Diagnostic value of integrin α3, β4, and β5 gene expression levels for the clinical outcome of tongue squamous cell carcinoma

Kurokawa, Akira; Nakagawa, Masaki; Kitamura, Nobuto; Noman, Arhab A.; Ohnishi, Makoto; Ohyama, Tokio; Kobayashi, Takanori; Shingaki, Susumu; Takagi, Ritsuo

doi:10.1002/cncr.23295

Cited by 60 publications

(40 citation statements)

References 39 publications

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“…For ITGA3, it has been established that α3β1 integrin is involved in the maintenance of basement membrane integrity through adhesion to laminin 5 and plays an essential role in the invasiveness and metastatic potential of tumor cells (30)(31)(32). However, there are contradictory reports regarding the significance of ITGA3 expression in various types of cancers (33)(34)(35)(36). Considering the results demonstrated recently that GAL3ST3 is involved in tumor metastasis by regulating the ability of adhesion to selectins and expression of integrins, more evidence is needed to clarify the relationship among these molecules (25).…”

Section: Discussionmentioning

confidence: 99%

DNA methylation status of a distinctively different subset of genes is associated with each histologic Lauren classification subtype in early gastric carcinogenesis

et al. 2014

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Abstract. DNA methylation change is known to play a crucial role in early gastric carcinogenesis. The present study aimed to identify and validate the correlation between differentially methylated regions (DMRs) and the subtypes of early gastric cancers (EGCs). Illumina Infinium methylation assay (IIMA; 450K BeadChip kit) was performed on fresh tumor and non-tumor tissues of 12 EGCs to screen the methylation status of 450,000 CpG sites. To evaluate the significance of DNA methylation in each histologic subtype, pyrosequencing assay (PA) was performed on 38 EGCs (18 intestinal-, 12 mixed-and 8 diffuse-type) using 12 genes selected from the screening. Between tumors of the intestinal-type (n=6), and diffuse-(n=4) plus mixed-types (n=2), 169 regions showed significant differences (intensity >3,000, Δβ >0.2) in IIMA. Hierarchical clustering using the 169 DMRs revealed distinct separation between the two groups. In PA using 12 selected genes from the IIMA results, the aberrant methylation statuses of DVL2 (p=0.0186) and ETS1 (p=0.0222) were significantly related to diffuse-and mixed-types rather than the intestinal-type, while C19orf35 (p=0.019) and CNRIP1 (p=0.0473) were related to the diffuse-type rather than intestinal-type, and GAL3ST2 (p=0.0158) and ITGA3 (p=0.0273) were related to the mixedtype rather than the other two types. The methylation of other genes, CLIP4, XKR6, CCDC57, MAML3 and SDC2, was related with age, tumor location, or Helicobacter infection rather than the histologic subtype. Aberrant DNA methylation of certain genes may be independently involved in each histologic subtype of EGC. Furthermore, mixed-type EGCs may be a distinctive histologic subtype based on the different subset of DMRs compared to those of other subtypes. IntroductionDespite its decreasing trend, gastric cancer (GC) still remains one of the most troublesome malignant diseases worldwide. It is the fourth most common cancer and the second leading cause of cancer-related death worldwide (1-3). In Asian countries such as Japan and Korea, it has the highest incidence among all malignancies although its overall survival rate has improved during the last few decades due to extensive screening programs (3,4). Due to the poor prognosis and limited treatment options of advanced GC, it remains a challenging task to determine effective molecular-pathological markers for early diagnosis with appropriate histological classification (5).Lauren classification, which subgroups GCs mainly as two types, intestinal and diffuse, was first introduced in 1965 and has been generally accepted as a distinct and simple histological classification of GCs by most pathologists (6). Since the two major types show distinctively different phenotypic, epidemiologic and biologic characteristics, it is believed that different genetic alterations may be implicated in each histologic type of the classification (7). However, a considerable number of GCs accounting for 10-15% of cases, share the histologic features of these two types and are designated as mixed-type ...

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Section: Discussionmentioning

confidence: 99%

DNA methylation status of a distinctively different subset of genes is associated with each histologic Lauren classification subtype in early gastric carcinogenesis

et al. 2014

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“…[9][10][11] Prior reports indicate that ITGB4 is upregulated in multiple tumor types, including pancreatic cancer. 8 In several cancers, high levels of ITGB4 expression have been linked to poor prognosis or aggressive behavior, [12][13][14][15][16] but the clinicopathological significance of ITGB4 overexpression in PDA remains unclear. The aim of the current study was to clarify the clinicopathological significance of ITGB4 overexpression in PDA and to suggest the potential function of ITGB4 in cancer EMT.…”

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confidence: 99%

Upregulation of integrin β4 promotes epithelial–mesenchymal transition and is a novel prognostic marker in pancreatic ductal adenocarcinoma

Masugi

Yamazaki

Emoto

et al. 2015

Laboratory Investigation

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Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and often lethal malignant tumor. Several studies have shown that epithelial-mesenchymal transition (EMT) is frequently observed in clinical samples of PDA and is related to high metastatic rates and poor outcomes. To identify candidate molecules regulating EMT in PDA, we previously used cDNA microarray analysis and identified integrin b4 (ITGB4) as one of the genes upregulated in high-EMT xenografts derived from PDA patients. The aim of the current study was to clarify the clinicopathological and functional significance of ITGB4 overexpression in PDA. ITGB4 upregulation in high-EMT xenografts was confirmed by immunohistochemistry. Immunohistochemical analyses of 134 surgically resected PDA cases revealed intratumoral heterogeneity with respect to ITGB4 expression and showed that cancer cells undergoing EMT often display strong diffuse ITGB4 expression. High levels of ITGB4 expression were significantly correlated with the hallmarks of EMT (solitary cell infiltration, reduced E-cadherin expression, and increased vimentin expression), with high tumor grade, and with the presence of lymph node metastasis, and showed an independent prognostic effect. Immunocytochemical analyses of PDA cell lines revealed that localization of ITGB4 changed from regions of cell-cell contact to diffuse cytoplasm and cell edges with occasional localization in filopodia during EMT. Knockdown of ITGB4 reduced the migratory and invasive ability of PDA cells. Overexpression of ITGB4 promoted cell scattering and cell motility in combination with downregulation of E-cadherin and upregulation of vimentin expression. In conclusion, we elucidated the prognostic and clinicopathological significance of ITGB4 overexpression in PDA and also the potential role for ITGB4 in the regulation of cancer invasion and EMT. Pancreatic cancer is the fourth most common cause of cancer death in men and women in the United States. 1 Despite medical improvements, pancreatic cancer remains one of the most lethal malignancies: the 5-year survival rate for patients with pancreatic cancer is only about 6%. 1 Pancreatic ductal adenocarcinoma (PDA), characterized by the formation of ducts resembling pancreatic ducts, is the most common histologic type of pancreatic cancer. Resectability is considered to be the most significant prognostic factor; however, at the time of diagnosis, only about 20% of patients with PDA are surgically resectable because of distant metastases or major vessel involvement. 2 Even after curative surgery, the 5-year survival rate is 10%-25%, mainly due to the highly aggressive biological behavior of this tumor, such as the high rate of local recurrence, peritoneal dissemination, liver metastases, and lymph node recurrence. 3 The epithelial-mesenchymal transition (EMT) is a series of cellular and molecular processes during which polarized epithelial cells lose cell-cell and cell-basement membrane interactions at the same time as acquiring mesenchymal and migratory properties. EMT is no...

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“…We found that patients carrying (Xu et al 2010) and tongue squamous cell carcinoma (Kurokawa et al 2008). As rs2675 was located in the 3′UTR of integrin β5, we assumed that this SNP might affect integrin β5 expression by binding with specific microRNA in the post-transcriptional regulation, and then contribute to OSCC progression.…”

Section: Discussionmentioning

confidence: 90%

Polymorphisms of microRNA-Binding Sites in Integrin Genes Are Associated with Oral Squamous Cell Carcinoma Susceptibility and Progression

Wang

Long

et al. 2014

Tohoku J. Exp. Med.

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Integrins, which act as an important role in the connection between cells and extra-cellular environments, are important cell surface receptors. Integrins have been demonstrated to play critical roles in many aspects of the progression of oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in microRNA-binding sites of integrin genes and the susceptibility and progression of OSCC in Chinese Han Population. We recruited 167 OSCC patients and 200 cancer-free controls from three independent medical centers. Genotyping was completed successfully for the five selected integrin SNPs: rs1062484 (integrin α3), rs11902171 (integrin α v), rs17468 (integrin β 1), rs3809865 (integrin β 3), and rs2675 (integrin β 5). The results demonstrated that the A allele of rs3809865 T/A (a T-to-A nucleotide change), a functional polymorphism in the 3′UTR of integrin β3 gene, was associated with OSCC risk (p < 0.05). In addition, the association analysis between this SNP and integrin β 3 mRNA expression level in the patients' peripheral blood mononuclear cells indicated that OSCC patients carrying the A allele would have a lower integrin β3 expression level (p = 0.047). Meanwhile, survival analysis showed that the C allele of rs2675 A/C (nucleotide change from A to C), another 3′UTR polymorphism in integrin β5 gene, was related with progression of OSCC. Overall, our results suggest that rs3809865 and rs2675 may contribute to OSCC risk and progression in Chinese Han Population. These two SNPs may be used as potential diagnostic and prognostic biomarkers for OSCC in future.

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Diagnostic value of integrin α3, β4, and β5 gene expression levels for the clinical outcome of tongue squamous cell carcinoma

Cited by 60 publications

References 39 publications

DNA methylation status of a distinctively different subset of genes is associated with each histologic Lauren classification subtype in early gastric carcinogenesis

DNA methylation status of a distinctively different subset of genes is associated with each histologic Lauren classification subtype in early gastric carcinogenesis

Upregulation of integrin β4 promotes epithelial–mesenchymal transition and is a novel prognostic marker in pancreatic ductal adenocarcinoma

Polymorphisms of microRNA-Binding Sites in Integrin Genes Are Associated with Oral Squamous Cell Carcinoma Susceptibility and Progression

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