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STXBP4 Drives Tumor Growth and Is Associated with Poor Prognosis through PDGF Receptor Signaling in Lung Squamous Cell Carcinoma.

ABSTRACT: Purpose: Expression of the ?N isoform of p63 (?Np63) is a diagnostic marker highly specific for lung squamous cell carcinoma (SCC). We previously found that Syntaxin Binding Protein 4 (STXBP4) regulates ?Np63 ubiquitination, suggesting that STXBP4 may also be an SCC biomarker. To address this issue, we investigated the role of STXBP4 expression in SCC biology and the impact of STXBP4 expression on SCC prognosis.Experimental Design: We carried out a clinicopathologic analysis of STXBP4 expression in 87 lung SCC patients. Whole transcriptome analysis using RNA-seq was performed in STXBP4-positive and STXBP4-negative tumors of lung SCC. Soft-agar assay and xenograft assay were performed using overexpressing or knockdown SCC cells.Results: Significantly higher levels of STXBP4 expression were correlated with accumulations of ?Np63 in clinical lung SCC specimens (Spearman rank correlation ? = 0.219). Notably, STXBP4-positive tumors correlated with three important clinical parameters: T factor (P < 0.001), disease stage (P = 0.030), and pleural involvement (P = 0.028). Whole transcriptome sequencing followed by pathway analysis indicated that STXBP4 is involved in functional gene networks that regulate cell growth, proliferation, cell death, and survival in cancer. Platelet-derived growth factor receptor alpha (PDGFR?) was a key downstream mediator of STXBP4 function. In line with this, shRNA mediated STXBP4 and PDGFRA knockdown suppressed tumor growth in soft-agar and xenograft assays.Conclusions: STXBP4 plays a crucial role in driving SCC growth and is an independent prognostic factor for predicting worse outcome in lung SCC. These data suggest that STXBP4 is a relevant therapeutic target for patients with lung SCC. Clin Cancer Res; 23(13); 3442-52. ©2017 AACR.

SUBMITTER: Otaka Y

PROVIDER: S-EPMC5496791 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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STXBP4 Drives Tumor Growth and Is Associated with Poor Prognosis through PDGF Receptor Signaling in Lung Squamous Cell Carcinoma.

Otaka Yukihiro Y Rokudai Susumu S Kaira Kyoichi K Fujieda Michiru M Horikoshi Ikuko I Iwakawa-Kawabata Reika R Yoshiyama Shinji S Yokobori Takehiko T Ohtaki Yoichi Y Shimizu Kimihiro K Oyama Tetsunari T Tamura Jun'ichi J Prives Carol C Nishiyama Masahiko M

Clinical cancer research : an official journal of the American Association for Cancer Research 20170113 13

<b>Purpose:</b> Expression of the ΔN isoform of p63 (ΔNp63) is a diagnostic marker highly specific for lung squamous cell carcinoma (SCC). We previously found that Syntaxin Binding Protein 4 (STXBP4) regulates ΔNp63 ubiquitination, suggesting that STXBP4 may also be an SCC biomarker. To address this issue, we investigated the role of STXBP4 expression in SCC biology and the impact of STXBP4 expression on SCC prognosis.<b>Experimental Design:</b> We carried out a clinicopathologic analysis of STX ...[more]

PMID: 28087642

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Project description:Purpose: In a previous study, we found that transforming growth factor beta-induced (TGFBI) is a hub gene strongly associated with oral squamous cell carcinoma (OSCC), using gene chip meta-analysis and PPI network analysis. Thus, the present study was established to explore the role of TGFBI in the pathogenesis of OSCC and to define the underlying mechanisms. Methods: The correlations between TGFBI expression and the clinicopathological features and prognosis of OSCC were analyzed. Then, TGFBI-knockout HSC-3 cell lines were constructed using the CRISPR/Cas9 system. Cell proliferation, migration, and invasion in vitro were determined by cell counting, CCK-8, colony formation, and Transwell assays. Moreover, a xenograft animal study was implemented to determine the tumorigenicity and metastatic ability associated with TGFBI in vivo. The genes and pathways differentially expressed after TGFBI knockout were determined using transcriptional sequencing and bioinformatics. Results: TGFBI expression was significantly higher in OSCC than in normal tissue. Its high expression was also correlated with high stage and was predictive of poor prognosis, as we expected. Knockout of TGFBI inhibited cell proliferation and clone formation, and enhanced cell migration and invasion in vitro. Besides, the xenograft animal study showed that TGFBI knockout suppressed tumor growth and metastasis in vivo. Furthermore, transcriptome sequencing revealed that genes associated with cell proliferation, metastasis, and inflammatory responses exhibited a change of expression upon TGFBI knockout. GO and KEGG analyses indicated that the function of TGFBI is related to responses to bacteria and inflammatory responses. Conclusions: TGFBI overexpression can promote OSCC and is associated with poor prognosis in OSCC patients. TGFBI knockout can inhibit cell proliferation and metastasis in vivo. TGFBI may alter cell responses to bacteria, which causes an imbalance in the immune inflammatory response and promotes the development of OSCC.

Dataset Information

STXBP4 Drives Tumor Growth and Is Associated with Poor Prognosis through PDGF Receptor Signaling in Lung Squamous Cell Carcinoma.

Publications

STXBP4 Drives Tumor Growth and Is Associated with Poor Prognosis through PDGF Receptor Signaling in Lung Squamous Cell Carcinoma.

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