Lin28B/Let-7 Regulates Expression of Oct4 and Sox2 and Reprograms Oral Squamous Cell Carcinoma Cells to a Stem-like State

林28 SOX2 异位表达 癌症研究 生物 癌症干细胞 染色质免疫沉淀 转录因子 干细胞 诱导多能干细胞 同源盒蛋白纳米 重编程 胚胎干细胞 HMGA2型 CD44细胞 细胞生物学 发起人 细胞 小RNA 基因表达 遗传学 基因
作者
Chian‐Shiu Chien,Mong‐Lien Wang,Pen‐Yuan Chu,Yuh-Lih Chang,Wei‐Hsiu Liu,Cheng-Chia Yu,Yuan‐Tzu Lan,Pin‐I Huang,Yi‐Yen Lee,Yi‐Wei Chen,Wen‐Liang Lo,Shih-Hwa Chiou
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:75 (12): 2553-2565 被引量:124
标识
DOI:10.1158/0008-5472.can-14-2215
摘要

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.
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