MUC1-C Induces the LIN28B→LET-7→HMGA2 Axis to Regulate Self-Renewal in NSCLC.
MUC1-C Induces the LIN28B→LET-7→HMGA2 Axis to Regulate Self-Renewal in NSCLC.
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DOI：
10.1158/1541-7786.mcr-14-0363
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发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Kufe D
中科院分区：
文献类型：
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作者：
Alam M;Ahmad R;Rajabi H;Kufe D
LIN 28 B →let-7通路有助于调节上皮-间充质转化（EMT）和干细胞自我更新。致癌MUC 1-C跨膜蛋白在肺癌和其他癌症中异常过表达;然而，MUC 1-C和LIN 28 B →let-7通路之间没有已知的关联。在非小细胞肺癌（NSCLC）中，沉默MUC 1-C下调RNA结合蛋白LIN 28 B并协调增加miRNA let-7。用显性阴性突变体或肽抑制剂靶向MUC 1-C功能提供了MUC 1-C诱导LIN 28 B →let-7信号传导的确认证据。从机制上讲，MUC 1-C促进NF-κB p65染色质占据LIN 28 B第一内含子，并激活LIN 28 B转录，这与let-7的抑制有关。与let-7介导的HMGA 2转录物抑制一致，MUC 1-C的靶向也降低了HMGA 2的表达。HMGA 2与干性相关，并作为let-7介导的TGFβ共受体TGFBR 3调节的竞争性内源性RNA（ceRNA）发挥作用。因此，靶向MUC 1-C抑制HMGA 2 mRNA和蛋白，这与TGFBR 3的减少、EMT表型的逆转和自我更新能力的抑制相关。这些发现支持了一个模型，其中MUC 1-C激活NSCLC中的EMT 28 B → EMT-7→ EMT HMGA 2轴，从而促进EMT性状和干性。
The LIN28B→let-7 pathway contributes to regulation of the epithelial-mesenchymal transition (EMT) and stem cell self-renewal. The oncogenic MUC1-C transmembrane protein is aberrantly overexpressed in lung and other carcinomas; however, there is no known association between MUC1-C and the LIN28B→let-7 pathway. Here in non-small cell lung cancer (NSCLC), silencing MUC1-C downregulates the RNA binding protein LIN28B and coordinately increases the miRNA let-7. Targeting MUC1-C function with a dominant-negative mutant or a peptide inhibitor provided confirming evidence that MUC1-C induces LIN28B→let-7 signaling. Mechanistically, MUC1-C promotes NF-κB p65 chromatin occupancy of the LIN28B first intron and activates LIN28B transcription, which is associated with suppression of let-7. Consistent with let-7-mediated inhibition of HMGA2 transcripts, targeting of MUC1-C also decreases HMGA2 expression. HMGA2 has been linked to stemness, and functions as a competing endogenous RNA (ceRNA) of let-7-mediated regulation of the TGFβ co-receptor TGFBR3. Accordingly, targeting MUC1-C suppresses HMGA2 mRNA and protein, which is associated with decreases in TGFBR3, reversal of the EMT phenotype and inhibition of self-renewal capacity. These findings support a model in which MUC1-C activates the ⇑LIN28B→⇓let-7→⇑HMGA2 axis in NSCLC and thereby promotes EMT traits and stemness.