ITGA3 and ITGB4 expression biomarkers estimate the risks of locoregional and hematogenous dissemination of oral squamous cell carcinoma

Nakagawa, Masaki; Noman, Arhab A.; Suzuki, Kenji; Kitamura, Hiroshi; Ohnishi, Makoto; Ohyama, Tokio; Kitamura, Nobuto; Kobayashi, Takanori; Uematsu, Kohya; Takahashi, Kazuyuki; Kodama, Naoki; Kawase, Tomoyuki; Hoshina, Hideyuki; Ikeda, Nobuyuki; Shingaki, Susumu; Takagi, Ritsuo

doi:10.1186/1471-2407-13-410

Cited by 55 publications

(44 citation statements)

References 38 publications

(37 reference statements)

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“…In breast cancer, ITGB4 overexpression is associated with aggressive behavior and poor prognosis, and ITGB4 was shown to be a prognostic indicator of poor survival and to correlate with nuclear grade and tumor size in breast cancer, cervical cancer, head and neck cancer, and pancreatic cancer41424344. In head and neck cancer, increased ITGB4 expression is associated with lymph node metastasis, distant metastasis, and increased mortality45. In pancreatic adenocarcinoma, increased ITGB4 expression is correlated with a number of EMT hallmarks, including solitary cell infiltration, reduced expression of E-cadherin, and increased expression of vimentin46.…”

Section: Discussionmentioning

confidence: 99%

Integrin β4 promotes cell invasion and epithelial-mesenchymal transition through the modulation of Slug expression in hepatocellular carcinoma

Liu

et al. 2017

Sci Rep

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Integrin β4 (ITGB4) is a transmembrane receptor involved in tumorigenesis and the invasiveness of many cancers. However, its role in hepatocellular carcinoma (HCC), one of the most prevalent human cancers worldwide, remains unclear. Here, we examined the involvement of ITGB4 in HCC and explored the underlying mechanisms. Real-time PCR and immunohistochemical analyses of tissues from 82 patients with HCC and four HCC cell lines showed higher ITGB4 levels in tumor than in adjacent non-tumor tissues and in HCC than in normal hepatic cells. Silencing of ITGB4 repressed cell proliferation, colony forming ability and cell invasiveness, whereas ectopic expression of ITGB4 promoted the proliferation and invasion of HCC cells and induced epithelial to mesenchymal transition (EMT) in parallel with the upregulation of Slug, as shown by transwell assays, WB and immunocytochemistry. Knockdown of Slug reduced cell viability inhibited invasion and reversed the effects of ITBG4 overexpression on promoting EMT, and AKT/Sox2-Nanog may also be involved. In a xenograft tumor model induced by injection of ITGB4-overexpressing cells into nude mice, ITGB4 promoted tumor growth and metastasis to the lungs. Taken together, our results indicate that ITGB4 plays a tumorigenic and pro-metastatic role mediated by Slug and suggest IGTB4 could be a prognostic indicator or a therapeutic target in patients with HCC.

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Section: Discussionmentioning

confidence: 99%

Integrin β4 promotes cell invasion and epithelial-mesenchymal transition through the modulation of Slug expression in hepatocellular carcinoma

Liu

et al. 2017

Sci Rep

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“…For example, integrin α5 acts downstream of Runt -related transcription factor 2 (RUNX2) and steroid receptor coactivator-1 (SRC-1) to promote breast cancer cell adhesion and metastasis to the bone (Li et al, 2016; Qin et al, 2011). A high ITGA3/CD9 expression ratio is associated with a high rate of lymph node metastasis and invasive histopathology of oral squamous cell carcinoma (Nagata et al, 2013), while enhanced ITGA3/ITGB1 signaling by downregulation of miR-223 contributes to migration and invasion of PCa cancer cells (Kurozumi et al, 2016). In addition, high levels of ITGA2B expression have been shown to correlate with poor prognosis for overall survival of clear cell renal cell carcinoma (Lu et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis

Zhu¹,

Zhang²,

Weichert-Leahey³

et al. 2017

Cancer Cell

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Summary A genome-wide association study identified LMO1, which encodes a LIM-domain-only transcriptional cofactor, as a neuroblastoma susceptibility gene that functions as an oncogene in high-risk neuroblastoma. Here we show that dβh promoter-mediated expression of LMO1 in zebrafish synergizes with MYCN to increase the proliferation of hyperplastic sympathoadrenal precursor cells, leading to a reduced latency and increased penetrance of neuroblastomagenesis. The transgenic expression of LMO1 also promoted hematogenous dissemination and distant metastasis, which was linked to neuroblastoma cell invasion and migration, and elevated expression levels of genes affecting tumor cell-extracellular matrix interaction, including loxl3, itga2b, itga3 and itga5. Our results provide in vivo validation of LMO1 as an important oncogene that promotes neuroblastoma initiation, progression, and widespread metastatic dissemination.

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“…One of these reports demonstrated that integrin β4 gene expression was associated with decreased survival in a cohort of 66 patients (99). In a larger study, increased integrin β4 gene expression was associated with the presence of lymph node metastases, distant metastases and patient death on univariate analysis, and was an independent predictor of distant metastases on multivariate analysis (100). …”

Section: Malignancies With Strong Evidence That Integrin β4 Expressiomentioning

confidence: 99%

Clinical significance of the integrin α6β4 in human malignancies

Stewart

O’Connor

2015

Laboratory Investigation

183

181

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Integrin α6β4 is a cellular adhesion molecule that binds to laminins in the extracellular matrix and nucleates the formation of hemidesmosomes. During carcinoma progression, integrin α6β4 is released from hemidesmosomes, where it can then signal to facilitate multiple aspects of tumor progression including sustaining proliferative signaling, tumor invasion and metastasis, evasion of apoptosis, and stimulation of angiogenesis. The integrin achieves these ends by cooperating with growth factor receptors including EGFR, ErbB-2, and c-Met to amplify downstream pathways such as PI3K, AKT, MAPK and the Rho family small GTPases. Furthermore, it dramatically alters the transcriptome toward a more invasive phenotype by controlling promoter DNA demethylation of invasion and metastasis-associated proteins, such as S100A4 and autotaxin, and upregulates and activates key tumor promoting transcription factors such as the NFATs and NFkB. Expression of integrin α6β4 has been studied in many human malignancies where its overexpression is associated with aggressive behavior and a poor prognosis. This review provides an assessment of integrin α6β4 expression patterns and their prognostic significance in human malignancies, and describes key signaling functions of integrin α6β4 that contribute to tumor progression.

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ITGA3 and ITGB4 expression biomarkers estimate the risks of locoregional and hematogenous dissemination of oral squamous cell carcinoma

Cited by 55 publications

References 38 publications

Integrin β4 promotes cell invasion and epithelial-mesenchymal transition through the modulation of Slug expression in hepatocellular carcinoma

Integrin β4 promotes cell invasion and epithelial-mesenchymal transition through the modulation of Slug expression in hepatocellular carcinoma

LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis

Clinical significance of the integrin α6β4 in human malignancies

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