title: B-cell lymphoma/leukemia 10 promotes oral cancer progression through STAT1/ATF4/S100P signaling pathway.
abstract: B-cell lymphoma/leukemia 10 (BCL10) is an apoptotic regulatory protein related to advanced TNM stage and disease recurrence in oral squamous cell carcinoma (OSCC). However, the regulatory mechanism of BCL10 in OSCC progression is still unknown. Here, we showed that knockdown of endogenous BCL10 could significantly reduce cell migration and invasion abilities, retard cell proliferation by G0/G1 phase accumulation and inhibit tumorigenicity in vivo. In molecular level, we identified S100P as a crucial downstream effector of BCL10-inhibited OSCC progression by high-throughput microarray analysis. S100P messenger RNA and protein expression levels were significantly diminished in silenced-BCL10 clones, and transfected S100P expression plasmids restored migration, invasion, proliferation abilities and tumorigenicity in shBCL10 transfectants. Furthermore, we provided evidence that BCL10 regulated S100P expression through signal transducers and activators of transcription 1 (STAT1) and activating transcription factor 4 (ATF4). Knockdown of BCL10 decreased S100P promoter activity, but showed no effect in truncated STAT1/ATF4 S100P promoter.  In addition, we also found that the P50/P65 signaling pathway was involved in BCL10-enhanced OSCC progression. Restored S100P in silenced-BCL10 clones could markedly reverse P65 activation via outside-in signaling. Taken together, we discovered a novel axis of BCL10-regulated OSCC progression via STAT1/ATF4/S100P/P65 signaling, which could predict the prognosis of OSCC and will be beneficial for developing therapeutic strategy against advanced OSCC.
authors.affiliation: Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan.
authors.forename: T-S
authors.initials: TS
authors.lastname: Wu
authors.affiliation: Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: C-T
authors.initials: CT
authors.lastname: Tan
authors.affiliation: Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan.
authors.forename: C-C
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: B-R
authors.initials: BR
authors.lastname: Lin
authors.affiliation: Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan.
authors.forename: W-T
authors.initials: WT
authors.lastname: Lai
authors.affiliation: 1] Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan [2] Department of Pediatrics, National Taiwan University Hospital YunLin Branch, Taipei, Taiwan.
authors.forename: S-T
authors.initials: ST
authors.lastname: Chen
authors.affiliation: Department of Dentistry and Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.
authors.forename: M Yen-Ping
authors.initials: MY
authors.lastname: Kuo
authors.affiliation: 1] Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan [2] Department of Physical Medicine and Rehabilitation, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: C-L
authors.initials: CL
authors.lastname: Rau
authors.affiliation: Institute of Biomedical Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: F-S
authors.initials: FS
authors.lastname: Jaw
authors.affiliation: Department of Dentistry and Graduate Institute of Clinical Dentistry, School of Dentistry, National Taiwan University, Taipei, Taiwan.
authors.forename: H-H
authors.initials: HH
authors.lastname: Chang
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D001665:Binding Sites; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D051379:Mice; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D011379:Prognosis; D011485:Protein Binding; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D002135:Calcium-Binding Proteins; D009363:Neoplasm Proteins; C103003:S100P protein, human; D050794:STAT1 Transcription Factor; D051701:Activating Transcription Factor 4