title: STXBP4 Drives Tumor Growth and Is Associated with Poor Prognosis through PDGF Receptor Signaling in Lung Squamous Cell Carcinoma.
abstract: Purpose: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.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 ΔNp63 in clinical lung SCC specimens (Spearman rank correlationρ= 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 (PDGFRα) was a key downstream mediator of STXBP4 function. In line with this, shRNA mediatedSTXBP4andPDGFRAknockdown 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.
authors.affiliation: Department of Molecular Pharmacology and Oncology, Gunma University, Gunma, Japan.|Department of General Medicine, Gunma University, Gunma, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Otaka
authors.affiliation: Department of Molecular Pharmacology and Oncology, Gunma University, Gunma, Japan.|Department of Biological Sciences, Columbia University, NY, USA.
authors.forename: Susumu
authors.initials: S
authors.lastname: Rokudai
authors.affiliation: Department of Oncology Clinical Development, Gunma University, Gunma, Japan.
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Kaira
authors.affiliation: Department of Molecular Pharmacology and Oncology, Gunma University, Gunma, Japan.
authors.forename: Michiru
authors.initials: M
authors.lastname: Fujieda
authors.affiliation: Department of Molecular Pharmacology and Oncology, Gunma University, Gunma, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Horikoshi
authors.affiliation: Department of Molecular Pharmacology and Oncology, Gunma University, Gunma, Japan.|Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Gunma, Japan.
authors.forename: Reika
authors.initials: R
authors.lastname: Iwakawa-Kawabata
authors.affiliation: Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Gunma, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Yoshiyama
authors.affiliation: Department of Molecular Pharmacology and Oncology, Gunma University, Gunma, Japan.|Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Gunma, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokobori
authors.affiliation: Department of Thoracic Visceral Organ Surgery, Gunma University, Gunma, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ohtaki
authors.affiliation: Department of Thoracic Visceral Organ Surgery, Gunma University, Gunma, Japan.
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Department of Pathology, Gunma University, Gunma, Japan.
authors.forename: Tetsunari
authors.initials: T
authors.lastname: Oyama
authors.affiliation: Department of General Medicine, Gunma University, Gunma, Japan.
authors.forename: Jun'ichi
authors.initials: J
authors.lastname: Tamura
authors.affiliation: Department of Biological Sciences, Columbia University, NY, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Prives
authors.affiliation: Department of Molecular Pharmacology and Oncology, Gunma University, Gunma, Japan.|Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Gunma, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nishiyama
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D011379:Prognosis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C498469:STXBP4 protein, human; D033921:Vesicular Transport Proteins; D020796:Receptor, Platelet-Derived Growth Factor alpha