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大学・研究所にある論文を検索できる 「Distinctive roles of syntaxin binding protein 4 and its action target, TP63, in lung squamous cell carcinoma: a theranostic study for the precision medicine」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。
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Distinctive roles of syntaxin binding protein 4 and its action target, TP63, in lung squamous cell carcinoma: a theranostic study for the precision medicine

Bilguun, Erkhem-Ochir ビルグン, エルヘム オチル 群馬大学

2021.03.23

概要

Background:
Despite recent advances in therapeutics, lung squamous cell carcinoma (LSCC) remainsa challenging disease to treat. The advent of immune-checkpoint inhibitors along with severalactive target agents such as antiangiogenic agents has altered LSCC treatment to some extent,but treatment options remain limited. To date, very few druggable mutations and active predictive biomarkers have been identified; thus, no LSCC-specific target therapy has yet been established. The development of precision medicine with truly active target drugs is eagerly awaited.We previously found that Syntaxin Binding Protein 4 (STXBP4) plays a crucial role inlesion growth and, therefore, clinical outcomes in LSCC patients through regulation of tumorprotein p63 (TP63) ubiquitination. ΔNp63 is an isoform of TP63, a member of the TP53 family,and its expression is widely used as a highly specific diagnostic marker for LSCC. STXBP4 binds to ΔNp63 and suppresses the anaphase-promoting complex/cyclosome (APC/C) complex-mediatedproteolysis of ΔNp63, and drives the oncogenic potential of ΔNp63α. STXBP4 may be a usefultherapeutic target and/or marker for patients with LSCC.
　
Methods:
To clarify the impact of STXBP4 and TP63 for LSCC therapeutics, we assessed relevanceof these proteins to outcome of 144 LSCC patients at Gunma University Hospital from April 2001to December 2014.In addition, we examined whether its action pathway is distinct from those of currently useddrugs in in vitro experiments including RNA-seq analysis through comparison with the otherputative exploratory targets and/or markers including VEGFR2 (vascular endothelial growthfactor receptor 2), TUBB3 (tubulin beta 3), and PD-L1 (programmed cell death 1 ligand 1),along with p53 (tumor protein p53), ΔNp63 and STMN1 (stathmin 1).
　
Results:
Kaplan– Meier analysis revealed that, along with vascular endothelial growth factor receptor 2 (VEGFR2), STXBP4 expression signified a worse prognosis in LSCC patients, both in terms ofoverall survival (OS, p = 0.002) and disease-free survival (DFS, p = 0.041). These prognosticimpacts of STXBP4 were confirmed in univariate Cox regression analysis, but not in the multivariateanalysis. Whereas, TP63 (ΔNp63) closely related to OS (p = 0.013), and shown to be an independentprognostic factor for poor OS in the multivariate analysis (p = 0.0324). The action pathway ofSTXBP4 on suppression of TP63 (ΔNp63) was unique: Ingenuity pathway analysis using the knowledgedatabase and our RNAseq analysis in human LSCC cell lines indicated that 35 pathways were activatedor inactivated in association with STXBP4, but the action pathway of STXBP4 was distinct from thoseof other current drug targets: STXBP4, TP63 and KDR (VEGFR2 gene) formed a cluster independent fromother target genes of tumor protein p53 (TP53), tubulin beta 3 (TUBB3), stathmin 1 (STMN1) andcluster of differentiation 274 (CD274: programmed cell death 1 ligand 1, PD-L1). STXBP4 itselfappeared not to be a potent predictive marker of individual drug response, but we found that TP63,main action target of STXBP4, might be involved in drug resistance mechanisms of LSCC.
　
Conclusion:
STXBP4 and the action target, TP63, could afford a key to the development of precision medicine for LSCC patients.

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