Gene Summary

Gene:ITGA4; integrin subunit alpha 4
Aliases: IA4, CD49D
Summary:The gene encodes a member of the integrin alpha chain family of proteins. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain that function in cell surface adhesion and signaling. The encoded preproprotein is proteolytically processed to generate light and heavy chains that comprise the alpha 4 subunit. This subunit associates with a beta 1 or beta 7 subunit to form an integrin that may play a role in cell motility and migration. This integrin is a therapeutic target for the treatment of multiple sclerosis, Crohn's disease and inflammatory bowel disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:integrin alpha-4
Source:NCBIAccessed: 01 September, 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 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: ITGA4 (cancer-related)

Zhao X, Lei Y, Li G, et al.
Integrative analysis of cancer driver genes in prostate adenocarcinoma.
Mol Med Rep. 2019; 19(4):2707-2715 [PubMed] Free Access to Full Article Related Publications
Large‑scale genomics studies have identified recurrently mutated genes in the ETS gene family, including fusions and copy number variations (CNVs), which are involved in the development of prostate adenocarcinoma (PRAD). However, the aetiology of PRAD remains to be fully elucidated. In the present study, 333 driver genes were identified using four computational tools: OncodriveFM, OncodriveCLUST, iCAGES and DrGaP. In addition, 32 driver pathways were identified using DrGaP. SPOP, TP53, SPTA1, AHNAK, HMCN1, ATM, FOXA1, CSMD3, LRP1B and FREM2 were the 10 most recurrently mutated genes in PRAD. ITGAL, TAGAP, SIGLEC10, RAC2 and ITGA4 were the five hub genes in the yellow module that were associated with the number of positive lymph nodes. Hierarchical clustering analysis of the 20 driver genes with the most frequent CNVs revealed three clusters of patients with PRAD. Cluster 3 tumours exhibited significantly higher numbers of positive lymph nodes, higher Gleason scores, more advanced cancer stages and poorer prognosis than cluster 1 and 2 tumours. A total of 48 genes were significantly associated with the number of positive lymph nodes, Gleason scores and pathologic stage in patients with PRAD. The identified set of cancer genes and pathways sheds light on the tumorigenesis of PRAD and creates avenues for the development of prognostic biomarkers and driver gene‑targeted therapies in PRAD.

Song J, Wu S, Xia X, et al.
Cell adhesion-related gene somatic mutations are enriched in aggressive papillary thyroid microcarcinomas.
J Transl Med. 2018; 16(1):269 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Approximately half of the documented increases in differentiated thyroid carcinoma is due to identification of papillary thyroid microcarcinomas (PTMCs). Knowing whether PTMC is aggressive is required for proper treatment, but until now, there has been no method for assessing these traits and understanding the underlying mechanisms for aggressiveness.
METHODS: We performed whole-exome sequencing of 16 PTMCs and matched normal thyroid tissues and GO/KEGG analysis to study genetic alterations and biological consequences associated with aggressive PTMCs, and then sequenced these genes using a next-generation gene-panel approach in an additional 70 PTMC samples including aggressive (n = 50) and non-aggressive (n = 20) groups.
RESULTS: We identified 254 somatic mutations of 234 genes, for which 178 mutations in 168 genes were found in the aggressive group, and 76 mutations in 74 genes were found in the non-aggressive group. Several recurrent mutations in BRAF, VCAN, ALDH1L1, and MUC5B were identified, and many novel but infrequent mutations in other genes were also found. The aggressive cohort had more mutational burdens than the non-aggressive group (P = 0.004). Nonsynonymous mutations of 13 genes (MUC5B, TNN, SSPO, PPFIA1, PCDHGA2, ITGA8, ITGA4, DCHS1, CRNN, ROCK1, RELN, LAMC2, and AEBP1) were involved in cell adhesion, and these were only present in the aggressive group. Targeted sequencing of these genes revealed significant enrichment in the aggressive group (P = 0.000004).
CONCLUSION: PTC may have evolved from PTMC due to sharing similar gene mutations, and the accumulation of such mutations promoted the aggressiveness of PTMC. Gene mutants associated with cell adhesion may be used to predict PTMC aggressiveness and allow more selective treatment.

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

Kriston C, Plander M, Márk Á, et al.
In contrast to high CD49d, low CXCR4 expression indicates the dependency of chronic lymphocytic leukemia (CLL) cells on the microenvironment.
Ann Hematol. 2018; 97(11):2145-2152 [PubMed] Related Publications
CD49d and CXCR4 are key determinants of interactions between chronic lymphocytic leukemia (CLL) tumor cells and their microenvironment. In this study, we investigated the effect of CD49d and CXCR4 expressions on survival of CLL cells. Primary CLL cells were cultured with CD49d ligand, VCAM-1, or bone marrow stromal cells (BMSCs); then, apoptosis and immunophenotype analyses were performed. VCAM-1 treatment could not induce direct apoptosis protection or immunophenotype change on the CD49d-expressing CLL cells, but resulted in actin reorganization. The BMSC-induced apoptosis protection was independent from the presence of CD49d expression of CLL cells, but showed an inverse correlation with their CXCR4 expression level. We suppose that CD49d contributes to enhanced survival of leukemic cells by mediating migration to the protective microenvironment, not by direct prevention of apoptosis. Moreover, CLL cells with low CXCR4 expression represent a subpopulation that is more dependent on the microenvironmental stimuli for survival, and show increased "death by neglect" when separated from the supportive niche.

Deng M, Yu R, Wang S, et al.
Limb-Bud and Heart Attenuates Growth and Invasion of Human Lung Adenocarcinoma Cells and Predicts Survival Outcome.
Cell Physiol Biochem. 2018; 47(1):223-234 [PubMed] Related Publications
BACKGROUND/AIMS: The transcription cofactor limb-bud and heart (LBH) is involved in embryonic development. However, its role in human lung cancer, especially lung adenocarcinoma (LUAD), remains unclear.
METHODS: A public database and tissue microarray (TMA) were used to compare differences in LBH expression and its relationship with clinical characteristics. Tissue from an additional 70 LUAD patients with follow-up records was used to explore the correlation of LBH expression with prognosis. Cellular and molecular studies validated the role of LBH in LUAD growth and invasion.
RESULTS: LBH was significantly down-regulated in lung cancer tissue samples and was correlated with the prognosis and clinical characteristics of lung cancer patients based on a public database and TMA. Survival analysis revealed that LBH-negative expression was associated with poor overall survival of LUAD patients (P = 0.021). Cox regression analysis showed that LBH expression status was a favorable independent prognostic factor (hazard ratio = 0.120, 95% confidence interval = 0.016-0.894, P = 0.039). LBH knockdown accelerated LUAD cell proliferation, migration, and invasion. Furthermore, bioinformatics analysis indicated that LBH was significantly related to the cell adhesion pathway. Western blot analysis confirmed that LBH could regulate the expression of integrin family members (integrin-α1, integrin-α2, integrin-α4, integrin-αv, and integrin-β4).
CONCLUSION: Our data suggest that LBH plays an important role in lung cancer. Importantly, LBH is an independent prognostic factor in LUAD and can attenuate cell growth and invasion. LBH may be a potential prognostic biomarker in LUAD patients.

Yoshida T, Ri M, Kinoshita S, et al.
Low expression of neural cell adhesion molecule, CD56, is associated with low efficacy of bortezomib plus dexamethasone therapy in multiple myeloma.
PLoS One. 2018; 13(5):e0196780 [PubMed] Free Access to Full Article Related Publications
Bortezomib (Btz) is an active agent used to treat multiple myeloma (MM). Not all patients who receive Btz-containing therapy show a favorable response. Interaction of cellular adhesion molecules with MM and bone marrow stromal cells is crucial for the survival of MM cells. However, little is known about the role of these molecules in the sensitivity of MM to Btz-containing therapy. Thus, we evaluated the correlation between the level of cellular adhesion molecules in MM cells and the efficacy of Btz plus dexamethasone (Bd) therapy. The expression of the neural cell adhesion molecule gene (NCAM, also known as CD56), ITGA4, CXCR4, and other genes were analyzed in 74 samples of primary MM cells collected from patients before they received Bd therapy. Of the eight genes tested, expression of NCAM was lower among patients who responded poorly to Bd therapy. In vitro expression of NCAM induced by transfection of MM cells enhanced their sensitivity to Btz treatment by causing accumulation of polyubiquitinated proteins. Our results indicate that expression of NCAM is associated with better response to Btz treatment and is a promising candidate biomarker for predicting response to therapies involving Btz.

Tooze JA, Hamzic E, Willis F, Pettengell R
Differences between chronic lymphocytic leukaemia and small lymphocytic lymphoma cells by proteomic profiling and SNP microarray analysis.
Cancer Genet. 2017; 218-219:20-38 [PubMed] Related Publications
The majority of malignant cells in chronic lymphocytic leukaemia (CLL) circulate in the peripheral blood whereas small lymphocytic lymphoma (SLL) cells reside in tissues. The aim of this study was to detect differences in chemokine receptor expression, DNA single nucleotide polymorphism (SNP) microarray analysis and proteomic profiling to help elucidate why the cells remain in their respective environments. We identified by flow cytometric studies of chemokine receptors and DNA SNP microarray analysis significant differences between cells from CLL and SLL patients. Proteomic analysis revealed two potential markers (m/z 3091 and 8707) to distinguish the two disorders. There was a significantly greater expression of leucocyte trafficking receptor CXCR3 (CD183) and migration and homing receptor CXCR4 (CD184), and significantly lower expression of cell adhesion molecule integrin α

Duchartre Y, Bachl S, Kim HN, et al.
Effects of CD49d-targeted antisense-oligonucleotide on α4 integrin expression and function of acute lymphoblastic leukemia cells: Results of in vitro and in vivo studies.
PLoS One. 2017; 12(11):e0187684 [PubMed] Free Access to Full Article Related Publications
We recently demonstrated the effectiveness of blocking CD49d with anti-functional antibodies or small molecule inhibitors as a rational targeted approach to the treatment of acute leukemia in combination with chemotherapy. Antisense oligonucleotide promises to be no less specific than antibodies and inhibitors, but more interesting for pharmacokinetics and pharmacodynamics. We addressed this using the published CD49d antisense drug ATL1102. In vitro, we incubated/nucleofected the ALL cell line Kasumi-2 with ATL1102. In vivo, immunodeficient hosts were engrafted with primary ALL cells and treated with ATL1102. Changes in expression of CD49d mRNA and CD49d protein, and of cooperating gene products, including ß1 integrin and CXCR4, as well as survival in the mouse experiments were quantified. We observed dose-dependent down-regulation of CD49d mRNA and protein levels and its partner integrin ß1 cell surface protein level and, up-regulation of CXCR4 surface expression. The suppression was more pronounced after nucleofection than after incubation, where down-regulation was significant only at the higher doses. In vivo effects of ATL1102 were not sufficient to translate into "clinical" benefit in the leukemia model. In summary, antisense oligonucleotides are successful tools for specifically modulating gene expression but sufficient delivery to down-regulate CD49d in vivo may be difficult to achieve.

Martínez-Trillos A, Pinyol M, Delgado J, et al.
The mutational landscape of small lymphocytic lymphoma compared to non-early stage chronic lymphocytic leukemia.
Leuk Lymphoma. 2018; 59(10):2318-2326 [PubMed] Related Publications
Small lymphocytic lymphoma (SLL) is considered as the non-leukemic form of presentation of chronic lymphocytic leukemia (CLL). We have compared the features, genomic alterations, and outcome of 890 patients with CLL and SLL. One hundred and thirteen patients presented as SLL and more frequently had unmutated-IGHV, CD38

Slattery ML, Mullany LE, Sakoda LC, et al.
The PI3K/AKT signaling pathway: Associations of miRNAs with dysregulated gene expression in colorectal cancer.
Mol Carcinog. 2018; 57(2):243-261 [PubMed] Free Access to Full Article Related Publications
The PI3K/AKT-signaling pathway is one of the most frequently activated signal-transduction pathways in cancer. We examined how dysregulated gene expression is associated with miRNA expression in this pathway in colorectal cancer (CRC). We used data from 217 CRC cases to evaluate differential pathway gene expression between paired carcinoma and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analyzed. We focused on genes most associated with CRC (fold change (FC) of >1.5 or <0.67) that were statistically significant after adjustment for multiple comparisons. Of the 304 genes evaluated, 76 had a FC of <0.67, and 57 had a FC of >1.50; 47 of these genes were associated with miRNA differential expression. There were 145 mRNA:miRNA seed-region matches of which 26 were inversely associated suggesting a greater likelihood of a direct association. Most miRNA:mRNA associations were with factors that stimulated the pathway. For instance, both IL6R and PDGFRA had inverse seed-region matches with seven miRNAs, suggesting that these miRNAs have a direct effect on these genes and may be key elements in activation of the pathway. Other miRNA:mRNA associations with similar impact on the pathway were miR-203a with ITGA4, miR-6071 with ITGAV, and miR-375 with THBS2, all genes involved in extracellular matrix function that activate PI3Ks. Gene expression in the PI3K/Akt-signaling pathway is dysregulated in CRC. MiRNAs were associated with many of these dysregulated genes either directly or in an indirect manner.

Krejcik J, Frerichs KA, Nijhof IS, et al.
Monocytes and Granulocytes Reduce CD38 Expression Levels on Myeloma Cells in Patients Treated with Daratumumab.
Clin Cancer Res. 2017; 23(24):7498-7511 [PubMed] Free Access to Full Article Related Publications

Barault L, Amatu A, Siravegna G, et al.
Discovery of methylated circulating DNA biomarkers for comprehensive non-invasive monitoring of treatment response in metastatic colorectal cancer.
Gut. 2018; 67(11):1995-2005 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
OBJECTIVE: Mutations in cell-free circulating DNA (cfDNA) have been studied for tracking disease relapse in colorectal cancer (CRC). This approach requires personalised assay design due to the lack of universally mutated genes. In contrast, early methylation alterations are restricted to defined genomic loci allowing comprehensive assay design for population studies. Our objective was to identify cancer-specific methylated biomarkers which could be measured longitudinally in cfDNA (liquid biopsy) to monitor therapeutic outcome in patients with metastatic CRC (mCRC).
DESIGN: Genome-wide methylation microarrays of CRC cell lines (n=149) identified five cancer-specific methylated loci (
RESULTS: Methylation in at least one marker was detected in all tumour tissue samples and in 156 mCRC patient cfDNA samples (85.7%). Plasma marker prevalence was 71.4% for
CONCLUSION: This five-gene methylation panel can be used to circumvent the absence of patient-specific mutations for monitoring tumour burden dynamics in liquid biopsy under different therapeutic regimens. This method might be proposed for assessing pharmacodynamics in clinical trials or when conventional imaging has limitations.

Prichard DO, Byrne AM, Murphy JO, et al.
Deoxycholic acid promotes development of gastroesophageal reflux disease and Barrett's oesophagus by modulating integrin-αv trafficking.
J Cell Mol Med. 2017; 21(12):3612-3625 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
The fundamental mechanisms underlying erosive oesophagitis and subsequent development of Barrett's oesophagus (BO) are poorly understood. Here, we investigated the contribution of specific components of the gastric refluxate on adhesion molecules involved in epithelial barrier maintenance. Cell line models of squamous epithelium (HET-1A) and BO (QH) were used to examine the effects of bile acids on cell adhesion to extracellular matrix proteins (Collagen, laminin, vitronectin, fibronectin) and expression of integrin ligands (α

Benedetti D, Tissino E, Pozzo F, et al.
NOTCH1 mutations are associated with high CD49d expression in chronic lymphocytic leukemia: link between the NOTCH1 and the NF-κB pathways.
Leukemia. 2018; 32(3):654-662 [PubMed] Related Publications
In chronic lymphocytic leukemia (CLL), stabilizing mutations of NOTCH1, affecting up to 10-15% of cases, have been associated to poor prognosis, disease progression and refractoriness to chemotherapy. NOTCH1 mutations are significantly overrepresented in trisomy 12 CLL, a disease subset frequently expressing CD49d, the α4 chain of the very-late-activation-4 integrin, a well-known key regulator of microenviromental interactions, and negative prognosticator in CLL. In the present study, by analysing a wide cohort of 1180 CLL, we observed a very strong association between the presence of NOTCH1 mutations and the expression of CD49d (P<0.0001), occurring also outside the trisomy 12 CLL subset. Using both the MEC-1 CLL-like cells stably transfected with the NOTCH1 intracellular domain and primary CLL cells bearing a mutated or wild-type NOTCH1 gene configuration, we provide evidence that triggering of the NOTCH1 pathway resulted in a positive CD49d expression regulation, which was driven by a NOTCH1-dependent activation of nuclear factot-κB (NF-κB). Consistently, pharmacological inhibition of the NOTCH1 and/or of the NF-κB pathways resulted in impaired NF-κB nuclear translocation with consequent down-modulation of CD49d expression. Altogether, our data link for the first time NOTCH1 mutations to CD49d expression regulation through the involvement of the NF-κB pathway in CLL.

Singh R, De Sarkar N, Sarkar S, et al.
Analysis of the whole transcriptome from gingivo-buccal squamous cell carcinoma reveals deregulated immune landscape and suggests targets for immunotherapy.
PLoS One. 2017; 12(9):e0183606 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: Gingivo-buccal squamous cell carcinoma (GBSCC) is one of the most common oral cavity cancers in India with less than 50% patients surviving past 5 years. Here, we report a whole transcriptome profile on a batch of GBSCC tumours with diverse tobacco usage habits. The study provides an entire landscape of altered expression with an emphasis on searching for targets with therapeutic potential.
METHODS: Whole transcriptomes of 12 GBSCC tumours and adjacent normal tissues were sequenced and analysed to explore differential expression of genes. Expression changes were further compared with those in TCGA head and neck cohort (n = 263) data base and validated in an independent set of 10GBSCC samples.
RESULTS: Differentially expressed genes (n = 2176) were used to cluster the patients based on their tobacco habits, resulting in 3 subgroups. Immune response was observed to be significantly aberrant, along with cell adhesion and lipid metabolism processes. Different modes of immune evasion were seen across 12 tumours with up-regulation or consistent expression of CD47, unlike other immune evasion genes such as PDL1, FUT4, CTLA4 and BTLA which were downregulated in a few samples. Variation in infiltrating immune cell signatures across tumours also indicates heterogeneity in immune evasion strategies. A few actionable genes such as ITGA4, TGFB1 and PTGS1/COX1 were over expressed in most samples.
CONCLUSION: This study found expression deregulation of key immune evasion genes, such as CD47 and PDL1, and reasserts their potential as effective immunotherapeutic targets for GBSCC, which requires further clinical studies. Present findings reiterate the idea of using transcriptome profiling to guide precision therapeutic strategies.

Konac E, Kiliccioglu I, Sogutdelen E, et al.
Do the expressions of epithelial-mesenchymal transition proteins, periostin, integrin-α4 and fibronectin correlate with clinico-pathological features and prognosis of metastatic castration-resistant prostate cancer?
Exp Biol Med (Maywood). 2017; 242(18):1795-1801 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Development of metastatic castration-resistant prostate cancer is a result of the lack of an apoptotic response by the tumor cells and loss of the ability to stick to adjacent cells through epithelial-mesenchymal transition. Although there are several strongly recommended biomarkers for determining prognosis of metastatic castration-resistant prostate cancer, only few of them may help decide the selection of the optimal treatment option. The mode of treatment sequencing in metastatic castration-resistant prostate cancer will be based on the individual characteristics of the patient. In this study, we aimed to explain the correlation between the expression characteristics of periostin, integrin-α4, and fibronectin in metastatic castration-resistant prostate cancer patients and their clinico-pathological data comprising Gleason score, PSA levels, and metastatic sites in the process of epithelial-mesenchymal transition. We evaluated by using Western blotting, periostin, integrin-α4, and fibronectin expressions in peripheral blood samples of metastatic castration-resistant prostate cancer patients ( n = 40), benign prostatic hyperplasia patients ( n = 20), and the healthy control group ( n = 20). Associations between changes in the protein expressions and clinico-pathological parameters were also analyzed in the metastatic castration-resistant prostate cancer group. When comparing BPH and healthy groups with the metastatic castration-resistant prostate cancer group, a reduced expression of integrin-α4 was found in metastatic patients, albeit being statistically insignificant ( P > 0.05). Protein expressions of periostin and fibronectin in the metastatic castration-resistant prostate cancer group were higher than those in the BPH and heathy groups ( P < 0.001). Increased periostin expression in metastatic patients was significantly associated with bone metastasis ( P < 0.05). Elevated periostin and fibronectin levels in metastatic castration-resistant prostate cancer patients may be appropriate targets of therapeutic intervention in the future. Impact statement Prostate cancer is the third most common cancer in the world and the most common cancer among men. Development of metastatic castration-resistant prostate cancer (mCRPC) is a result of the lack of an apoptotic response by the tumor cells and loss of the ability to stick to adjacent cells through epithelial-mesenchymal transition (EMT). The present study analyzes for the first time the expressions of EMT marker proteins - periostin, integrin α4, fibronectin - in mCRPC and in benign prostatic hyperplasia (BPH) with the aim to determine the clinical relevance of changes in these three proteins vis-a-vis the PCa aggressive phenotype. In doing so, it sheds light on the molecular mechanism underlying the disease. We concluded that elevated periostin and fibronectin levels in mCRPC patients may be appropriate targets of therapeutic intervention in the future; hence, adopting methods that target these proteins may help treat prostate cancer effectively.

Nakagawa T, Matsusaka K, Misawa K, et al.
Frequent promoter hypermethylation associated with human papillomavirus infection in pharyngeal cancer.
Cancer Lett. 2017; 407:21-31 [PubMed] Related Publications
Oropharyngeal squamous cell carcinoma (OPSCC) incidence has increased dramatically due to human papillomavirus (HPV); however, associated epigenetic alterations are not well studied. We performed genome-wide DNA methylation analysis using an Infinium 450k BeadArray for clinical OPSCC and non-cancerous samples and cancer cell lines with/without 5-aza-2'-deoxycytidine and/or trichostatin A treatment. Frequent promoter hypermethylation and methylation-associated silencing were detected in 144 genes, which included those involved in cell-cell signaling and neuron differentiation. The methylation of nine genes (GHSR, ITGA4, RXRG, UTF1, CDH8, FAN19A4, CTNNA2, NEFH, and CASR) was quantitatively validated in 70 pharyngeal SCC cases by pyrosequencing. Hypermethylation significantly correlated with HPV-L1 positivity, but not with age or smoking status. p16

Morandi L, Gissi D, Tarsitano A, et al.
CpG location and methylation level are crucial factors for the early detection of oral squamous cell carcinoma in brushing samples using bisulfite sequencing of a 13-gene panel.
Clin Epigenetics. 2017; 9:85 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: Oral squamous cell carcinoma (OSCC) is usually diagnosed at an advanced stage and is commonly preceded by oral premalignant lesions. The mortality rates have remained unchanged (50% within 5 years after diagnosis), and it is related to tobacco smoking and alcohol intake. Novel molecular markers for early diagnosis are urgently needed. The purpose of this study was to evaluate the diagnostic value of methylation level in a set of 18 genes by bisulfite next-generation sequencing.
METHODS: With minimally invasive oral brushing, 28 consecutive OSCC, one squamous cell carcinoma with sarcomatoid features, six high-grade squamous intraepithelial lesions (HGSIL), 30 normal contralateral mucosa from the same patients, and 65 healthy donors were evaluated for DNA methylation analyzing 18 target genes by quantitative bisulfite next-generation sequencing. We further evaluated an independent cohort (validation dataset) made of 20 normal donors, one oral fibroma, 14 oral lichen planus (OLP), three proliferative verrucous leukoplakia (PVL), and two OSCC.
RESULTS: Comparing OSCC with normal healthy donors and contralateral mucosa in 355 CpGs, we identified the following epigenetically altered genes:
CONCLUSIONS: Our data highlight the importance of CpG location and correct estimation of DNA methylation level for highly accurate early diagnosis of OSCC.

Friedlander P, Wassmann K, Christenfeld AM, et al.
Whole-blood RNA transcript-based models can predict clinical response in two large independent clinical studies of patients with advanced melanoma treated with the checkpoint inhibitor, tremelimumab.
J Immunother Cancer. 2017; 5(1):67 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates clinical efficacy in a subset of advanced melanoma patients. An unmet clinical need exists for blood-based response-predictive gene signatures to facilitate clinically effective and cost-efficient use of such immunotherapeutic interventions.
METHODS: Peripheral blood samples were collected in PAXgene® tubes from 210 treatment-naïve melanoma patients receiving tremelimumab in a worldwide, multicenter phase III study (discovery dataset). A central panel of radiologists determined objective response using RECIST criteria. Gene expression for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene pre-treatment response-predictive classifier model was identified. An independent population (N = 150) of refractory melanoma patients receiving tremelimumab after chemotherapy enrolled in a worldwide phase II study (validation dataset). The classifier model, using the same genes, coefficients and constants for objective response and one-year survival after treatment, was applied to the validation dataset.
RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17, CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC, TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set. This model was validated in the validation set with AUCs of 0.62 (95% confidence interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year survival (95% confidence interval 0.59 to 0.75 p = 0.0002).
CONCLUSIONS: To our knowledge, this is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response. The data suggest that the model captures a biological signature representative of genes needed for a robust anti-cancer immune response. It also identifies non-responders to tremelimumab at baseline prior to treatment.

Zhao W, Mo Y, Wang S, et al.
Quantitation of DNA methylation in Epstein-Barr virus-associated nasopharyngeal carcinoma by bisulfite amplicon sequencing.
BMC Cancer. 2017; 17(1):489 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: Epigenetic changes, including DNA methylation, disrupt normal cell function, thus contributing to multiple steps of carcinogenesis. Nasopharyngeal carcinoma (NPC) is endemic in southern China and is highly associated with Epstein-Barr virus (EBV) infection. Significant changes of the host cell methylome are observed in EBV-associated NPC with cancer development. Epigenetic marks for NPC diagnosis are urgently needed. In order to explore DNA methylation marks, we investigated DNA methylation of candidate genes in EBV-associated nasopharyngeal carcinoma.
METHODS: We first employed methyl-capture sequencing and cDNA microarrays to compare the genome-wide methylation profiles of seven NPC tissues and five non-cancer nasopharyngeal epithelium (NNE) tissues. We found 150 hypermethylated CpG islands spanning promoter regions and down-regulated genes. Furthermore, we quantified the methylation rates of seven candidate genes using bisulfite amplicon sequencing for nine NPC and nine NNE tissues.
RESULTS: All seven candidate genes showed significantly higher methylation rates in NPC than in NNE tissues, and the ratios (NPC/NNE) were in descending order as follows: ITGA4 > RERG > ZNF671 > SHISA3 > ZNF549 > CR2 > RRAD. In particular, methylation levels of ITGA4, RERG, and ZNF671 could distinguish NPC patients from NNE subjects.
CONCLUSIONS: We identified the DNA methylation rates of previously unidentified NPC candidate genes. The combination of genome-wide and targeted methylation profiling by next-generation sequencers should provide useful information regarding cancer-specific aberrant methylation.

Mukai S, Oue N, Oshima T, et al.
Overexpression of PCDHB9 promotes peritoneal metastasis and correlates with poor prognosis in patients with gastric cancer.
J Pathol. 2017; 243(1):100-110 [PubMed] Related Publications
Gastric cancer (GC) is one of the most common human cancers. Genes expressed only in cancer tissue, especially on the cell membrane, may be useful biomarkers for cancer diagnosis and therapeutics. In the present study, we focused on the PCDHB9 gene, which encodes the transmembrane protein protocadherin B9. Immunohistochemical analysis revealed that 62 (36%) of 173 GC cases were positive for protocadherin B9. Protocadherin B9 staining was mainly observed on the GC cell membrane. Expression of protocadherin B9 was frequently found in intestinal-type GC and correlated with poor prognosis in patients with intestinal-type GC. Although PCDHB9 knockdown or forced expression of PCDHB9 did not change cell growth or invasion activity in a GC cell line, cell adhesion to fibronectin was significantly reduced by PCDHB9 knockdown and significantly enhanced by overexpression of PCDHB9. Expression levels of ITGA3, ITGA4, ITGA5, and ITGB1 were significantly reduced by knockdown of PCDHB9 and significantly enhanced by overexpression of PCDHB9. Furthermore, both the number and the size of spheres in culture were significantly decreased by PCDHB9 knockdown and significantly increased by overexpression of PCDHB9. In a peritoneal dissemination mouse model, the weight of the total disseminated nodules of MKN-74 cells was significantly increased by forced expression of PCDHB9. These results indicate that protocadherin B9 plays an important role in the progression rather than the pathogenesis of intestinal-type GC. Specific inhibitors of protocadherin B9 may constitute promising anti-cancer drugs with fewer side-effects. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Waldschmidt JM, Simon A, Wider D, et al.
CXCL12 and CXCR7 are relevant targets to reverse cell adhesion-mediated drug resistance in multiple myeloma.
Br J Haematol. 2017; 179(1):36-49 [PubMed] Related Publications
Cell adhesion-mediated drug resistance (CAM-DR) by the bone marrow (BM) is fundamental to multiple myeloma (MM) propagation and survival. Targeting BM protection to increase the efficacy of current anti-myeloma treatment has not been extensively pursued. To extend the understanding of CAM-DR, we hypothesized that the cytotoxic effects of novel anti-myeloma agents may be abrogated by the presence of BM stroma cells (BMSCs) and restored by addition of the CXCL12 antagonist NOX-A12 or the CXCR4 inhibitor plerixafor. Following this hypothesis, we evaluated different anti-myeloma agents alone, with BMSCs and when combined with plerixafor or NOX-A12. We verified CXCR4, CD49d (also termed ITGA4) and CD44 as essential mediators of BM adhesion on MM cells. Additionally, we show that CXCR7, the second receptor of stromal-derived-factor-1 (CXCL12), is highly expressed in active MM. Co-culture proved that co-treatment with plerixafor or NOX-A12, the latter inhibiting CXCR4 and CXCR7, functionally interfered with MM chemotaxis to the BM. This led to the resensitization of MM cells to the anti-myeloma agents vorinostat and pomalidomide and both proteasome inhibitors bortezomib and carfilzomib. Within a multicentre phase I/II study, NOX-A12 was tested in combination with bortezomib-dexamethasone, underlining the feasibility of NOX-A12 as an active add-on agent to antagonize myeloma CAM-DR.

Emmons MF, Anreddy N, Cuevas J, et al.
MTI-101 treatment inducing activation of Stim1 and TRPC1 expression is a determinant of response in multiple myeloma.
Sci Rep. 2017; 7(1):2685 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
The emergence of drug resistance continues to be a major hurdle towards improving patient outcomes for the treatment of Multiple Myeloma. MTI-101 is a first-in-class peptidomimetic that binds a CD44/ITGA4 containing complex and triggers necrotic cell death in multiple myeloma cell lines. In this report, we show that acquisition of resistance to MTI-101 correlates with changes in expression of genes predicted to attenuate Ca

Strati P, Parikh SA, Chaffee KG, et al.
CD49d associates with nodal presentation and subsequent development of lymphadenopathy in patients with chronic lymphocytic leukaemia.
Br J Haematol. 2017; 178(1):99-105 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
CD49d is a surface integrin that is expressed on chronic lymphocytic leukaemia (CLL) cells, and strongly correlates with more aggressive disease. Given its association with cell-cell adhesion and leucocyte trafficking, we hypothesized that patients with high CD49d expression would experience a clinical course dominated by lymphadenopathy. CD49d expression was measured by flow cytometry and considered positive if expressed by ≥30% of CLL cells. The study included 797 newly diagnosed CLL/small lymphocytic leukaemia patients; 279 (35%) were CD49d positive. CD49d-positive patients were more likely to present with lymphadenopathy (P < 0·001); a finding that persisted after adjusting for fluorescence in situ hybridisation (FISH) and IGHV mutation status [odds ratio (OR) 2·51; 95% confidence interval (CI) 1·64-3·83; P < 0·001]. Among CLL Rai 0 patients, CD49d positivity was associated with shorter time to development of lymphadenopathy (3·2 years vs not reached, P < 0·01). This association was maintained after adjusting for either FISH [hazard ratio (HR) 2·18; 95% CI 1·25-3·81; P = 0·006) or IGHV status (HR 2·02; 95% CI 1·11-3·69; P = 0·02) individually, but was attenuated when adjusting by both (HR 1·72; 95% CI 0·88-3·38; P = 0·11).These data demonstrate that CD49d-positive CLL patients experience a disease course dominated by lymphadenopathy. These findings could have implications for therapy selection and disease monitoring.

Patkar N, Rabade N, Kadam PA, et al.
Immunogenetics of chronic lymphocytic leukemia.
Indian J Pathol Microbiol. 2017 Jan-Mar; 60(1):38-42 [PubMed] Related Publications
INTRODUCTION: Cytogenetic aberrations as well as presence of IGVH mutations are the underlying reason for clinical heterogeneity in Chronic Lymphocytic Leukemia (CLL). The presence of IGVH mutations as well as the predominant gene usage shows geographical variations. However, there is no study from India addressing immunogenetics of CLL. In a first Indian study we document the immunogenetics of CLL in a large tertiary hospital.
METHODS: We analyzed IGVH mutation status, VH gene usage, cytogenetic abnormalities using FISH, immunophenotyping data and correlated them with standard clinical variables in 84 patients of CLL.
RESULTS: Advanced Rai stage (Stage 3/4) was seen in 45% of our patients, where as 13q deletion was the commonest clonal cytogenetic abnormality detected in 48.4% of the cases. IGVH unmutated cases (55.2%) showed higher proportion expressing CD38 and CD49d, a preferential usage for VH1 and VH3 families (55.2%), presentation at an advanced Rai stage (52.8%) as well as more frequent presence of p53 deletions. As compared to the IGVH mutated cases greater proportion of IGVH unmutated patients (70%) required treatment. However, there was no significant difference in the time to treatment between mutated and unmutated cases which can be attributed to relatively short median follow up of 10 months.
CONCLUSION: To summarize, we have seen a higher proportion of IGVH unmutated patients in our cohort (55.2%). The commonly used VH genes in the Indian population are IGVH 2-5, IGVH 1-2 and IGVH 1-69. Longer clinical follow up and a larger cohort is necessary to confirm the prognostic value of IGVH mutation analysis in Indian Patients with CLL.

Poplawski P, Rybicka B, Boguslawska J, et al.
Induction of type 1 iodothyronine deiodinase expression inhibits proliferation and migration of renal cancer cells.
Mol Cell Endocrinol. 2017; 442:58-67 [PubMed] Related Publications
Type 1 iodothyronine deiodinase (DIO1) regulates peripheral metabolism of thyroid hormones that control cellular proliferation, differentiation and metabolism. The significance of DIO1 in cancer is unknown. In this study we hypothesized that diminished expression of DIO1, observed in renal cancer, contributes to the carcinogenic process in the kidney. Here, we demonstrate that ectopic expression of DIO1 in renal cancer cells changes the expression of genes controlling cell cycle, including cyclin E1 and E2F5, and results in inhibition of proliferation. The expression of genes encoding collagens (COL1A1, COL4A2, COL5A1), integrins (ITGA4, ITGA5, ITGB3) and transforming growth factor-β-induced (TGFBI) is significantly altered in renal cancer cells with induced expression of DIO1. Finally, we show that overexpression of DIO1 inhibits migration of renal cancer cells. In conclusion, we demonstrate for the first time that loss of DIO1 contributes to renal carcinogenesis and that its induced expression protects cells against cancerous proliferation and migration.

Gandoglia I, Ivaldi F, Carrega P, et al.
In vitro VLA-4 blockade results in an impaired NK cell-mediated immune surveillance against melanoma.
Immunol Lett. 2017; 181:109-115 [PubMed] Related Publications
Natalizumab (NTZ) is a monoclonal antibody targeting the α4β1 integrin (CD49d/CD29), very late antigen-4 (VLA-4), which is approved for treatment of relapsing-remitting multiple sclerosis (RR-MS). A possible association between NTZ treatment and a higher risk of melanoma is under debate. Natural Killer (NK) cells, which express VLA-4, represent an innate barrier limiting spreading of melanoma under steady state conditions. Indeed, because of their expression of activating receptors, they are very efficient in recognizing and killing melanoma cells without the need of a previous priming. For this reason, we aimed at assessing whether NK-cell functions might be impaired by sustained exposure to NTZ. To investigate this possibility we isolated NK cells from healthy donors and tested their cytotoxic and migratory functions against primary melanoma cells derived from subcutaneous and lymph node metastases. Flow cytometry analysis demonstrated expression of CD49d on both freshly isolated NK cells and activated NK cells. Moreover, VLA-4 and its receptor, vascular cell adhesion protein-1 (VCAM-1) were similarly expressed on freshly isolated NK cells. However, upon a short exposure to NTZ, expression of VLA-4 on NK cells decreased. Analysis of NK receptor expression upon exposure of NK cells from three healthy donors to NTZ indicated that DNAM-1 and NKp46 are apparently decreased, while NKG2A is increased. The degranulation of NK cells towards melanoma cells, which express both VLA-4 and VCAM-1, was not affected when NTZ was added to the co-culture or when both NK cells and melanoma cells were each pre-exposed to NTZ for over 12h. In contrast, degranulation was significantly inhibited after 48h of pre-incubation indicating that NTZ can influence NK-cell degranulation towards melanoma cells only after a prolonged exposure. Using a migration chamber assay, we observed that the migration of NK cells towards melanoma cells was dependent upon the concentration of melanoma cells in the lower chamber, and that it was significantly reduced in presence of NTZ. Our results show that upon exposure to NTZ both cytolytic activity and migration toward melanoma cells were affected, suggesting that binding of NTZ to NK cells affects pathways involved in these NK-cell functions. We analyzed the expression of CD49d on NK cells from MS patients treated with NTZ and observed that it decreases with time of treatment. These data suggest that blockade of VLA-4 on NK-cell surface alters some key functions involved in the immune surveillance toward melanoma by NK cells and may provide a mechanistic explanation for the reported occurrence of melanoma in MS patients treated with NTZ.

Hanieh H, Mohafez O, Hairul-Islam VI, et al.
Novel Aryl Hydrocarbon Receptor Agonist Suppresses Migration and Invasion of Breast Cancer Cells.
PLoS One. 2016; 11(12):e0167650 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: Despite the remarkable progress to fight against breast cancer, metastasis remains the dominant cause of treatment failure and recurrence. Therefore, control of invasiveness potential of breast cancer cells is crucial. Accumulating evidences suggest Aryl hydrocarbon receptor (Ahr), a helix-loop-helix transcription factor, as a promising target to control migration and invasion in breast cancer cells. Thus, an Ahr-based exploration was performed to identify a new Ahr agonist with inhibitory potentials on cancer cell motility.
METHODS: For prediction of potential interactions between Ahr and candidate molecules, bioinformatics analysis was carried out. The interaction of the selected ligand with Ahr and its effects on migration and invasion were examined in vitro using the MDA-MB-231 and T47D cell lines. The silencing RNAs were transfected into cells by electroporation. Expressions of microRNAs (miRNAs) and coding genes were quantified by real-time PCR, and the protein levels were detected by western blot.
RESULTS: The in silico and in vitro results identified Flavipin as a novel Ahr agonist. It induces formation of Ahr/Ahr nuclear translocator (Arnt) heterodimer to promote the expression of cytochrome P450 family 1 subfamily A member 1 (Cyp1a1). Migration and invasion of MDA-MB-231 and T47D cells were inhibited with Flavipin treatment in an Ahr-dependent fashion. Interestingly, Flavipin suppressed the pro-metastatic factor SRY-related HMG-box4 (Sox4) by inducing miR-212/132 cluster. Moreover, Flavipin inhibited growth and adhesion of both cell lines by suppressing gene expressions of B-cell lymphoma 2 (Bcl2) and integrinα4 (ITGA4).
CONCLUSION: Taken together, the results introduce Flavipin as a novel Ahr agonist, and provide first evidences on its inhibitory effects on cancer cell motility, suggesting Flavipin as a candidate to control cell invasiveness in breast cancer patients.

Bowman RL, Klemm F, Akkari L, et al.
Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies.
Cell Rep. 2016; 17(9):2445-2459 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Extensive transcriptional and ontogenetic diversity exists among normal tissue-resident macrophages, with unique transcriptional profiles endowing the cells with tissue-specific functions. However, it is unknown whether the origins of different macrophage populations affect their roles in malignancy. Given potential artifacts associated with irradiation-based lineage tracing, it remains unclear if bone-marrow-derived macrophages (BMDMs) are present in tumors of the brain, a tissue with no homeostatic involvement of BMDMs. Here, we employed multiple models of murine brain malignancy and genetic lineage tracing to demonstrate that BMDMs are abundant in primary and metastatic brain tumors. Our data indicate that distinct transcriptional networks in brain-resident microglia and recruited BMDMs are associated with tumor-mediated education yet are also influenced by chromatin landscapes established before tumor initiation. Furthermore, we demonstrate that microglia specifically repress Itga4 (CD49D), enabling its utility as a discriminatory marker between microglia and BMDMs in primary and metastatic disease in mouse and human.

Blunt MD, Koehrer S, Dobson RC, et al.
The Dual Syk/JAK Inhibitor Cerdulatinib Antagonizes B-cell Receptor and Microenvironmental Signaling in Chronic Lymphocytic Leukemia.
Clin Cancer Res. 2017; 23(9):2313-2324 [PubMed] Article available free on PMC after 01/11/2019 Related Publications

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