Lin28B/Let-7 Regulates Expression of Oct4 and Sox2 and Reprograms Oral Squamous Cell Carcinoma Cells to a Stem-like State
Lin28B/Let-7 Regulates Expression of Oct4 and Sox2 and Reprograms Oral Squamous Cell Carcinoma Cells to a Stem-like State
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DOI：
10.1158/0008-5472.can-14-2215
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发表时间：
2015-06-15
期刊：
影响因子：
11.2
通讯作者：
Chiou, Shih-Hwa
中科院分区：
文献类型：
--
作者：
Chien, Chian-Shiu;Wang, Mong-Lien;Chiou, Shih-Hwa
Lin 28是细胞重编程和诱导多能干细胞（iPSC）生成的关键因子，通过抑制Let-7对致瘤性做出关键贡献。然而，目前尚不清楚Lin 28是否参与调节癌症干细胞样细胞（CSC），包括口腔鳞状细胞癌细胞（OSCC）。在这项研究中，我们证明了高水平的Lin 28 B，Oct 4和Sox 2与高百分比的CD 44（+）ALDH 1（+）CSC在OSCC中的相关性。在CD 44（+）ALDH 1（+）/OSCC细胞中，Lin 28 B的异位表达足以增强Oct 4/Sox 2的表达和CSC的特性，而Let 7的共过表达有效地逆转了这些现象。我们鉴定了ARID 3B和HMGA 2作为Lin 28 B/Let 7信号传导的下游效应子，调节内源性Oct 4和Sox 2表达。Let 7靶向ARID 3B和HMGA 2的3'非翻译区并抑制它们的表达，而ARID 3B和HMGA 2通过启动子结合分别增加Oct 4和Sox 2的转录。染色质免疫沉淀分析揭示了ARID 3B和Oct 4启动子中的特定ARID 3B结合序列之间的直接关联。值得注意的是，通过调节Oct 4/Sox 2的表达，Lin 28 B-Let 7通路不仅调节了OSCC中的干细胞特性，而且还决定了正常人口腔角质形成细胞重编程为iPSC的效率。临床上，Lin 28 B（高）-Let 7（低）表达模式与OSCC标本中ARID 3B、HMGA 2、OCT 4和SOX 2的高水平表达高度相关。总之，我们的研究结果显示了Lin 28 B/Let 7如何调节口腔鳞状细胞癌中关键的癌干细胞样特性。(C)2015年AACR。
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, bymodulating 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. (C) 2015 AACR.