title: Lin28B/Let-7 Regulates Expression of Oct4 and Sox2 and Reprograms Oral Squamous Cell Carcinoma Cells to a Stem-like State.
abstract: Lin28, a key factor for cellular reprogramming and generation of induced pluripotent stem cell (iPSC), makes a critical contribution to tumorigenicity by suppressing Let-7. However, it is unclear whether Lin28 is involved in regulating cancer stem-like cells (CSC), including in oral squamous carcinoma cells (OSCC). In this study, we demonstrate a correlation between high levels of Lin28B, Oct4, and Sox2, and a high percentage of CD44(+)ALDH1(+) CSC in OSCC. Ectopic Lin28B expression in CD44(-)ALDH1(-)/OSCC cells was sufficient to enhance Oct4/Sox2 expression and CSC properties, whereas Let7 co-overexpression effectively reversed these phenomena. We identified ARID3B and HMGA2 as downstream effectors of Lin28B/Let7 signaling in regulating endogenous Oct4 and Sox2 expression. Let7 targeted the 3' untranslated region of ARID3B and HMGA2 and suppressed their expression, whereas ARID3B and HMGA2 increased the transcription of Oct4 and Sox2, respectively, through promoter binding. Chromatin immunoprecipitation assays revealed a direct association between ARID3B and a specific ARID3B-binding sequence in the Oct4 promoter. Notably, by modulating Oct4/Sox2 expression, the Lin28B-Let7 pathway not only regulated stemness properties in OSCC but also determined the efficiency by which normal human oral keratinocytes could be reprogrammed to iPSC. Clinically, a Lin28B(high)-Let7(low) expression pattern was highly correlated with high levels of ARID3B, HMGA2, OCT4, and SOX2 expression in OSCC specimens. Taken together, our results show how Lin28B/Let7 regulates key cancer stem-like properties in oral squamous cancers.
authors: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan.
authors: Chian-Shiu
authors: CS
authors: Chien
authors: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors: Mong-Lien
authors: ML
authors: Wang
authors: School of Medicine, National Yang-Ming University, Taipei, Taiwan. Laryngology and Head and Neck Surgery, Department of Otolaryngology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Pen-Yuan
authors: PY
authors: Chu
authors: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan. Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Yuh-Lih
authors: YL
authors: Chang
authors: Graduate Institute of Medical Sciences, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan.
authors: Wei-Hsiu
authors: WH
authors: Liu
authors: Institute of Oral Science, School of Dentistry & Oral Medicine Research Center, Chung Shan Medical University, Taipei, Taiwan.
authors: Cheng-Chia
authors: CC
authors: Yu
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Yuan-Tzu
authors: YT
authors: Lan
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Pin-I
authors: PI
authors: Huang
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Yi-Yen
authors: YY
authors: Lee
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Yi-Wei
authors: YW
authors: Chen
authors: Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan. Division of Oral and Maxillofacial Surgery, Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan. shchiou@vghtpe.gov.tw wllo@vghtpe.gov.tw.
authors: Wen-Liang
authors: WL
authors: Lo
authors: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. School of Medicine, National Yang-Ming University, Taipei, Taiwan. Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan. Genomics Research Center, Academia Sinica, Taipei, Taiwan. shchiou@vghtpe.gov.tw wllo@vghtpe.gov.tw.
authors: Shih-Hwa
authors: SH
authors: Chiou
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis* / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: C516326:LIN28B protein, human; D035683:MicroRNAs; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016601:RNA-Binding Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C487931:mirnlet7 microRNA, human