PMID- 32993587
OWN - NLM
STAT- MEDLINE
DCOM- 20210414
LR  - 20210414
IS  - 1471-2407 (Electronic)
IS  - 1471-2407 (Linking)
VI  - 20
IP  - 1
DP  - 2020 Sep 29
TI  - Distinctive roles of syntaxin binding protein 4 and its action target, TP63, in 
      lung squamous cell carcinoma: a theranostic study for the precision medicine.
PG  - 935
LID - 10.1186/s12885-020-07448-2 [doi]
LID - 935
AB  - BACKGROUND: Lung squamous cell carcinoma (LSCC) remains a challenging disease to 
      treat, and further improvements in prognosis are dependent upon the 
      identification of LSCC-specific therapeutic biomarkers and/or targets. We 
      previously found that Syntaxin Binding Protein 4 (STXBP4) plays a crucial role in 
      lesion growth and, therefore, clinical outcomes in LSCC patients through 
      regulation of tumor protein p63 (TP63) ubiquitination. METHODS: To clarify the 
      impact of STXBP4 and TP63 for LSCC therapeutics, we assessed relevance of these 
      proteins to outcome of 144 LSCC patients and examined whether its action pathway 
      is distinct from those of currently used drugs in in vitro experiments including 
      RNA-seq analysis through comparison with the other putative exploratory targets 
      and/or markers. 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 of overall survival (OS, 
      p = 0.002) and disease-free survival (DFS, p = 0.041). These prognostic impacts 
      of STXBP4 were confirmed in univariate Cox regression analysis, but not in the 
      multivariate analysis. Whereas, TP63 (DeltaNp63) closely related to OS (p = 0.013), 
      and shown to be an independent prognostic factor for poor OS in the multivariate 
      analysis (p = 0.0324). The action pathway of STXBP4 on suppression of TP63 
      (DeltaNp63) was unique: Ingenuity pathway analysis using the knowledge database and 
      our RNA-seq analysis in human LSCC cell lines indicated that 35 pathways were 
      activated or inactivated in association with STXBP4, but the action pathway of 
      STXBP4 was distinct from those of other current drug targets: STXBP4, TP63 and 
      KDR (VEGFR2 gene) formed a cluster independent from other target genes of tumor 
      protein p53 (TP53), tubulin beta 3 (TUBB3), stathmin 1 (STMN1) and cluster of 
      differentiation 274 (CD274: programmed cell death 1 ligand 1, PD-L1). STXBP4 
      itself appeared 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.
FAU - Bilguun, Erkhem-Ochir
AU  - Bilguun EO
AD  - Department of General Surgical Science, Gunma University Graduate School of 
      Medicine, 3-9-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
AD  - Department of Molecular Pharmacology and Oncology, Gunma University Graduate 
      School of Medicine, 3-9-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
FAU - Kaira, Kyoichi
AU  - Kaira K
AD  - Department of Respiratory Medicine, Comprehensive Cancer Center, International 
      Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka-City, Saitama, 
      350-1298, Japan.
FAU - Kawabata-Iwakawa, Reika
AU  - Kawabata-Iwakawa R
AD  - Division of Integrated Oncology Research, Gunma University Initiative for 
      Advanced Research, 3-9-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
FAU - Rokudai, Susumu
AU  - Rokudai S
AD  - Department of Molecular Pharmacology and Oncology, Gunma University Graduate 
      School of Medicine, 3-9-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
FAU - Shimizu, Kimihiro
AU  - Shimizu K
AD  - Department of General Surgical Science, Gunma University Graduate School of 
      Medicine, 3-9-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
AD  - Department of Surgery, Division of General Thoracic Surgery, Shinshu University 
      Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
FAU - Yokobori, Takehiko
AU  - Yokobori T
AD  - Division of Integrated Oncology Research, Gunma University Initiative for 
      Advanced Research, 3-9-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
FAU - Oyama, Tetsunari
AU  - Oyama T
AD  - Department of Diagnostic Pathology, Gunma University Graduate School of Medicine, 
      3-9-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
FAU - Shirabe, Ken
AU  - Shirabe K
AD  - Department of General Surgical Science, Gunma University Graduate School of 
      Medicine, 3-9-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
FAU - Nishiyama, Masahiko
AU  - Nishiyama M
AUID- ORCID: 0000-0001-9731-7183
AD  - Gunma University, 3-9-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan. 
      m.nishiyama@gunma-u.ac.jp.
AD  - Higashi Sapporo Hospital, 7-35, 3-3 Higashi-Sapporo, Shiroishi-ku, Sapporo, 
      003-8585, Japan. m.nishiyama@gunma-u.ac.jp.
LA  - eng
GR  - 17K15038/Japan Society for the Promotion of Science/
GR  - Promotion Plan for the Platform of Human Resource Development for Cancer/Ministry 
      of Education, Culture, Sports, Science, and Technology (MEXT) of Japan/
GR  - Gunma University Initiative for Advanced Research/Ministry of Education, Culture, 
      Sports, Science, and Technology (MEXT) of Japan/
PT  - Journal Article
DEP - 20200929
PL  - England
TA  - BMC Cancer
JT  - BMC cancer
JID - 100967800
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (CKAP4 protein, human)
RN  - 0 (Membrane Proteins)
RN  - 0 (STXBP4 protein, human)
RN  - 0 (Vesicular Transport Proteins)
RN  - 15H5577CQD (Docetaxel)
RN  - EC 2.7.10.1 (KDR protein, human)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Aged
MH  - Aged, 80 and over
MH  - Biomarkers, Tumor/genetics
MH  - Carcinoma, Squamous Cell/*drug therapy/genetics/pathology
MH  - Cell Proliferation/drug effects
MH  - Cisplatin/administration & dosage
MH  - Disease-Free Survival
MH  - Docetaxel/administration & dosage
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Lung Neoplasms/*drug therapy/genetics/pathology
MH  - Male
MH  - Membrane Proteins/*genetics
MH  - Middle Aged
MH  - Precision Medicine
MH  - Prognosis
MH  - Vascular Endothelial Growth Factor Receptor-2/*genetics
MH  - Vesicular Transport Proteins/*genetics
PMC - PMC7526255
OTO - NOTNLM
OT  - Biomarker
OT  - Drug therapy
OT  - Lung squamous cell carcinoma
OT  - Molecular target
OT  - STXBP4
COIS- The authors declare that they have no competing interests.
EDAT- 2020/10/01 06:00
MHDA- 2021/04/15 06:00
PMCR- 2020/09/29
CRDT- 2020/09/30 05:46
PHST- 2020/06/27 00:00 [received]
PHST- 2020/09/21 00:00 [accepted]
PHST- 2020/09/30 05:46 [entrez]
PHST- 2020/10/01 06:00 [pubmed]
PHST- 2021/04/15 06:00 [medline]
PHST- 2020/09/29 00:00 [pmc-release]
AID - 10.1186/s12885-020-07448-2 [pii]
AID - 7448 [pii]
AID - 10.1186/s12885-020-07448-2 [doi]
PST - epublish
SO  - BMC Cancer. 2020 Sep 29;20(1):935. doi: 10.1186/s12885-020-07448-2.