Cell Prolif. 2019; 52(3):e12592 [PubMed] Related Publications
OBJECTIVES: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has significant therapeutic efficacy in non-small-cell lung cancer (NSCLC) patients. However, acquired resistance is inevitable and limits the long-term efficacy of EGFR-TKI. Our study aimed to investigate the role of ras-associated binding protein 25 (Rab25) in mediating EGFR-TKI resistance in NSCLC.
MATERIALS AND METHODS: Rab25 expression in NSCLC patients was measured by immunohistochemical staining. Western blotting was used to analyse the expression of molecules in the Rab25, EGFR and Wnt signalling pathways. Lentiviral vectors were constructed to knock in and knock out Rab25. The biological function of Rab25 was demonstrated by cell-counting kit-8 and flow cytometry. The interaction between Rab25 and β1 integrin was confirmed by co-immunoprecipitation.
RESULTS: Rab25 overexpression induced erlotinib resistance, whereas Rab25 knockdown reversed this refractoriness in vitro and in vivo. Moreover, Rab25 interacts with β1 integrin and promotes its trafficking to the cytoplasmic membrane. The membrane-β1 integrin induced protein kinase B (AKT) phosphorylation and subsequently activated the Wnt/β-catenin signalling pathway, promoting cell proliferation. Furthermore, high Rab25 expression was associated with poor response to EGFR-TKI treatment in NSCLC patients.
CONCLUSIONS: Rab25 mediates erlotinib resistance by activating the β1 integrin/AKT/β-catenin signalling pathway. Rab25 may be a predictive biomarker and has potential therapeutic value in NSCLC patients with acquired resistance to EGFR-TKI.

Matsuyama T, Ishikawa T, Takahashi N, et al.
Transcriptomic expression profiling identifies ITGBL1, an epithelial to mesenchymal transition (EMT)-associated gene, is a promising recurrence prediction biomarker in colorectal cancer.
Mol Cancer. 2019; 18(1):19 [PubMed] Free Access to Full Article Related Publications
The current histopathological risk-stratification criteria in colorectal cancer (CRC) patients following a curative surgery remain inadequate. In this study, we undertook a systematic, genomewide, biomarker discovery approach to identify and validate key EMT-associated genes that may facilitate recurrence prediction in CRC. Genomewide RNA expression profiling results from two datasets (GSE17538; N = 173 and GSE41258; N = 307) were used for biomarker discovery. These results were independently validated in two, large, clinical cohorts (testing cohort; N = 201 and validation cohort; N = 468). We performed Gene Set Enrichment Analysis (GSEA) for understanding the function of the candidate markers, and evaluated their correlation with the mesenchymal CMS4 subtype. We identified integrin subunit beta like 1 (ITGBL1) as a promising candidate biomarker, and its high expression associated with poor overall survival (OS) in stage I-IV patients and relapse-free survival (RFS) in stage I-III patients. Subgroup validation in multiple independent patient cohorts confirmed these findings, and demonstrated that high ITGBL1 expression correlated with shorter RFS in stage II patients. We developed a RFS prediction model which robustly predicted RFS (the area under the receiver operating curve (AUROC): 0.74; hazard ratio (HR): 2.72) in CRC patients. ITGBL1 is a promising EMT-associated biomarker for recurrence prediction in CRC patients, which may contribute to improved risk-stratification in CRC.

Aksorn N, Chanvorachote P
Integrin as a Molecular Target for Anti-cancer Approaches in Lung Cancer.
Anticancer Res. 2019; 39(2):541-548 [PubMed] Related Publications
Integrins are cell-matrix adhesion molecules providing both mechanical engagement of cell to extracellular matrix, and generation of cellular signals that are implicated in cancer malignancies. The concept that integrins play important roles in cell survival, proliferation, motility, differentiation, and ensuring appropriate cell localization, leads to the hypothesis that inhibition of certain integrins would benefit cancer therapy. In lung cancer, integrins αv, α5, β1, β3, and β5 have been shown to augment survival and metastatic potential of cancer cells. This review presents data suggesting integrins as molecular targets for anti-cancer approaches, and the mechanisms through which integrins confer resistance of lung cancer to chemotherapeutics and metastasis. The better understanding of these key molecules may benefit the discovery of anti-cancer drugs and strategies.

Zhang L, Zhang T, Deng Z, Sun L
MicroRNA‑3653 inhibits the growth and metastasis of hepatocellular carcinoma by inhibiting ITGB1.
Oncol Rep. 2019; 41(3):1669-1677 [PubMed] Free Access to Full Article Related Publications
microRNAs (miRNAs) play critical roles in hepatocellular carcinoma (HCC). However, the expression and biological function of miR‑3653 in HCC remain unknown. The present study demonstrated that miR‑3653 expression was significantly decreased in HCC tissues and cells using qRT‑PCR. A decreased miR‑3653 level was associated with unfavorable clinical features and poor prognosis of HCC patients. MTT, BrdU, Transwell and western blot assays showed that miR‑3653 overexpression inhibited the growth, migration, invasion and epithelial‑mesenchymal transition (EMT) of HCCLM3 cells while its knockdown promoted the growth and metastatic ability of Hep3B cells. In vivo experiments showed that miR‑3653 overexpression inhibited the subcutaneous and the lung metastasis of HCCLM3 cells in nude mice. Mechanistically, integrin‑β1 (ITGB1) was identified to be the downstream target of miR‑3653 in HCC. ITGB1 overexpression reversed the inhibitory effects of miR‑3653 on the growth, metastasis and EMT of HCCLM3 cells.

Asiri A, Raposo TP, Alfahed A, Ilyas M
TGFβ1-induced cell motility but not cell proliferation is mediated through Cten in colorectal cancer.
Int J Exp Pathol. 2018; 99(6):323-330 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Cten (C-terminal tensin-like) is a member of the tensin protein family found in complex with integrins at focal adhesions. It promotes epithelial-mesenchymal transition (EMT) and cell motility. The precise mechanisms regulating Cten are unknown, although we and others have shown that Cten could be under the regulation of several cytokines and growth factors. Since transforming growth factor beta 1 (TGF-β1) regulates integrin function and promotes EMT/cell motility, we were prompted to investigate whether TGF-β1 induces EMT and cell motility through Cten signalling in colorectal cancer. TGF-β1 signalling was modulated by either stimulation with TGF-β1 or knockdown of TGF-β1 in the CRC cell lines SW620 and HCT116. The effect of this modulation on expression of Cten, EMT markers and on cellular function was tested. The role of Cten as a direct mediator of TGF-β1 signalling was investigated in a CRC cell line in which the Cten gene had been deleted (SW620

You GR, Cheng AJ, Lee LY, et al.
Prognostic signature associated with radioresistance in head and neck cancer via transcriptomic and bioinformatic analyses.
BMC Cancer. 2019; 19(1):64 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Radiotherapy is an indispensable treatment modality in head and neck cancer (HNC), while radioresistance is the major cause of treatment failure. The aim of this study is to identify a prognostic molecular signature associated with radio-resistance in HNC for further clinical applications.
METHODS: Affymetrix cDNA microarrays were used to globally survey different transcriptomes between HNC cell lines and isogenic radioresistant sublines. The KEGG and Partek bioinformatic analytical methods were used to assess functional pathways associated with radioresistance. The SurvExpress web tool was applied to study the clinical association between gene expression profiles and patient survival using The Cancer Genome Atlas (TCGA)-head and neck squamous cell carcinoma (HNSCC) dataset (n = 283). The Kaplan-Meier survival analyses were further validated after retrieving clinical data from the TCGA-HNSCC dataset (n = 502) via the Genomic Data Commons (GDC)-Data-Portal of National Cancer Institute. A panel maker molecule was generated to assess the efficacy of prognostic prediction for radiotherapy in HNC patients.
RESULTS: In total, the expression of 255 molecules was found to be significantly altered in the radioresistant cell sublines, with 155 molecules up-regulated 100 down-regulated. Four core functional pathways were identified to enrich the up-regulated genes and were significantly associated with a worse prognosis in HNC patients, as the modulation of cellular focal adhesion, the PI3K-Akt signaling pathway, the HIF-1 signaling pathway, and the regulation of stem cell pluripotency. Total of 16 up-regulated genes in the 4 core pathways were defined, and 11 over-expressed molecules showed correlated with poor survival (TCGA-HNSCC dataset, n = 283). Among these, 4 molecules were independently validated as key molecules associated with poor survival in HNC patients receiving radiotherapy (TCGA-HNSCC dataset, n = 502), as IGF1R (p = 0.0454, HR = 1.43), LAMC2 (p = 0.0235, HR = 1.50), ITGB1 (p = 0.0336, HR = 1.46), and IL-6 (p = 0.0033, HR = 1.68). Furthermore, the combined use of these 4 markers product an excellent result to predict worse radiotherapeutic outcome in HNC (p < 0.0001, HR = 2.44).
CONCLUSIONS: Four core functional pathways and 4 key molecular markers significantly contributed to radioresistance in HNC. These molecular signatures may be used as a predictive biomarker panel, which can be further applied in personalized radiotherapy or as radio-sensitizing targets to treat refractory HNC.

Lu Y, Tang L, Zhang Z, et al.
Long Noncoding RNA TUG1/miR-29c Axis Affects Cell Proliferation, Invasion, and Migration in Human Pancreatic Cancer.
Dis Markers. 2018; 2018:6857042 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Given the low resection rate and chemoresistance of patients with pancreatic cancer (PC), their survival rates are typically poor. Long noncoding RNAs (lncRNAs) have recently been shown to play an important role in tumourigenesis and human cancer progression, including in PC. In this study, we aimed to investigate the role of taurine-upregulated gene 1 (TUG1) in PC. A quantitative polymerase chain reaction was used to analyse TUG1 expression in PC tissues and peritumoural normal tissues. TUG1 was overexpressed in PC tissues compared with that in peritumoural normal tissues, and the high expression of TUG1 was associated with the poor prognosis of patients with PC. Furthermore, TUG1 knockdown significantly inhibited the proliferation and invasion of PC cells both in vitro and in vivo, while overexpression TUG1 promoted tumour cell proliferation, migration, and invasion. TUG1 directly targeted miR-29c, a tumour suppressor in several cancers. TUG1 knockdown significantly increased the expression of miR-29c and subsequently induced the downregulation of integrin subunit beta 1 (ITGB1), matrix metalloproteinase-2 (MMP2), and matrix metalloproteinase-9 (MMP9). The downregulation of miR-29c abolished the TUG1 knockdown-mediated inhibition of tumour growth in vitro and in vivo, whereas the upregulation of miR-29c enhanced the effects of TUG1 knockdown on PC cells. In conclusion, we demonstrate for the first time the oncogenic role of TUG1 in PC. The downregulation of TUG1 significantly inhibited the growth and migratory ability of PC cells in vitro and in vivo by targeting miR-29c. Our study provides a novel potential diagnostic biomarker and therapeutic target for PC.

Chernaya G, Mikhno N, Khabalova T, et al.
The expression profile of integrin receptors and osteopontin in thyroid malignancies varies depending on the tumor progression rate and presence of BRAF V600E mutation.
Surg Oncol. 2018; 27(4):702-708 [PubMed] Related Publications
Thyroid cancer (TC) is one of the most common malignancy of the human endocrine system. BRAF V600E mutation is the most frequent genetic alteration of papillary carcinoma, the most frequent TC, which effects RAS-RAF-MEK intracellular signaling pathway. These alterations in RAS-RAF-MEK pathway lead to changes in expression levels of cell membrane integrin receptors and their ligand - extracellular matrix protein osteopontin, which in turn increases the metastatic potential of tumor cells. Thus, integrins and their ligand osteopontin can be considered as potential biomarkers of tumor progression and aggressive tumor phenotypes. The aim of the study was to evaluate the expression levels of integrin receptors ITGA2, ITGA3, ITGAV, ITGA6, ITGA9, ITGB1, ITGB3 and their ligands OPNa, OPNb in the thyroid cancer with different BRAF V600E mutation status.
METHODS: Thyroid tumor samples of 70 patients obtained during surgical treatment were analyzed. Expression levels of the investigated genes were evaluated by real time RT-PCR. Fluorescent immunohistochemistry (IHC) was used to confirm the PCR results and to estimate the amount of protein levels. For IHC frozen sections were used. BRAF V600E mutation was determined using allele-specific amplification. Nonparametric criteria (Kruskal Wallis, Wilcoxon and Mann-Whitney tests) were used to evaluate group differences. P values of less than 0.05 were considered as statistically significant.
RESULTS: A higher gene expression level of ITGA2 (1.9-fold, p = 0.037), ITGA3 (21.1-fold, p = 0.041) and ITGA5 (2.08-fold, p = 0.048) was observed in papillary thyroid cancer (PTC) tissue in comparison with median expression level in control samples (conventionally normal tissue of thyroid gland). These changes were confirmed by IHC (significant changes for α2 integrin). ITGAV expression level was statistically significantly higher in follicular thyroid cancer (FTC) (2.0-fold, p = 0.040). Next, high gene expression levels in tissue samples of lymph node metastases were observed for ITGA5 (2.92-fold, p = 0.015), OPNb (4.36-fold, p = 0.037). For genes ITGA3 (37.48-fold, p = 0.017790), ITGA6 (18.76-fold, p = 0.028921) and ITGA9 (12.52-fold, p = 0.026710) higher expression level was detected in T
CONCLUSION: Identified changes in expression levels of the studied genes indicate that they could play an important role in tumor progression, and their expression could be affected by the product of mutant BRAF gene. Integrins and their ligand osteopontin might be considered as potential markers in determining prognosis and treatment of TC.

Liu Y, Li F, Yang YT, et al.
IGFBP2 promotes vasculogenic mimicry formation via regulating CD144 and MMP2 expression in glioma.
Oncogene. 2019; 38(11):1815-1831 [PubMed] Related Publications
Vasculogenic mimicry (VM) refers to the fluid-conducting channels formed by aggressive tumor cells rather than endothelial cells (EC) with elevated expression of genes associated with vascularization. VM has been considered as one of the reasons that glioblastoma becomes resistant to anti-VEGF therapy. However, the molecular basis underlying VM formation remains unclear. Here we report that the insulin-like growth factor-binding protein 2 (IGFBP2) acts as a potent factor to enhance VM formation in glioma. Evidence showed that elevated IGFBP2 expression was positively related with VM formation in patients with glioma. Enforced expression of IGFBP2 increased network formation of glioma cells in vitro by activating CD144 and MMP2 (Matrix Metalloproteinase 2). U251 cells with stable knockdown of IGFBP2 led to decreased VM formation and tumor progression in orthotopic mouse model. Mechanistically, IGFBP2 interacts with integrin α5 and β1 subunits and augments CD144 expression in a FAK/ERK pathway-dependent manner. Luciferase reporter and ChIP assay suggested that IGFBP2 activated the transcription factor SP1, which could bind to CD144 promoter. Thus, IGFBP2 acts as a stimulator of VM formation in glioma cells via enhancing CD144 and MMP2 expression.

Zhao Q, Busch B, Jiménez-Soto LF, et al.
Integrin but not CEACAM receptors are dispensable for Helicobacter pylori CagA translocation.
PLoS Pathog. 2018; 14(10):e1007359 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Translocation of the Helicobacter pylori (Hp) cytotoxin-associated gene A (CagA) effector protein via the cag-Type IV Secretion System (cag-T4SS) into host cells is a hallmark of infection with Hp and a major risk factor for severe gastric diseases, including gastric cancer. To mediate the injection of CagA, Hp uses a membrane-embedded syringe-like molecular apparatus extended by an external pilus-like rod structure that binds host cell surface integrin heterodimers. It is still largely unclear how the interaction of the cag-T4SS finally mediates translocation of the CagA protein into the cell cytoplasm. Recently certain carcinoembryonic antigen-related cell adhesion molecules (CEACAMs), acting as receptor for the Hp outer membrane adhesin HopQ, have been identified to be involved in the process of CagA host cell injection. Here, we applied the CRISPR/Cas9-knockout technology to generate defined human gastric AGS and KatoIII integrin knockout cell lines. Although confocal laser scanning microscopy revealed a co-localization of Hp and β1 integrin heterodimers on gastric epithelial cells, Hp infection studies using the quantitative and highly sensitive Hp β-lactamase reporter system clearly show that neither β1 integrin heterodimers (α1β1, α2β1 or α5β1), nor any other αβ integrin heterodimers on the cell surface are essential for CagA translocation. In contrast, deletion of the HopQ adhesin in Hp, or the simultaneous knockout of the receptors CEACAM1, CEACAM5 and CEACAM6 in KatoIII cells abolished CagA injection nearly completely, although bacterial binding was only reduced to 50%. These data provide genetic evidence that the cag-T4SS-mediated interaction of Hp with cell surface integrins on human gastric epithelial cells is not essential for CagA translocation, but interaction of Hp with CEACAM receptors is facilitating CagA translocation by the cag-T4SS of this important microbe.

Zhang W, Zhang M, Liu L, et al.
MicroRNA-183-5p Inhibits Aggressiveness of Cervical Cancer Cells by Targeting Integrin Subunit Beta 1 (ITGB1).
Med Sci Monit. 2018; 24:7137-7145 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND Accumulating studies demonstrate that microRNAs play crucial roles in multiple processes of cancer progression. Lower levels of miR-183 have been observed in diverse types of tumors but the mechanism and precise function of miR-183-5p in cervical cancer have largely not been investigated. MATERIAL AND METHODS The level of miR-183-5p in different cervical cancer cell lines and clinical tissues was detected qRT-PCR assays. Transwell and wound-healing migration assays were conducted to assess the functional roles of miR-183-5p in over-expressing cervical cancer cells in vitro. Rescue assays were carried out to confirm the contribution of integrin subunit Beta 1 (ITGB1) to the aggressiveness of cancer cells regulated by miR-183-5p. RESULTS miR-183-5p was reduced in clinical tissues of cervical cancer and cell lines when compared to the normal subjects and normal cervical epithelial cell line, respectively. In addition, over-expression of miR-183-5p markedly inhibited migration and invasion in cervical cancer cells, and increased aggressiveness was observed in miR-183-5p inhibitor transfected cells. Furthermore, the luciferase reporter assays revealed that ITGB1 was the gene directly regulated by miR-183-5p. Notably, a negative association between the ITGB1 and miR-183-5p was found, and the gene expressions of ITGB1 was mediated by miR-183-5p in cervical cancer cells. CONCLUSIONS miR-183-5p serves as a latent anti-oncogene by targeting the metastasis-promoter gene, ITGB1.

Zhang H, Fredericks T, Xiong G, et al.
Membrane associated collagen XIII promotes cancer metastasis and enhances anoikis resistance.
Breast Cancer Res. 2018; 20(1):116 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Increased collagen expression and deposition are associated with cancer progression and poor prognosis in breast cancer patients. However, function and regulation of membrane-associated collagen in breast cancer have not been determined. Collagen XIII is a type II transmembrane protein within the collagen superfamily. Experiments in tissue culture and knockout mouse models show that collagen XIII is involved in cell adhesion and differentiation of certain cell types. In the present study, we determined roles of collagen XIII in breast cancer progression and metastasis.
METHODS: We analyzed the association of collagen XIII expression with breast cancer development and metastasis using published gene expression profiles generated from human breast cancer tissues. Utilizing gain- and loss- of function approaches and 3D culture assays, we investigated roles of collagen XIII in regulating invasive tumor growth. Using the tumorsphere/mammosphere formation assay and the detachment cell culture assay, we determined whether collagen XIII enhances cancer cell stemness and induces anoikis resistance. We also inhibited collagen XIII signaling with β1 integrin function-blocking antibody. Finally, using the lung colonization assay and the orthotopic mammary tumor model, we investigated roles of collagen XIII in regulating breast cancer colonization and metastasis. Cox proportional hazard (log-rank) test, two-sided Student's t-test (two groups) and one-way ANOVA (three or more groups) analyses were used in this study.
RESULTS: Collagen XIII expression is significantly higher in human breast cancer tissue compared with normal mammary gland. Increased collagen XIII mRNA levels in breast cancer tissue correlated with short distant recurrence free survival. We showed that collagen XIII expression promoted invasive tumor growth in 3D culture, enhanced cancer cell stemness, and induced anoikis resistance. Collagen XIII expression induced β1 integrin activation. Blocking β1 integrin activation significantly reduced collagen XIII-induced invasion and mammosphere formation. Importantly, silencing collagen XIII in MDA-MB-231 cells reduced lung colonization and metastasis.
CONCLUSIONS: Our results demonstrate a novel function of collagen XIII in promoting cancer metastasis, cell invasion, and anoikis resistance.

Huang L, Li X, Gao W
Long non-coding RNA linc-ITGB1 promotes cell proliferation, migration, and invasion in human hepatoma carcinoma by up-regulating ROCK1.
Biosci Rep. 2018; 38(5) [PubMed] Article available free on PMC after 01/12/2019 Related Publications

Stojanović N, Dekanić A, Paradžik M, et al.
Differential Effects of Integrin
Mol Pharmacol. 2018; 94(6):1334-1351 [PubMed] Related Publications
Low survival rates of patients with metastatic triple-negative breast cancer (TNBC) and melanoma, in which current therapies are ineffective, emphasize the need for new therapeutic approaches. Integrin

Li X, Yin A, Zhang W, et al.
Jam3 promotes migration and suppresses apoptosis of renal carcinoma cell lines.
Int J Mol Med. 2018; 42(5):2923-2929 [PubMed] Related Publications
As a common type of renal cancer, renal cell carcinoma (RCC) has a high annual mortality rate. The incidence of RCC has been increasing in China and worldwide. A large number cases of RCC are diagnosed at late stages, often with local and/or systematic metastasis. Surgical resection of RCC is only suitable for a small number of patients with early stage tumors, and thus, novel therapeutic methods are required. Junctional adhesion molecule 3 (Jam3) is a member of the junctional adhesion molecule family, which has been linked to epithelial and cancer cell proliferation. The present study investigated whether the Jam3 gene affected RCC growth via proliferation and apoptosis. The expression and biological function of Jam3 in renal carcinoma cells was investigated. The mRNA and protein levels of Jam3 were examined by reverse transcription‑polymerase chain reaction and western blot analyses. The role of Jam3 in the migration and apoptosis of renal carcinoma cells was determined using small interfering RNA, wound‑healing assays, flow cytometry, and cell migration assays. In the cell migration assays, E‑cadherin, N‑cadherin, integrin β1, and matrix metalloproteinase (MMP)‑2 proteins were detected by western blot analysis. It was shown that the expression of Jam3 was significantly elevated in human renal carcinoma cells compared with that in renal tubular epithelial cells. The knockdown of Jam3 inhibited renal carcinoma cell migration and promoted renal carcinoma cell apoptosis. It also increased the protein levels of E‑cadherin and reduced the protein levels of N‑cadherin, integrin β1 and MMP‑2. The inhibition of Jam3 promoted migration and suppressed apoptosis of renal carcinoma cells via regulation of the expression of E‑cadherin, N‑cadherin, integrin β1 and MMP‑2. Therefore, Jam3 was suggested as a novel target gene for the diagnosis and treatment of RCC.

Fajka-Boja R, Marton A, Tóth A, et al.
Increased insulin-like growth factor 1 production by polyploid adipose stem cells promotes growth of breast cancer cells.
BMC Cancer. 2018; 18(1):872 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Adipose-tissue stem cells (ASCs) are subject of intensive research since their successful use in regenerative therapy. The drawback of ASCs is that they may serve as stroma for cancer cells and assist tumor progression. It is disquieting that ASCs frequently undergo genetic and epigenetic changes during their in vitro propagation. In this study, we describe the polyploidization of murine ASCs and the accompanying phenotypical, gene expressional and functional changes under long term culturing.
METHODS: ASCs were isolated from visceral fat of C57BL/6 J mice, and cultured in vitro for prolonged time. The phenotypical changes were followed by microscopy and flow cytometry. Gene expressional changes were determined by differential transcriptome analysis and changes in protein expression were shown by Western blotting. The tumor growth promoting effect of ASCs was examined by co-culturing them with 4 T1 murine breast cancer cells.
RESULTS: After five passages, the proliferation of ASCs decreases and cells enter a senescence-like state, from which a proportion of cells escape by polyploidization. The resulting ASC line is susceptible to adipogenic, osteogenic and chondrogenic differentiation, and expresses the stem cell markers CD29 and Sca-1 on an upregulated level. Differential transcriptome analysis of ASCs with normal and polyploid karyotype shows altered expression of genes that are involved in regulation of cancer, cellular growth and proliferation. We verified the increased expression of Klf4 and loss of Nestin on protein level. We found that elevated production of insulin-like growth factor 1 by polyploid ASCs rendered them more potent in tumor growth promotion in vitro.
CONCLUSIONS: Our model indicates how ASCs with altered genetic background may support tumor progression.

Csoboz B, Gombos I, Tatrai E, et al.
Chemotherapy induced PRL3 expression promotes cancer growth via plasma membrane remodeling and specific alterations of caveolae-associated signaling.
Cell Commun Signal. 2018; 16(1):51 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: The outcome of cancer therapy is greatly defined by the ability of a tumor cell to evade treatment and re-establish its bulk mass after medical interventions. Consequently, there is an urgent need for the characterization of molecules affecting tumor reoccurrence. The phosphatase of regenerating liver 3 (PRL3) protein was recently emerged among the targets that could affect such a phenomenon.
METHODS: The expression induction of PRL3 in melanoma cells treated with chemotherapeutic agents was assessed by western blotting. The effect of PRL3 expression on cancer growth was investigated both in vitro and in vivo. The association of PRL3 with the caveolae structures of the plasma membrane was analyzed by detergent free raft purification. The effect of PRL3 expression on the membrane organization was assayed by electron microscopy and by membrane biophysical measurements. Purification of the plasma membrane fraction and co-immunoprecipitation were used to evaluate the altered protein composition of the plasma membrane upon PRL3 expression.
RESULTS: Here, we identified PRL3 as a genotoxic stress-induced oncogene whose expression is significantly increased by the presence of classical antitumor therapeutics. Furthermore, we successfully connected the presence of this oncogene with increased tumor growth, which implies that tumor cells can utilize PRL3 effects as a survival strategy. We further demonstrated the molecular mechanism that is connected with the pro-growth action of PRL3, which is closely associated with its localization to the caveolae-type lipid raft compartment of the plasma membrane. In our study, PRL3 was associated with distinct changes in the plasma membrane structure and in the caveolar proteome, such as the dephosphorylation of integrin β1 at Thr788/Thr789 and the increased partitioning of Rac1 to the plasma membrane. These alterations at the plasma membrane were further associated with the elevation of cyclin D1 in the nucleus.
CONCLUSIONS: This study identifies PRL3 as an oncogene upregulated in cancer cells upon exposure to anticancer therapeutics. Furthermore, this work contributes to the existing knowledge on PRL3 function by characterizing its association with the caveolae-like domains of the plasma membrane and their resident proteins.

Yang X, Deng Y, He RQ, et al.
Upregulation of HOXA11 during the progression of lung adenocarcinoma detected via multiple approaches.
Int J Mol Med. 2018; 42(5):2650-2664 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
The altered expression of homeobox (HOX)A11 has been observed in various malignant tumor types, but it has remained to be determined in human lung adenocarcinoma (LUAD). In the present study, the expression of HOXA11 in LUAD and the potential associated mechanisms were assessed. Data from The Cancer Genome Atlas and Oncomine microarrays were gathered and in‑house polymerase chain reaction data were produced to investigate the altered expression of HOXA11 in LUAD and its association with various clinicopathological characteristics. Genes co‑expressed with HOXA11 were also identified by searching the cBioPortal and Multi Experiment Matrix databases, and performing a bioinformatics analysis, through which the potential molecular mechanisms of HOXA11 in LUAD were explored. The data analyses indicated that HOXA11 was overexpressed in the LUAD samples, and together with its co‑expressed genes, it was indicated to participate in various key signaling pathways, including the focal adhesion, extracellular matrix‑receptor interaction, axon guidance and small cell lung cancer signaling pathways. Furthermore, collagen type III α 1 chain (COL3A1), ephrin B2 (EFNB2), integrin subunit α 8 (ITGA8) and syndecan 2 (SDC2) were confirmed to be differentially expressed in LUAD vs. normal controls at the mRNA and protein level. Of note, LUAD patients with low expression of HOXA11 and ITGB1 had better overall survival rates. The present study indicated that HOXA11 may function as an oncogene in LUAD, and HOXA11 protein probably combines with ITGB1, COL3A1, EFNB2, ITGA8 and SDC2 to have a role in the focal adhesion pathway.

Eke I, Makinde AY, Aryankalayil MJ, et al.
Long-term Tumor Adaptation after Radiotherapy: Therapeutic Implications for Targeting Integrins in Prostate Cancer.
Mol Cancer Res. 2018; 16(12):1855-1864 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
Adaptation of tumor cells to radiotherapy induces changes that are actionable by molecular targeted agents and immunotherapy. This report demonstrates that radiation-induced changes in integrin expression can be targeted 2 months later. Integrins are transmembrane cell adhesion molecules that are essential for cancer cell survival and proliferation. To analyze the short- and long-term effects of radiation on the integrin expression, prostate cancer cells (DU145, PC3, and LNCaP) were cultured in a 3D extracellular matrix and irradiated with either a single dose of radiation (2-10 Gy) or a multifractionated regimen (2-10 fractions of 1 Gy). Whole human genome microarrays, immunoblotting, immunoprecipitation assays, and immunofluorescence staining of integrins were performed. The results were confirmed in a prostate cancer xenograft model system. Interestingly, β1 and β4 integrins (

Han Y, Liu Y, Fu X, et al.
miR-9 inhibits the metastatic ability of hepatocellular carcinoma via targeting beta galactoside alpha-2,6-sialyltransferase 1.
J Physiol Biochem. 2018; 74(3):491-501 [PubMed] Related Publications
Glycosylation of cell surface proteins regulates critical cellular functions, including invasion and metastasis in cancer cells. Emerging evidence has shown that microRNAs (miRNAs) are involved in regulating both the glycosylation modifications on cell surface and the progression of cancer. In this study, we investigated the role of miR-9 in α-2,6-linked sialylation and the metastasis of mouse hepatocellular carcinoma (HCC). According to array-based miRNA expression profiling data of HCC cell lines Hepa1-6, Hca-P, and Hca-F with different lymphatic metastatic capacities, reverse correlation was found between miR-9 expression levels and the metastatic potential in these HCC cells. Additionally, β-galactoside α-2,6-sialyltransferase 1 (St6gal1) expression level is associated negatively with miR-9 and positively with metastatic potential. Bioinformatics analysis indicated that miR-9 could target St6gal1, which was verified by luciferase reporter assays. miR-9 overexpression reduced expression of St6gal1, which subsequently suppressed HCC cells metastatic potential. Moreover, upregulation of miR-9 could inhibit integrin-β1/FAK-mediated cell motility and migration signaling in mouse HCC cells. Together, our results suggest that miR-9 could act as a tumor suppressor and regulate mouse HCC cells migration and invasion by inhibiting the α-2,6-linked sialylation. This finding may provide insight into the relationship between abnormal miRNA expression and aberrant cell surface glycosylation during tumor lymphatic metastasis.

Olof Olsson P, Gustafsson R, Salnikov AV, et al.
Inhibition of integrin α
Cell Commun Signal. 2018; 16(1):36 [PubMed] Article available free on PMC after 01/12/2019 Related Publications
BACKGROUND: Chemotherapeutic efficacy can be improved by targeting the structure and function of the extracellular matrix (ECM) in the carcinomal stroma. This can be accomplished by e.g. inhibiting TGF-β1 and -β3 or treating with Imatinib, which results in scarcer collagen fibril structure in xenografted human KAT-4/HT29 (KAT-4) colon adenocarcinoma.
METHODS: The potential role of α
RESULTS: Both KAT-4 and Capan-2 cells expressed the α
CONCLUSION: Our data demonstrate that the α

Yang YX, Wei L, Zhang YJ, et al.
Long non-coding RNA p10247, high expressed in breast cancer (lncRNA-BCHE), is correlated with metastasis.
Clin Exp Metastasis. 2018; 35(3):109-121 [PubMed] Related Publications
Recent studies have shown that long non-coding RNAs (lncRNAs) have key functions during breast cancer development. Considering the complexity of IncRNAs regulatory network, the identification of novel and functional lncRNAs associated with breast cancer is thus very important. By using Agilent LncRNA Human Gene Expression Microarray, we identified a number of lncRNAs that were differentially expressed in breast cancer compared to their corresponding adjacent tissues. According to the microarray, the expression of p10247, henceforth named as lncRNA-BCHE (standing for lncRNA high expressed in breast cancer), was found to be uniformly higher in all the five breast cancer tissues tested, and this was further confirmed in 56 breast cancer tissues by real-time RT-PCR. The function of lncRNA-BCHE in breast cancer cells was tested by knockdown and over-expression experiments in vitro. We also analyzed the public cohorts of breast cancer patients on the Kaplan Meier plotter platform. Clinical analysis revealed that the expression of lncRNA-BCHE was significantly correlated with advanced clinical stage and lymph node metastasis. Our data indicate that lncRNA-BCHE regulates the growth, migration and invasion of breast cancer cells. In addition, we found that these functions are mediated, at least in part, by the regulation of integrin subunit beta 1 (ITGB1) levels. The expression of ITGB1 serves as a negative prognostic factor and metastasis risk predictor in breast cancer, irrespective of subtype and therapeutic regimen. In summary, our results suggest that lncRNA-BCHE is an oncogenic lncRNA enhancing the growth and metastatic potential of breast cancer cells, and a potential predictor of breast cancer metastatic progression.

Shinde A, Libring S, Alpsoy A, et al.
Autocrine Fibronectin Inhibits Breast Cancer Metastasis.
Mol Cancer Res. 2018; 16(10):1579-1589 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Both epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are linked to metastasis via their ability to increase invasiveness and enhance tumor-initiating capacity. Growth factors, cytokines, and chemotherapies present in the tumor microenvironment (TME) are capable of inducing EMT, but the role of the extracellular matrix (ECM) in this process remains poorly understood. Here, a novel tessellated three-dimensional (3D) polymer scaffolding is used to produce a fibrillar fibronectin matrix that induces an EMT-like event that includes phosphorylation of STAT3 and requires expression of β1 integrin. Consistent with these findings, analysis of the METABRIC dataset strongly links high-level fibronectin (FN) expression to decreased patient survival. In contrast,

Zhang R, Zhang TT, Zhai GQ, et al.
Evaluation of the HOXA11 level in patients with lung squamous cancer and insights into potential molecular pathways via bioinformatics analysis.
World J Surg Oncol. 2018; 16(1):109 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: This study was carried out to discover the underlying role that HOXA11 plays in lung squamous cancer (LUSC) and uncover the potential corresponding molecular mechanisms and functions of HOXA11-related genes.
METHODS: Twenty-three clinical paired LUSC and non-LUSC samples were utilized to examine the level of HOXA11 using quantitative real-time polymerase chain reaction (qRT-PCR). The clinical significance of HOXA11 was systematically analyzed based on 475 LUSC and 18 non-cancerous adjacent tissues from The Cancer Genome Atlas (TCGA) database. A total of 102 LUSC tissues and 121 non-cancerous tissues were available from Oncomine to explore the expressing profiles of HOXA11 in LUSC. A meta-analysis was carried out to further assess the differential expression of HOXA11 in LUSC, including in-house qRT-PCR data, expressing data extracted from TCGA and Oncomine databases. Moreover, the enrichment analysis and potential pathway annotations of HOXA11 in LUSC were accomplished via Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The expression of hub genes and according correlations with HOXA11 were assessed to further explore the biological role of HOXA11 in LUSC.
RESULTS: HOXA11 expression in LUSC had a tendency to be upregulated in comparison to adjacent non-cancerous tissues by qRT-PCR. TCGA data displayed that HOXA11 was remarkably over-expressed in LUSC compared with that in non-LUSC samples, and the area under curves (AUC) was 0.955 (P < 0.001). A total of 1523 co-expressed genes were sifted for further analysis. The most significant term enriched in the KEGG pathway was focal adhesion. Among the six hub genes of HOXA11, including PARVA, ILK, COL4A1, COL4A2, ITGB1, and ITGA5, five (with the exception of COL4A1) were significantly decreased compared with the normal lung tissues. Moreover, the expression of ILK was negatively related to HOXA11 (r = - 0.141, P = 0.002).
CONCLUSION: High HOXA11 expression may lead to carcinogenesis and the development of LUSC. Furthermore, co-expressed genes might affect the prognosis of LUSC.

Di Modugno F, Spada S, Palermo B, et al.
hMENA isoforms impact NSCLC patient outcome through fibronectin/β1 integrin axis.
Oncogene. 2018; 37(42):5605-5617 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
We demonstrated previously that the splicing of the actin regulator, hMENA, generates two alternatively expressed isoforms, hMENA

Pan L, Yang H, Xu C, et al.
ZNF750 inhibited the malignant progression of oral squamous cell carcinoma by regulating tumor vascular microenvironment.
Biomed Pharmacother. 2018; 105:566-572 [PubMed] Related Publications
OBJECTIVE: Squamous cell carcinoma is often associated with the deletion or mutation of zinc finger protein 750 (ZNF750), its deletion or mutation is associated with squamous epithelial malignant biological characteristics. The present study is to explore the mechanism of ZNF750 to suppress the tumor malignant process by regulation tumor microenvironment.
METHODS: To evaluate the changes of tumor microenvironment in oral squamous cells carcinoma cell line CAL-27 cell, the expression of angiogenin, vascular endothelial growth factor (VEGF), prolyl hydroxylase 2 (PHD2), G protein signal regulated protein 5 (RGS5), integrin A5 (ITGA5), integrin B1 (ITGB1) and CD44 were detected by Western-blot. The changes of platelet derived growth factor (PDGFB) and tumor vascular marker CD105 (Endoglin) mRNA were estimated by qPCR. The effect of over-expressed ZNF750 on cell viability and lateral migration capacity was investigated by CCK-8 and cell scratch assay in three oral squamous cells carcinoma.
RESULTS: ZNF750 could effectively inhibit the protein or mRNA expression of angiogenin, VEGF, RGS5 and CD105, repressed the cell adhesion molecules ITGA5, ITGB1 and CD44, but up-regulate the protein or mRNA expression of PHD2 and PDGFB. The cell viability and lateral migration ability of three oral squamous cells carcinoma were reduced by over-expression of ZNF750.
CONCLUSION: ZNF750 could modulate the tumor vascular microenvironment to inhibit the oral squamous cells carcinoma malignant progression.

Qiu X, Feng JR, Qiu J, et al.
ITGBL1 promotes migration, invasion and predicts a poor prognosis in colorectal cancer.
Biomed Pharmacother. 2018; 104:172-180 [PubMed] Related Publications
Colorectal cancer (CRC) is one of the most common malignancies worldwide; its progression and prognosis are associated with oncogenes. The present study aimed to identify differentially expressed genes (DEGs) and explore the role and potential mechanism of integrin subunit β like 1 (ITGBL1) in CRC. The microarray dataset GSE41258 was used to screen DEGs involved in CRC. Survival analysis was performed to predict the prognosis of CRC patients. To validate ITGBL1 expression, immunohistochemistry, quantitative real-time PCR and western blotting were performed in CRC tissues and cells. Subsequently, the effects of ITGBL1 were evaluated through colony formation, cell proliferation, migration and invasion assays. Finally, we took advantage of Gene Ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) to explore potential function and mechanism of ITGBL1 in CRC. In our study, 182 primary CRC tissues and 54 normal colon tissues were contained in GSE41258 dataset. A total of 318 DEGs were screened, among which ITGBL1 was found to be significantly up-regulated in CRC, and its high expression was associated with shortened survival of CRC patients. Moreover, knockdown of ITGBL1 promoted CRC cell proliferation, migration and invasion. Finally, GO analysis revealed that ITGBL1 was associated with cell adhesion. GSEA indicated that ITGBL1 was enriched in ECM receptor interaction and focal adhesion. In conclusion, a novel oncogene ITGBL1 was identified and demonstrated to be associated with the progression and prognosis of CRC, which might be a potential therapeutic target and prognostic biomarker for CRC patients.

McAtee CO, Booth C, Elowsky C, et al.
Prostate tumor cell exosomes containing hyaluronidase Hyal1 stimulate prostate stromal cell motility by engagement of FAK-mediated integrin signaling.
Matrix Biol. 2019; 78-79:165-179 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
The hyaluronidase Hyal1 is clinically and functionally implicated in prostate cancer progression and metastasis. Elevated Hyal1 accelerates vesicular trafficking in prostate tumor cells, thereby enhancing their metastatic potential in an autocrine manner through increased motility and proliferation. In this report, we found Hyal1 protein is a component of exosomes produced by prostate tumor cell lines overexpressing Hyal1. We investigated the role of exosomally shed Hyal1 in modulating tumor cell autonomous functions and in modifying the behavior of prostate stromal cells. Catalytic activity of Hyal1 was necessary for enrichment of Hyal1 in the exosome fraction, which was associated with increased presence of LC3BII, an autophagic marker, in the exosomes. Hyal1-positive exosome contents were internalized from the culture medium by WPMY-1 prostate stromal fibroblasts. Treatment of prostate stromal cells with tumor exosomes did not affect proliferation, but robustly stimulated their migration in a manner dependent on Hyal1 catalytic activity. Increased motility of exosome-treated stromal cells was accompanied by enhanced adhesion to a type IV collagen matrix, as well as increased FAK phosphorylation and integrin engagement through dynamic membrane residence of β1 integrins. The presence of Hyal1 in tumor-derived exosomes and its ability to impact the behavior of stromal cells suggests cell-cell communication via exosomes is a novel mechanism by which elevated Hyal1 promotes prostate cancer progression.

Ishizuka Y, Koshinaga T, Hirano T, et al.
NRP1 knockdown promotes the migration and invasion of human neuroblastoma-derived SK‑N‑AS cells via the activation of β1 integrin expression.
Int J Oncol. 2018; 53(1):159-166 [PubMed] Related Publications
Neuropilin 1 (NRP1) is a transmembrane glycoprotein, which regulates many aspects of cellular function by functioning as co-receptor of various ligands. Recent studies have suggested that NRP1 promotes tumorigenesis, not only by activating the growth of tumor vessels, but also by activating the growth or migration of tumor cells themselves. The present study was performed to elucidate the roles of NRP1 in the development and/or progression of neuroblastoma (NB). In contrast to previous observations in various types of cancer, the analysis of public datasets indicated that lower levels of NRP1 expression were significantly associated with a shorter survival period of patients with NB. Consistent with this finding, wound-healing assay and Matrigel invasion assay revealed that NB cells in which NRP1 was knocked down exhibited increased migratory and invasive abilities. Further analyses indicated that β1 integrin expression was markedly increased in NB cells in which NRP1 was knocked down, and NB cells in which β1 integrin was knocked down exhibited decreased migratory and invasive abilities. The results presented herein indicate that NRP1 exerts tumor suppressive effects in NB, at least in part by regulating the expression of β1 integrin.

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