Gene Summary

Gene:ITGB3; integrin subunit beta 3
Aliases: GT, CD61, GP3A, BDPLT2, GPIIIa, BDPLT16
Summary:The ITGB3 protein product is the integrin beta chain beta 3. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. Integrin beta 3 is found along with the alpha IIb chain in platelets. Integrins are known to participate in cell adhesion as well as cell-surface mediated signalling. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:integrin beta-3
Source:NCBIAccessed: 30 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 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

Latest Publications: ITGB3 (cancer-related)

Tong Y, Ye L, Li S, et al.
The association of 6 variants of 8q24 and the risk of glioma: A meta-analysis.
Medicine (Baltimore). 2019; 98(27):e16205 [PubMed] Free Access to Full Article Related Publications
With the advances in sequencing technologies and genome-wide association studies (GWAS), several inherited variants that increase glioma risk have been identified. Ten studies including 8818 cases and 17,551 controls were collected to conduct a meta-analysis to evaluate the associations between 6 variants in 8q24 and glioma risk. Of the 6 variants located in 8q24, 2 have strong significant associations with the risk of glioma, including rs4295627 (P = .003, odds ratio [OR] = 1.21), rs55705857 (P = 2.31 × 10, OR = 3.54). In particular, both homozygous GG (P = 1.91 × 10, OR1 = 2.01) and heterozygous GT (P = 7.75 × 10, OR2 = 1.35) genotypes of rs4295627 were associated with glioma risk. Further studies are needed to explore the role of the 8q24 variants involved in the etiology of glioma.

Kobunai T, Matsuoka K, Takechi T
ChIP-seq Analysis to Explore DNA Replication Profile in Trifluridine-treated Human Colorectal Cancer Cells
Anticancer Res. 2019; 39(7):3565-3570 [PubMed] Related Publications
BACKGROUND/AIM: Trifluridine (FTD) is a key component of the novel oral antitumor drug trifluridine/tipiracil that has been approved for the treatment of metastatic colorectal cancer. In this study, a comprehensive analysis of DNA replication profile in FTD-treated colon cancer cells was performed.
MATERIALS AND METHODS: HCT-116 cells were exposed to BrdU or FTD and subjected to DNA immunoprecipitation. Immunoprecipitated DNA was sequenced; the density of aligned reads along the genome was calculated. Peak finding, gene ontology, and motif analysis were performed using MACS, GREAT, and MEME, respectively.
RESULTS: We identified 6,043 and 5,080 high-confidence FTD and BrdU peaks in HCT-116 cells, respectively. Of 6,043 FTD peaks, 2,911 peaks were uncommon to BrdU. We observed that FTD was preferentially incorporated into genomic regions containing simple repeats, CpG islands, and gene bodies. Conserved motifs in FTD peaks contained dinucleotide repeats such as (GT)n.
CONCLUSION: Global FTD incorporation patterns delineated FTD, preferentially incorporating loci in cancer cells.

Vázquez-Ibarra KC, Bustos-Carpinteyro AR, García-Ruvalcaba A, et al.
The ERBB2 gene polymorphisms rs2643194, rs2934971, and rs1058808 are associated with increased risk of gastric cancer.
Braz J Med Biol Res. 2019; 52(5):e8379 [PubMed] Free Access to Full Article Related Publications
Gastric cancer (GC) is the third most lethal type of cancer worldwide. Single nucleotide polymorphisms (SNPs) in regulatory sites or coding regions can modify the expression of genes involved in gastric carcinogenesis, as ERBB2, which encodes for the tyrosine-kinase receptor HER-2. The aim of this work was to analyze the association of the polymorphisms: rs2643194, rs2517951, rs2643195, rs2934971, and rs1058808 with GC, as they have not yet been analyzed in GC patients, as well as to report their frequency in the general Mexican population (GMP). We studied genomic DNA from subjects with GC (n=74), gastric inflammatory diseases (GID, n=76 control subjects), and GMP (n=102). Genotypes were obtained by means of real-time PCR and DNA-sequencing. The risks for GC were estimated through odds ratio (OR) using the Cochran-Armitage trend test and multinomial logistic regression. Increased risk for GC was observed under the dominant inheritance model for the rs2643194 TT or CT genotypes with an OR of 2.75 (95%CI 1.12-6.75, P=0.023); the rs2934971 TT or GT genotypes with an OR of 2.41 (95%CI 1.01-5.76, P=0.043), and the rs1058808 GG or CG genotypes with an OR of 2.21 (95%CI 1.00-4.87, P=0.046). The SNPs rs2643194, rs2934971, and rs1058808 of the ERBB2 gene were associated with increased risk for GC.

Cheng J, Li Y, Kong J
Ginkgetin inhibits proliferation of HeLa cells via activation of p38/NF-κB pathway.
Cell Mol Biol (Noisy-le-grand). 2019; 65(4):79-82 [PubMed] Related Publications
Effect of ginkgetin on proliferation of human cervical cancer (HeLa) cells and the underlying mechanism   were investigated. Human cervical cancer (HeLa) cells were cultured at 37 °C in 10 % fetal bovine serum (FBS) supplemented RPMI 1640 medium in a humidified incubator containing 5 % CO2. Cell proliferation was determined using MTT assay, while real-time quantitative polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to determine the levels of expression of interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin 8 (IL-8). The expressions of p38 mitogen-activated protein kinases (p38 MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κB) were determined using Western blotting. Treatment of HeLa cells with ginkgetin significantly and time- and dose-dependently inhibited their proliferation (p < 0.05). The invasion of the cells were also significantly and dose-dependently decreased, when compared with control cells (p < 0.05). The expressions of p-p38 and p-NF-κB were significantly and dose-dependently down-regulated, relative to control group (p < 0.05). However, the expressions of p38 and NF-κB in ginkgetin-treated cells were not significantly different from those of control group (p > 0.05). The results of qRT-PCR and ELISA showed that the levels of expression of TNF-α, IL-1β and IL-8 mRNAs were significantly and dose-dependently reduced in HeLa cells after 48 h of treatment with ginkgetin, when compared with the control group (p < 0.05). The anti-proliferative effect of ginkgetin on HeLa cells is exerted via a mechanism involving the p38/NF-κB pathway.

Liu F, Cox CD, Chowdhury R, et al.
SPINT2 is hypermethylated in both IDH1 mutated and wild-type glioblastomas, and exerts tumor suppression via reduction of c-Met activation.
J Neurooncol. 2019; 142(3):423-434 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
PURPOSE: Both IDH1-mutated and wild-type gliomas abundantly display aberrant CpG island hypermethylation. However, the potential role of hypermethylation in promoting gliomas, especially the most aggressive form, glioblastoma (GBM), remains poorly understood.
METHODS: We analyzed RRBS-generated methylation profiles for 11 IDH1
RESULTS: We identified SPINT2 as a candidate tumor-suppressor gene within a group of CpG islands (designated G
CONCLUSIONS: We defined a previously under-recognized group of coordinately methylated CpG islands common to both IDH1

Yang MH, Zhao L, Wang L, et al.
Nuclear lncRNA HOXD-AS1 suppresses colorectal carcinoma growth and metastasis via inhibiting HOXD3-induced integrin β3 transcriptional activating and MAPK/AKT signalling.
Mol Cancer. 2019; 18(1):31 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Long noncoding RNAs (lncRNAs) have been indicated to play critical roles in cancer development and progression. LncRNA HOXD cluster antisense RNA1 (HOXD-AS1) has recently been found to be dysregulated in several cancers. However, the expression levels, cellular localization, precise function and mechanism of HOXD-AS1 in colorectal carcinoma (CRC) are largely unknown.
METHODS: Real-time PCR and in situ hybridization were used to detect the expression of HOXD-AS1 in CRC tissue samples and cell lines. Gain- and loss-of-function experiments were performed to investigate the biological roles of HOXD-AS1 in CRC cell line. RNA pull down, RNA immunoprecipitation and chromatin immunoprecipitation assays were conducted to investigate the mechanisms underlying the functions of HOXD-AS1 in CRC.
RESULTS: We observed that HOXD-AS1 was located in the nucleus of CRC cells and that nuclear HOXD-AS1 was downregulated in most CRC specimens and cell lines. Lower levels of nuclear HOXD-AS1 expression were associated with poor outcomes of CRC patients. HOXD-AS1 downregulation enhanced proliferation and migration of CRC cells in vitro and facilitated CRC tumourigenesis and metastasis in vivo. Mechanistic investigations revealed that HOXD-AS1 could suppress HOXD3 transcription by recruiting PRC2 to induce the accumulation of the repressive marker H3K27me3 at the HOXD3 promoter. Subsequently, HOXD3, as a transcriptional activator, promoted Integrin β3 transcription, thereby activating the MAPK/AKT signalling pathways.
CONCLUSION: Our results reveal a previously unrecognized HOXD-AS1-HOXD3-Integrin β3 regulatory axis involving in epigenetic and transcriptional regulation constitutes to CRC carcinogenesis and progression.

Li G, Cai L, Zhou L
Microarray gene expression profiling and bioinformatics analysis reveal key differentially expressed genes in clival and sacral chordoma cell lines.
Neurol Res. 2019; 41(6):554-561 [PubMed] Related Publications
OBJECTIVE: Chordoma is a rare tumor with a certain rate of distant metastasis. Skull base and sacrum are the two most common origin sites. This study tends to identify key differentially expressed genes (DEGs) between classical clival and sacral chordomas, provide new targets for future treatment options of chordomas.
METHODS: The gene expression profiles of GSE95084 and GSE68497 were downloaded from Gene Expression Omnibus database and were analyzed using the limma R package. Function and enrichment analyses of DEGs were performed based on DAVID Database. Protein-protein interaction (PPI) network was constructed using the Cytoscape based on the data collected from STRING online datasets. Hub genes selection and modules analyses of the PPI network were conducted by plugin cytoHubba and MCODE of Cytoscape software, respectively.
RESULT: In total, 728 genes, including 363 up-regulated genes and 365 down-regulated genes were selected as DEGs. Notably, GO analysis showed that both up-regulated and down-regulated DEGs were mainly involved in cell component such as an integral component of the membrane, plasma membrane and extracellular exosome. DEGs were mainly enriched in pathways like Pathways in cancer, PI3K-Akt signaling pathway, Cytokine-cytokine receptor interaction. FYN, ITGB3, ACTN2 and IGF1 were identified as hub genes and they were all involved in focal adhesion signaling pathway. Furthermore, five significant network modules were obtained from the PPI network.
CONCLUSION: This study helps to further understand the molecular characteristics of classic chordomas of two distinct sites. Hub genes FYN, ITGB3, ACTN2, and IGF1, as well as focal adhesion signaling pathway, would be new targets for future treatment options of chordomas.

Mjelle R, Sjursen W, Thommesen L, et al.
Small RNA expression from viruses, bacteria and human miRNAs in colon cancer tissue and its association with microsatellite instability and tumor location.
BMC Cancer. 2019; 19(1):161 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: MicroRNAs (miRNA) and other small RNAs are frequently dysregulated in cancer and are promising biomarkers for colon cancer. Here we profile human, virus and bacteria small RNAs in normal and tumor tissue from early stage colon cancer and correlate the expression with clinical parameters.
METHODS: Small RNAs from colon cancer tissue and adjacent normal mucosa of 48 patients were sequenced using Illumina high-throughput sequencing. Clinical parameters were correlated with the small RNA expression data using linear models. We performed a meta-analysis by comparing publicly available small RNA sequencing datasets with our original sequencing data to confirm the main findings.
RESULTS: We identified 331 differentially expressed miRNAs between tumor and normal samples. We found that the major changes in miRNA expression between left and right colon are due to miRNAs located within the Hox-developmental genes, including miR-10b, miR-196b and miR-615. Further, we identified new miRNAs associated with microsatellite instability (MSI), including miR-335, miR-26 and miR-625. We performed a meta-analysis on all publicly available miRNA-seq datasets and identified 117 common miRNAs that were differentially expressed between tumor and normal tissue. The miRNAs miR-135b and miR-31 were the most significant upregulated miRNA in tumor across all datasets. The miRNA miR-133a was the most strongly downregulated miRNA in our dataset and also showed consistent downregulation in the other datasets. The miRNAs associated with MSI and tumor location in our data showed similar changes in the other datasets. Finally, we show that small RNAs from Epstein-Barr virus and Fusobacterium nucleatum are differentially expressed between tumor and normal adjacent tissue.
CONCLUSIONS: Small RNA profiling in colon cancer tissue revealed novel RNAs associated with MSI and tumor location. We show that Fusobacterium nucleatum are detectable at the RNA-level in colon tissue, and that both Fusobacterium nucleatum and Epstein-Barr virus separate tumor and normal tissue.

Maknı L, Ben Hamda C, Al-ansarı A, et al.
Association of common IL-10 promoter gene variants with the susceptibility to head and neck cancer in Tunisia
Turk J Med Sci. 2019; 49(1):123-128 [PubMed] Related Publications
Background/aim: We investigated the association of three IL-10 promoter single-nucleotide polymorphisms and altered IL-10 plasma levels with the risk of head and neck cancer (HNC).
Materials and methods: Study subjects comprised 194 HNC patients [137 nasopharyngeal cancer (NPC) and 57 laryngeal cancer (LC)], and 263 healthy controls. Genotyping of rs1800896 (-1082A>G), rs1800871 (-819C>T), and rs1800872 (-592A>C) IL-10 variants was performed by real-time PCR; IL-10 levels were measured by enzyme amplified immuno sensitivity assay (EAISA).
Results: Study subjects comprised 194 HNC patients [137 nasopharyngeal cancer (NPC) and 57 laryngeal cancer (LC)], and 263 healthy controls. Genotyping of rs1800896 (-1082A>G), rs1800871 (-819C>T), and rs1800872 (-592A>C) IL-10 variants was performed by real-time PCR; IL-10 levels were measured by enzyme amplified immuno sensitivity assay (EAISA).
Conclusion: Our results demonstrate that IL-10-1082, IL-10-819, and IL-10-592 variants, and haplotypes GC and GT constitute biomarkers for early detection of HNC, especially NPC subtype. IL-10 -819T/C and TA haplotype may be used as biomarkers for early detection of LC.

Deng S, He SY, Zhao P, Zhang P
The role of oncostatin M receptor gene polymorphisms in bladder cancer.
World J Surg Oncol. 2019; 17(1):30 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: Oncostatin M receptor (OSMR) represents a part of the interleukin-six (IL6) cytokine group that was discovered recently to be closely associated with cell's growth and differentiation, inflammation, and enhancement of metastatic capacity. A comprehensive study suggests a close relationship between OSMR and papillary thyroid cancer, colorectal cancer, breast cancer, and other tumors. However, the relationship between OSMR and bladder cancer has yet to be determined.
METHODS: Three hundred six patients (including 142 patients with muscle-invasive bladder cancer and 164 patients with non-muscle-invasive bladder cancer) as well as 459 normal controls were included in this study. Two tag SNPs of OSMR, rs2278329, and rs2292016 were genotyped by TaqMan® SNP Genotyping Assay method and then the associations with bladder cancer were analyzed, as well as risk factors and prognosis.
RESULTS: Patients with bladder cancer and controls did not differ significantly in terms of genotype frequencies and allele frequency distribution of rs2278329 (P = 0.77, OR = 0.97) and rs2292016 (P = 0.39, OR = 1.20) respectively. For rs2278329, no differences were found in terms of risk factors in stratified analyses. However, rs2292016 was associated with recurrence and tumor grade. GT/TT was found to increase the risk of relapse compared to the patients without allele T (GG genotype) (P = 0.016, OR = 1.878, 95% CI = 1.12-3.14) with the T allele of rs2292016 being a risk factor for recurrence (P = 0.032, OR = 0.67, 95% CI = 0.47-0.97). Besides, patients with GT genotype often present with high-grade bladder cancer (P = 0.003, OR = 2.33, 95% CI = 1.32-4.17). Multiple Cox regression analysis showed that rs2278329 and rs2292016 were related to the recurrence-free survival and overall survival in non muscle invasive bladder cancer (NMIBC) patients. For rs2278329, GA genotype could affect recurrence-free survival (P = 0.01, OR = 2.16, 95% CI = 1.17-3.98). For rs2292016, TT/GT genotype had a lower risk of death compared with GG homozygote genotype, and T was a protective factor for overall survival in bladder cancer (P = 0.029, OR = 0.22, 95% CI = 0.06-0.86).
CONCLUSIONS: OSMR genotype frequencies were found to be associated with higher recurrence in bladder cancer, and it may serve as a biomarker candidate gene to predict prognosis of this disease. Further validation of OSMR as biomarker is required.

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.

Celik N, Aydin S, Ugur K, et al.
Patatin-like phospholipase domain containing 3-gene (adiponutrin), preptin, kisspeptin and amylin regulates oocyte developmental capacity in PCOS.
Cell Mol Biol (Noisy-le-grand). 2018; 64(15):7-12 [PubMed] Related Publications
This study was planned to test whether follicular fluid (FF) levels of patatin-like phospholipase domain containing 3-gene (PNPLA3:adiponutrin), preptin, kisspeptin, and amylin change in polycystic ovarian syndrome (PCOS). A total of 40 infertile volunteers undergoing IVF/ICSI were included in the study. They were divided into two groups as PCOS (n=20) and control group without PCOS (n=20). The controls were recruited from subjects with a poor ovarian response. The PCOS and control participants were matched according to their body mass index (BMI). Each group of participants underwent ovarian stimulation with GnRH antagonist protocol. Blood and FF samples of one dominant follicle were obtained from each subject during the oocyte pick-up. FF and serum levels of PNPLA3, preptin, kisspeptin and amylin were measured through ELISA. Amylin and adiponutrin median values were not different according to study groups (p>0.05). FF-preptin median values in the control group were similar to the serum preptin values of control and PCOS groups (Z=0.970, p=1.000 and Z=2.631, p=0.051, respectively). Medians of the serum preptin in control and PCOS groups were the same (Z=1.649; p=0.595). FF-preptin median values of PCOS group were significantly lower than the preptin median values of the control group. Serum preptin levels were positively correlated with HOMA-IR, but not with pregnancy rates and the number of retrieved oocytes. Serum kisspeptin levels were negatively correlated with the number of retrieved oocytes and pregnancy rates. While amylin and adiponutrin have no role in the folliculogenesis, kisspeptin and preptin work together for regulating follicle developmental capacity in PCOS.

Hong SK, Lee H, Kwon OS, et al.
Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer.
Mol Cancer. 2018; 17(1):175 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Even when targets responsible for chemoresistance are identified, drug development is often hampered due to the poor druggability of these proteins. We systematically analyzed therapy-resistance with a large-scale cancer cell transcriptome and drug-response datasets and predicted the candidate drugs based on the gene expression profile. Our results implicated the epithelial-mesenchymal transition as a common mechanism underlying resistance to chemotherapeutic drugs. Notably, we identified ITGB3, whose expression was abundant in both drug resistance and mesenchymal status, as a promising target to overcome chemoresistance. We also confirmed that depletion of ITGB3 sensitized cancer cells to conventional chemotherapeutic drugs by modulating the NF-κB signaling pathway. Considering the poor druggability of ITGB3 and the lack of feasible drugs to directly inhibit this protein, we took an in silico screening for drugs mimicking the transcriptome-level changes caused by knockdown of ITGB3. This approach successfully identified atorvastatin as a novel candidate for drug repurposing, paving an alternative path to drug screening that is applicable to undruggable targets.

Zhang J, Liu L, Lin Z, et al.
SNP-SNP and SNP-environment interactions of potentially functional HOTAIR SNPs modify the risk of hepatocellular carcinoma.
Mol Carcinog. 2019; 58(5):633-642 [PubMed] Related Publications
HOX transcript antisense intergenic RNA (HOTAIR) has been widely regarded as a functional lncRNA contributing to multiple cancers. However, few studies have examined the effect of single nucleotide polymorphisms (SNPs) in HOTAIR on the occurrence and development of hepatocellular carcinoma (HCC). In this study, three potentially functional HOTAIR SNPs (rs17105613, rs12427129, and rs3816153) were selected using bioinformatic tools. A case-control study including 1262 cases and 1559 controls was conducted to explore the association of HOTAIR SNPs with the risk of HCC in a Southern Chinese population. We found that SNPs rs12427129 and rs3816153 were associated with the risk of HCC in dominant genetic models (CC: CT + TT, adjusted odds ratio (OR) = 0.72, 95% confidence interval (CI) = 0.57-0.90 and GG: GT + TT, adjusted OR = 1.30, 95%CI = 1.08-1.57). Additionally, SNP-environment interactions for rs12427129, rs3816153, and HBsAg status were found to enhance the risk of HCC, with FDR-P as an additive interaction equal to 0.0006 and 0.0144, respectively. In multifactor dimensionality reduction (MDR) analysis, the three-factor model (HBsAg status, rs12427129 and rs3816153) yielded the highest test accuracy of 77.74% (permutation P < 0.001). Interestingly, the effect of rs12427129 and rs3816153 on the risk of HCC could be modified by HBsAg status, while the rs12427129 CT/TT genotype could antagonize the detrimental effect of rs3816153 GT/TT genotype on HCC. Our findings suggest that rs12427129 and rs3816153, including their SNP-SNP and SNP-environment interaction with HBsAg status, potentially play important roles on the susceptibility to HCC.

Kim HJ, Kang TW, Haam K, et al.
Whole genome MBD-seq and RRBS analyses reveal that hypermethylation of gastrointestinal hormone receptors is associated with gastric carcinogenesis.
Exp Mol Med. 2018; 50(12):156 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
DNA methylation is a regulatory mechanism in epigenetics that is frequently altered during human carcinogenesis. To detect critical methylation events associated with gastric cancer (GC), we compared three DNA methylomes from gastric mucosa (GM), intestinal metaplasia (IM), and gastric tumor (GT) cells that were microscopically dissected from an intestinal-type early gastric cancer (EGC) using methylated DNA binding domain sequencing (MBD-seq) and reduced representation bisulfite sequencing (RRBS) analysis. In this study, we focused on differentially methylated promoters (DMPs) that could be directly associated with gene expression. We detected 2,761 and 677 DMPs between the GT and GM by MBD-seq and RRBS, respectively, and for a total of 3,035 DMPs. Then, 514 (17%) of all DMPs were detected in the IM genome, which is a precancer of GC, supporting that some DMPs might represent an early event in gastric carcinogenesis. A pathway analysis of all DMPs demonstrated that 59 G protein-coupled receptor (GPCR) genes linked to the hypermethylated DMPs were significantly enriched in a neuroactive ligand-receptor interaction pathway. Furthermore, among the 59 GPCRs, six GI hormone receptor genes (NPY1R, PPYR1, PTGDR, PTGER2, PTGER3, and SSTR2) that play an inhibitory role in the secretion of gastrin or gastric acid were selected and validated as potential biomarkers for the diagnosis or prognosis of GC patients in two cohorts. These data suggest that the loss of function of gastrointestinal (GI) hormone receptors by promoter methylation may lead to gastric carcinogenesis because gastrin and gastric acid have been known to play a role in cell differentiation and carcinogenesis in the GI tract.

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.

Jin D, Zhang M, Hua H
Impact of polymorphisms in DNA repair genes XPD, hOGG1 and XRCC4 on colorectal cancer risk in a Chinese Han Population.
Biosci Rep. 2019; 39(1) [PubMed] Article available free on PMC after 01/05/2020 Related Publications
BACKGROUND: This research aimed to study the associations between XPD (G751A, rs13181), hOGG1 (C326G, rs1052133) and XRCC4 (G1394T, rs6869366) gene polymorphisms and the risk of colorectal cancer (CRC) in a Chinese Han population.
METHOD: A total of 225 Chinese Han patients with CRC were selected as the study group, and 200 healthy subjects were recruited as the control group. The polymorphisms of XPD G751A, hOGG1 C326G and XRCC4 G1394T loci were detected by the RFLP-PCR technique in the peripheral blood of all subjects.
RESULTS: Compared with individuals carrying the XPD751 GG allele, the A allele carriers (GA/AA) had a significantly increased risk of CRC (adjusted OR = 2.109, 95%CI = 1.352-3.287,
CONCLUSION: Our results suggest that XPD G751A, hOGG1 C326G and XRCC4 G1394T gene polymorphisms might play an important role in colorectal carcinogenesis and increase the risk of developing CRC in the Chinese Han population. The interaction between smoking and these gene polymorphisms would increase the risk of CRC.

Aydin AF, Vural P, Doğru-Abbasoğlu S, Çil E
The endothelin 1 and endothelin receptor A gene polymorphisms increase the risk of developing papillary thyroid cancer.
Mol Biol Rep. 2019; 46(1):199-205 [PubMed] Related Publications
The endothelin (EDN) axis (EDN1 and EDN1 receptor A, EDNRA) is involved in cellular growth, differentiation, invasiveness, and tumor progression in several cancers. We wanted to examine the possible impact of single nucleotide polymorphisms (SNPs) of EDN1 and EDNRA genes on papillary thyroid cancer (PTC) development and general characteristics of PTC. Study population consist of 113 PTC patients and 185 controls. EDN1 (G5665T, T-1370G) and EDNRA (C TT70G, G-231A) SNPs were investigated by real-time PCR. The GG genotype of EDNRA + 70 SNP was associated with threefold increased PTC risk (p = 0.01), and the combined CG + GG genotype was 2.48 fold higher among PTC patients compared to controls. The variant EDNRA - 231 allele was overrepresented in PTC patients according to controls (p = 0.05). The combined GT + TT genotype of EDN1 5665 SNP was related with late (age after 40 years) PTC onset (p = 0.04), and was more prominent among male patients with PTC according to females (p = 0.03). No significant associations between PTC and - 1370 SNP were found. There were no relationships between laboratory parameters and investigated polymorphisms. The EDNRA + 70 SNP was associated with PTC development. The EDN1 5665 SNP was linked with increased risk for late PTC onset and was more prominent among male patients with PTC.

Cheng C, Xiaohua W, Ning J, et al.
MiR-122 exerts anti-proliferative and apoptotic effects on nasopharyngeal carcinoma cells via the PI3K/AKT signaling pathway.
Cell Mol Biol (Noisy-le-grand). 2018; 64(13):21-25 [PubMed] Related Publications
To investigate the effects of microRNA-122 (miR-122) on the proliferation and apoptosis of nasopharyngeal carcinoma (NPC) HONE-1 cells, and its correlation with the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Human NPC cell line (HONE-1) was transfected with miR-122 inhibitor (anti-miR-122 group), negative controls (vector control group) via lipofectamines, and HONE-1 cell lines undergoing no transfection were selected (non-transfection group). The expression of miR-122, cell proliferation, apoptosis, and expressions of PI3K/AKT pathway and downstream target proteins in the three groups were determined using fluorescence quantitative polymerase chain reaction (qPCR), cell counting kit-8 (CCK8), immunofluorescence (IF) and Western blotting, respectively. The expression of miR-122 in the anti-miR-122 group was significantly lower than corresponding expressions in the non-transfection and vector control groups after 48h of transfection (p <0.05). The proliferation of cells in the anti-miR-122 group was significantly reduced with time after transfection (p <0.05). After 48h of transfection, the extent of apoptosis in the anti-miR-122 group (47.11 ± 1.95%) was significantly higher than that in normal control (7.37 ± 0.82%) and vector control group (8.54 ± 0.96%; p <0.05). There were no significant differences in the expressions of PI3K, AKT, mTOR protein, and the downstream signal proteins (p70S6K and 4E-BP1) in the three groups (p >0.05). However, the expressions of phosphorylated forms of these proteins were significantly lower in the anti-miR-122 group than in the non-transfection and vector control groups (p <0.05). IF results revealed that there were no significant differences in the fluorescence intensity value of PI3K and Akt among the three groups of patients (p>0.05). Inhibition of the expression of miR-122 in NPC suppresses the proliferation, and promotes their apoptosis through the PI3K/AKT signal transduction pathway.

Horst AK, Najjar SM, Wagener C, Tiegs G
CEACAM1 in Liver Injury, Metabolic and Immune Regulation.
Int J Mol Sci. 2018; 19(10) [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a transmembrane glycoprotein that is expressed on epithelial, endothelial and immune cells. CEACAM1 is a differentiation antigen involved in the maintenance of epithelial polarity that is induced during hepatocyte differentiation and liver regeneration. CEACAM1 regulates insulin sensitivity by promoting hepatic insulin clearance, and controls liver tolerance and mucosal immunity. Obese insulin-resistant humans with non-alcoholic fatty liver disease manifest loss of hepatic CEACAM1. In mice, deletion or functional inactivation of CEACAM1 impairs insulin clearance and compromises metabolic homeostasis which initiates the development of obesity and hepatic steatosis and fibrosis with other features of non-alcoholic steatohepatitis, and adipogenesis in white adipose depot. This is followed by inflammation and endothelial and cardiovascular dysfunctions. In obstructive and inflammatory liver diseases, soluble CEACAM1 is shed into human bile where it can serve as an indicator of liver disease. On immune cells, CEACAM1 acts as an immune checkpoint regulator, and deletion of

Cen WN, Pang JS, Huang JC, et al.
The expression and biological information analysis of miR-375-3p in head and neck squamous cell carcinoma based on 1825 samples from GEO, TCGA, and peer-reviewed publications.
Pathol Res Pract. 2018; 214(11):1835-1847 [PubMed] Related Publications
BACKGROUND: The specific expression level and clinical significance of miR-375-3p in HNSCC had not been fully stated, as well as the overall biological function and molecular mechanisms. Therefore, we purpose to carry out a comprehensive meta-analysis to further explore the clinical significance and potential function mechanism of miR-375-3p in HNSCC.
METHODS: HNSCC-related data was gained from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and peer-reviewed journals. A meta-analysis was carried out to comprehensively explore the relationship between miR-375-3p expression level and clinicopathological features of HNSCC. And summary receiver operating characteristic (SROC) curve analysis was applied for evaluating disease diagnosis value of miR-375-3p. In addition, a biological pathway analysis was also performed to assess the possible molecular mechanism of miR-375-3p in HNSCC.
RESULTS: A total of 24 available records and references were added into analysis. The overall pooled meta-analysis outcome revealed a relatively lower expression level of miR-375-3p in HNSCC specimens than that in non-cancerous controls (P < 0.001). And SROC curve analysis showed that the pooled area under the SROC curve (AUC) was 0.90 (95%CI: 0.88-0.93). In addition, biological pathway analysis indicated that LAMC1, EDIL3, FN1, VEGFA, IGF2BP2, and IGF2BP3 maybe the latent target genes of miR-375-3p, which were greatly enriched in the pathways of beta3 integrin cell surface interactions and the binding of RNA via the insulin-like growth factor-2 mRNA-binding protein (IGF2BPs/IMPs/VICKZs).
CONCLUSION: MiR-375-3p expression clearly decreased in HNSCC samples compared with non-cancerous controls. Meanwhile, miR-375-3p may serve as a tumor suppressor via regulating tumor-related genes LAMC1, EDIL3, FN1, VEGFA, IGF2BP2, and IGF2BP3 in HNSCC.

Zhao X, Hua M, Yan S, et al.
The Genetic Polymorphisms of NLRP3 Inflammasome Associated with T Helper Cells in Patients with Multiple Myeloma.
J Immunol Res. 2018; 2018:7569809 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
The pathogenesis of multiple myeloma (MM) remains unclear and the NLRP3 inflammasome has been more and more recognized in the progression of many diseases. To investigate the role of the NLRP3 inflammasome in MM, we determined the genetic polymorphisms and expression of NLRP3 inflammasome-related genes (IL-1

Chen H, Wang J, Zhuang Y, Wu H
Identification of the potential molecular mechanism and driving mutations in the pathogenesis of familial intestinal gastric cancer by whole exome sequencing.
Oncol Rep. 2018; 40(4):2316-2324 [PubMed] Related Publications
The genetic alterations in familial intestinal gastric cancer (FIGC) have not been clearly understood. Aiming to explore the molecular basis and the driving mutations underlying the pathogenesis of FIGC, we performed exome sequencing of the blood samples of the members of an extended family with FIGC. The differences in mutation patterns between family members with gastric cancer and controls were analysed and the overlapped variants were screened by comparing previously published data for blood and tumours from gastric cancer patients. The overlapped genes harbouring insertions‑deletions (INDELs) and single‑nucleotide variants (SNVs) were subjected to function, pathway and network analysis. The INDELs were enriched in DNA packaging and in the neurological system process related to the biological process (BP), while SNVs were closely related to cell‑function‑related BPs. ESR was the significant node with marked centrality in the SNV network. ERK 1/2 was the hub node in the INDEL network, interacting with EZK and IGF2R. Sequencing analysis revealed ESR1 homozygous mutations in exon 1 (216G > C) and exon 10 (2234C > T) and EZR1 heterozygous deletion of 68‑69 GT nucleotides in exon 13 of the family members. The IGF2R gene only demonstrated a mutation in exon 48 of the propositus. All hub proteins had direct or indirect interactions in the protein‑protein interaction network.

Krishn SR, Singh A, Bowler N, et al.
Prostate cancer sheds the αvβ3 integrin in vivo through exosomes.
Matrix Biol. 2019; 77:41-57 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
The αvβ3 integrin has been shown to promote aggressive phenotypes in many types of cancers, including prostate cancer. We show that GFP-labeled αvβ3 derived from cancer cells circulates in the blood and is detected in distant lesions in NOD scid gamma (NSG) mice. We, therefore, hypothesized that αvβ3 travels through exosomes and tested its levels in pools of vesicles, which we designate extracellular vesicles highly enriched in exosomes (ExVs), and in exosomes isolated from the plasma of prostate cancer patients. Here, we show that the αvβ3 integrin is found in patient blood exosomes purified by sucrose or iodixanol density gradients. In addition, we provide evidence that the αvβ3 integrin is transferred through ExVs isolated from prostate cancer patient plasma to β3-negative recipient cells. We also demonstrate the intracellular localization of β3-GFP transferred via cancer cell-derived ExVs. We show that the ExVs present in plasma from prostate cancer patients contain higher levels of αvβ3 and CD9 as compared to plasma ExVs from age-matched subjects who are not affected by cancer. Furthermore, using PSMA antibody-bead mediated immunocapture, we show that the αvβ3 integrin is expressed in a subset of exosomes characterized by PSMA, CD9, CD63, and an epithelial-specific marker, Trop-2. Finally, we present evidence that the levels of αvβ3, CD63, and CD9 remain unaltered in ExVs isolated from the blood of prostate cancer patients treated with enzalutamide. Our results suggest that detecting exosomal αvβ3 integrin in prostate cancer patients could be a clinically useful and non-invasive biomarker to follow prostate cancer progression. Moreover, the ability of αvβ3 integrin to be transferred from ExVs to recipient cells provides a strong rationale for further investigating the role of αvβ3 integrin in the pathogenesis of prostate cancer and as a potential therapeutic target.

Cai H, Saiyin H, Liu X, et al.
Nogo-B promotes tumor angiogenesis and provides a potential therapeutic target in hepatocellular carcinoma.
Mol Oncol. 2018; 12(12):2042-2054 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Tumor angiogenesis is one of the hallmarks of cancer as well as an attractive target for cancer therapy. Characterization of novel pathways that act in parallel with the VEGF/VEGFR axis to promote tumor angiogenesis may provide insights into novel anti-angiogenic therapeutic targets. We found that the expression level of Nogo-B is positively correlated with tumor vessel density in hepatocellular carcinoma (HCC). While Nogo-B depletion inhibited tumor angiogenesis, Nogo-B overexpression promoted tumor angiogenesis in a tumor xenograft subcutaneous model of the human HCC cell line. Mechanically, Nogo-B regulates tumor angiogenesis based on its association with integrin α

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 01/05/2020 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

Liu M, Gou L, Xia J, et al.
LncRNA ITGB2-AS1 Could Promote the Migration and Invasion of Breast Cancer Cells through Up-Regulating ITGB2.
Int J Mol Sci. 2018; 19(7) [PubMed] Article available free on PMC after 01/05/2020 Related Publications
In the previous study, we screened a novel lncRNA-ITGB2-AS1, which was down-regulated by bone morphogenetic protein 9 (BMP9) in breast cancer cell. Studying ITGB2-AS1 will lay the foundation for the exploring mechanism of the BMP9 inhibitory effect on breast cancer. The expression analysis related to ITGB2-AS1 in clinical samples was conducted on online websites. The overexpression plasmid or siRNA fragment was transfected into breast cancer cells to alter its gene expression. The MTT assay and flow cytometry were used to measure cell viability and cell cycle. Additionally, cell migration and invasion were detected by wound healing and transwell assay. The results of biological function experiments showed that ITGB2-AS1 could promote the migration and invasion of breast cancer. Furthermore, ITGB2-AS1 increased the mRNA and protein expression of ITGB2. Consistent with ITGB2-AS1, ITGB2 exerted the promotion effect on the migration and invasion of breast cancer and activated integrin-related FAK signaling. The OL plasmid expressing the truncation of ITGB2-AS1, which was complementary to ITGB2, was essential for activation of FAK signaling. In conclusion, LncRNA ITGB2-AS1 could promote the migration and invasion of breast cancer cells by up-regulating ITGB2.

Adams O, Janser FA, Dislich B, et al.
A specific expression profile of LC3B and p62 is associated with nonresponse to neoadjuvant chemotherapy in esophageal adenocarcinomas.
PLoS One. 2018; 13(6):e0197610 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Paclitaxel is a powerful chemotherapeutic drug, used for the treatment of many cancer types, including esophageal adenocarcinomas (EAC). Autophagy is a lysosome-dependent degradation process maintaining cellular homeostasis. Defective autophagy has been implicated in cancer biology and therapy resistance. We aimed to assess the impact of autophagy on chemotherapy response in EAC, with a special focus on paclitaxel. Responsiveness of EAC cell lines, OE19, FLO-1, OE33 and SK-GT-4, to paclitaxel was assessed using Alamar Blue assays. Autophagic flux upon paclitaxel treatment in vitro was assessed by immunoblotting of LC3B-II and quantitative assessment of WIP1 mRNA. Immunohistochemistry for the autophagy markers LC3B and p62 was applied on tumor tissue from 149 EAC patients treated with neoadjuvant chemotherapy, including pre- and post-therapeutic samples (62 matched pairs). Tumor response was assessed by histology. For comparison, previously published data on 114 primary resected EAC cases were used. EAC cell lines displayed differing responsiveness to paclitaxel treatment; however this was not associated with differential autophagy regulation. High p62 cytoplasmic expression on its own (p ≤ 0.001), or in combination with low LC3B (p = 0.034), was associated with nonresponse to chemotherapy, regardless of whether or not the regiments contained paclitaxel, but there was no independent prognostic value of LC3B or p62 expression patterns for EAC after neoadjuvant treatment. p62 and related pathways, most likely other than autophagy, play a role in chemotherapeutic response in EAC in a clinical setting. Therefore p62 could be a novel therapeutic target to overcome chemoresistance in EAC.

Nemlich Y, Baruch EN, Besser MJ, et al.
ADAR1-mediated regulation of melanoma invasion.
Nat Commun. 2018; 9(1):2154 [PubMed] Article available free on PMC after 01/05/2020 Related Publications
Melanoma cells use different migratory strategies to exit the primary tumor mass and invade surrounding and subsequently distant tissues. We reported previously that ADAR1 expression is downregulated in metastatic melanoma, thereby facilitating proliferation. Here we show that ADAR1 silencing enhances melanoma cell invasiveness and ITGB3 expression. The enhanced invasion is reversed when ITGB3 is blocked with antibodies. Re-expression of wild-type or catalytically inactive ADAR1 establishes this mechanism as independent of RNA editing. We demonstrate that ADAR1 controls ITGB3 expression both at the post-transcriptional and transcriptional levels, via miR-22 and PAX6 transcription factor, respectively. These are proven here as direct regulators of ITGB3 expression. miR-22 expression is controlled by ADAR1 via FOXD1 transcription factor. Clinical relevance is demonstrated in patient-paired progression tissue microarray using immunohistochemistry. The novel ADAR1-dependent and RNA-editing-independent regulation of invasion, mediated by ITGB3, strongly points to a central involvement of ADAR1 in cancer progression and metastasis.

Huang SQ, Zhou ZX, Zheng SL, et al.
Association of variants of miRNA processing genes with cervical precancerous lesion risk in a southern Chinese population.
Biosci Rep. 2018; 38(3) [PubMed] Article available free on PMC after 01/05/2020 Related Publications
The miRNA processing genes play essential roles in the biosynthesis of mammalian miRNAs, and their genetic variants are involved in the development of various cancers. Our study aimed to determine the potential association between miRNA processing gene polymorphisms and cervical precancerous lesions. Five single nucleotide polymorphisms (SNPs), including Ran-GTP (

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