Clinical Significance of Integrin Subunit Beta 4 in Head and Neck Squamous Cell Carcinoma

Li, Guosheng; Hou, Wei; Chen, Gang; Ying, Yang; Chen, Xiaoyi; Zhang, Xiao-Guohui; Liang, Yao; Li, Mingxuan; Huang, Zhi‐Guang; Dang, Yi‐Wu; Liang, Qinghua; Wu, Huayu; Wei, Hongyu

doi:10.1089/cbr.2020.3943

Cited by 10 publications

(7 citation statements)

References 48 publications

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“…5). This finding is in accordance with mRNA and protein expression of ITGB4 in a large cohort of n = 2330 HNSCC patients, in which ITGB4 was upregulated in HNSCC and distinguished HNSCC from non-HNSCC tissue [42]. Co-localization of ITGB4 and its ligand laminin 5 was observed at the tumor-stroma interface and an absence of ITGB4 expression correlated with a lack of laminin 5 deposition, demonstrating their co-dependence (Fig.…”

Section: Molecular Analyses Of Both Tumor Bulk and Single Malignant C...supporting

confidence: 88%

A transcriptomic map of EGFR-induced epithelial-to-mesenchymal transition identifies prognostic and therapeutic targets for head and neck cancer

et al. 2022

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Background Epidermal growth factor receptor (EGFR) is both a driver oncogene and a therapeutic target in advanced head and neck squamous cell carcinoma (HNSCC). However, response to EGFR treatment is inconsistent and lacks markers for treatment prediction. This study investigated EGFR-induced epithelial-to-mesenchymal transition (EMT) as a central parameter in tumor progression and identified novel prognostic and therapeutic targets, and a candidate predictive marker for EGFR therapy response. Methods Transcriptomic profiles were analyzed by RNA sequencing (RNA-seq) following EGFR-mediated EMT in responsive human HNSCC cell lines. Exclusive genes were extracted via differentially expressed genes (DEGs) and a risk score was determined through forward feature selection and Cox regression models in HNSCC cohorts. Functional characterization of selected prognostic genes was conducted in 2D and 3D cellular models, and findings were validated by immunohistochemistry in primary HNSCC. Results An EGFR-mediated EMT gene signature composed of n = 171 genes was identified in responsive cell lines and transferred to the TCGA-HNSCC cohort. A 5-gene risk score comprising DDIT4, FADD, ITGB4, NCEH1, and TIMP1 prognosticated overall survival (OS) in TCGA and was confirmed in independent HNSCC cohorts. The EGFR-mediated EMT signature was distinct from EMT hallmark and partial EMT (pEMT) meta-programs with a differing enrichment pattern in single malignant cells. Molecular characterization showed that ITGB4 was upregulated in primary tumors and metastases compared to normal mucosa and correlated with EGFR/MAPK activity in tumor bulk and single malignant cells. Preferential localization of ITGB4 together with its ligand laminin 5 at tumor-stroma interfaces correlated with increased tumor budding in primary HNSCC tissue sections. In vitro, ITGB4 knock-down reduced EGFR-mediated migration and invasion and ITGB4-antagonizing antibody ASC8 impaired 2D and 3D invasion. Furthermore, a logistic regression model defined ITGB4 as a predictive marker of progression-free survival in response to Cetuximab in recurrent metastatic HNSCC patients. Conclusions EGFR-mediated EMT conveyed through MAPK activation contributes to HNSCC progression upon induction of migration and invasion. A 5-gene risk score based on a novel EGFR-mediated EMT signature prognosticated survival of HNSCC patients and determined ITGB4 as potential therapeutic and predictive target in patients with strong EGFR-mediated EMT.

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Section: Molecular Analyses Of Both Tumor Bulk and Single Malignant C...supporting

confidence: 88%

A transcriptomic map of EGFR-induced epithelial-to-mesenchymal transition identifies prognostic and therapeutic targets for head and neck cancer

et al. 2022

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“…Elevated BCAT1 expression in HNSCC has been reported by Wang et al 45 However, some limitations like limited samples ( n < 380) can be seen in the study. Moreover, HNSCC is complex given its multiple sites sources; for instance, a gene may be upregulated in some subgroups but not in the other subtypes 47,48 . Through comprehensively investigating a large sample ( n of public data = 1818, n of in‐house tissue microarrays = 258), our study demonstrated that BCAT1 was significantly highly expressed in HNSCC at both the mRNA and protein levels in all four subgroups of HNSCC—LSCC, OSCC, PSCC, and USCC.…”

Section: Discussionmentioning

confidence: 89%

“…Moreover, HNSCC is complex given its multiple sites sources; for instance, a gene may be upregulated in some subgroups but not in the other subtypes. 47 , 48 Through comprehensively investigating a large sample ( n of public data = 1818, n of in‐house tissue microarrays = 258), our study demonstrated that BCAT1 was significantly highly expressed in HNSCC at both the mRNA and protein levels in all four subgroups of HNSCC—LSCC, OSCC, PSCC, and USCC. This suggests the trend of BCAT1 expression in HNSCC is consistent with the majority of tumors (ACC, etc.).…”

Section: Discussionmentioning

confidence: 89%

BCAT1: A risk factor in multiple cancers based on a pan‐cancer analysis

Huang

Liang

et al. 2022

Cancer Medicine

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Background Although branched chain amino acid transaminase 1 (BCAT1) has been identified to play an essential role in multiple tumors, no studies on its role in pan‐cancer have been consulted before. Methods The study comprehensively analyzes the expression, potential mechanisms, and clinical significance of BCAT1 in pan‐cancer through utilizing 16,847 samples, providing novel clues for the treatment of cancers. A Kruskal–Wallis test and the Wilcoxon rank‐sum and signed‐rank tests were applied to investigate diverse BCAT1 expression between various groups (e.g., cancer tissues versus normal tissues). Spearman’s rank correlation coefficient was used in all correlation analyses in the study. Cox analyses and Kaplan‐Meier curves were utilized to identify the prognosis significance of BCAT1 expression in cancers. The significance of BCAT1 expression in differentiating cancer and non‐cancer tissues was explored via the area under the receiver operating characteristic curves (AUC). Results The differential expression of BCAT1 was detected in various cancers (p < 0.05), which is relevant to some DNA methyltransferases expression. BCAT1 expression was associated with mismatch repair gene expression, immune checkpoint inhibitors expression, microsatellite instability, and tumor mutational burden in some cancers, indicating its potential in immunotherapy. BCAT1 expression showed prognosis significance and played a risk role in multiple cancers (hazard ratio > 0, p < 0.05). BCAT1 expression also demonstrated conspicuous ability to distinguish some cancers tissues from their normal tissues (AUC > 0.7), indicating its potential to detect cancers. Further analyses on head and neck squamous cell carcinoma certified upregulated BCAT1 expression at both mRNA and protein levels in this disease based on in‐house tissue microarrays and multicenter datasets. Conclusions For the first time, the research comprehensively demonstrates the overexpression of BCAT1 in pan‐cancer, which improves the understanding of the pathogenesis of BCAT1 in pan‐cancer. Upregulated BCAT1 expression represented a poor prognosis for cancers patients, and it serves as a potential marker for cancer immunotherapy.

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“…Lysates were then collected and used for Western blotting for total and phosphorylated Erk, p38, and JNK (representative blots shown) (*p < 0.05 compared with pLV controls). (Li et al, 2017) and breast cancer metastases (Abdel-Ghany et al, 2001), and ITGB4 expression has been identified as a prognostic marker in pancreatic ductal cancer, colon cancer, and head and neck squamous cell carcinomas (Nagata et al, 2013;Masugi et al, 2015;Li et al, 2019Li et al, , 2020. Our recent study identified differential effects of ITGB4 splice variants on the migration of esophageal squamous cells and found ITGB4E is uniquely associated with decreased cancer cell migration (Kelly et al, 2020).…”

Section: Discussionmentioning

confidence: 95%

Integrin Beta 4E Promotes Endothelial Phenotypic Changes and Attenuates Lung Endothelial Cell Inflammatory Responses

et al. 2022

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We previously reported integrin beta 4 (ITGB4) is an important mediator of lung vascular protection by simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitor. In this study, we report increased endothelial cell (EC) expression specifically of ITGB4E, an ITGB4 mRNA splice variant, by simvastatin with effects on EC protein expression and inflammatory responses. In initial experiments, human pulmonary artery ECs were treated using simvastatin (5 μM, 24 h) prior to immunoprecipitation of integrin alpha 6 (ITGA6), which associates with ITGB4, and Western blotting for full-length ITGB4 and ITGB4E, uniquely characterized by a truncated 114 amino acid cytoplasmic domain. These experiments confirmed a significant increase in both full-length ITGB4 and ITGB4E. To investigate the effects of increased ITGB4E expression alone, ECs were transfected with ITGB4E or control vector, and cells were seeded in wells containing Matrigel to assess effects on angiogenesis or used for scratch assay to assess migration. Decreased angiogenesis and migration were observed in ITGB4E transfected ECs compared with controls. In separate experiments, PCR and Western blots from transfected cells demonstrated significant changes in EC protein expression associated with increased ITGB4E, including marked decreases in platelet endothelial cell adhesion molecule-1 (PECAM-1) and vascular endothelial-cadherin (VE-cadherin) as well as increased expression of E-cadherin and N-cadherin along with increased expression of the Slug and Snail transcription factors that promote endothelial-to-mesenchymal transition (EndMT). We, then, investigated the functional effects of ITGB4E overexpression on EC inflammatory responses and observed a significant attenuation of lipopolysaccharide (LPS)-induced mitogen-activated protein kinase (MAPK) activation, including decreased phosphorylation of both extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), as well as reduced inflammatory cytokines (IL-6 and IL-8), expressed in the media of EC after either LPS or excessive cyclic stretch (CS). Finally, EC expression-increased ITGB4E demonstrated decreased barrier disruption induced by thrombin as measured by transendothelial electrical resistance. Our data support distinct EC phenotypic changes induced by ITGB4E that are also associated with an attenuation of cellular inflammatory responses. These findings implicate ITGB4E upregulation as an important mediator of lung EC protection by statins and may lead to novel therapeutic strategies for patients with or at risk for acute lung injury (ALI).

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Clinical Significance of Integrin Subunit Beta 4 in Head and Neck Squamous Cell Carcinoma

Cited by 10 publications

References 48 publications

A transcriptomic map of EGFR-induced epithelial-to-mesenchymal transition identifies prognostic and therapeutic targets for head and neck cancer

A transcriptomic map of EGFR-induced epithelial-to-mesenchymal transition identifies prognostic and therapeutic targets for head and neck cancer

BCAT1: A risk factor in multiple cancers based on a pan‐cancer analysis

Integrin Beta 4E Promotes Endothelial Phenotypic Changes and Attenuates Lung Endothelial Cell Inflammatory Responses

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