miR‑196a‑5p modulates gastric cancer stem cell characteristics by targeting Smad4.
miR‑196a‑5p modulates gastric cancer stem cell characteristics by targeting Smad4.
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miR-196a-5p通过靶向Smad4调节胃癌干细胞特性
DOI：
10.3892/ijo.2017.3965
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发表时间：
2017-06
影响因子：
5.2
通讯作者：
Ran Y
中科院分区：
文献类型：
--
作者：
Pan Y;Shu X;Sun L;Yu L;Sun L;Yang Z;Ran Y
癌症干细胞（CSC）是未分化的癌细胞，具有高致瘤活性、自我更新能力和多谱系分化潜力。临床证据表明肿瘤块中的CSC是促进癌症侵袭和转移的细胞决定因素。 MicroRNA (miRNA) 已成为癌症干细胞特征的重要调节剂。揭示调节 CSC 的候选 miRNA 可能会提供新的癌症治疗靶点。我们分析了调节胃癌干细胞样细胞特征的 miRNA 表达谱。使用干细胞标记 CD44 通过荧光激活细胞分选对胃癌干细胞 (GCSC) 进行分选。功能研究表明，CD44(+)细胞比CD44(-)细胞形成更多的球形集落，并表现出更高的侵袭性。 miRNA微阵列分析显示，与CD44(-)细胞相比，CD44(+)细胞中miR-196a-5p的表达显着上调。抑制 miR-196a-5p 导致 GCSC 集落形成和侵袭减少。 miR-196a-5p 通过靶向 mRNA 的 3'-UTR 来降低 Smad4 的表达。胃癌组织中Smad4的表达与肿瘤的分化状态、TNM分期、浸润深度相关。 Smad4 的过度表达消除了癌症干细胞样细胞中 miR-196a-5p 对上皮间质转化 (EMT) 的刺激。总的来说，这些数据表明 miR-196a-5p 通过靶向 GCSC 中的 Smad4 在 EMT 和侵袭中发挥关键作用。 miR-196a-5p可能作为胃癌治疗的潜在靶点。
Cancer stem cells (CSCs) are undifferentiated cancer cells with a high tumorigenic activity, the ability to undergo self-renewal, and a multilineage differentiation potential. Clinical evidence suggests that CSCs in a tumor mass are the cellular determinants to promote cancer invasion and metastasis. MicroRNAs (miRNAs) have emerged as important modulators of cancer stem cell characteristics. Unveiling the candidate miRNAs that regulate CSCs may provide novel therapeutic targets against cancer. We analyzed the miRNA expression profiles regulating the cancer stem-like cell characteristics in gastric cancer. Gastric cancer stem cells (GCSCs) were sorted using the stem cell marker CD44 by fluorescence-activated cell sorting. Functional studies revealed that CD44(+) cells formed more sphere colonies and showed higher invasiveness than CD44(−) cells. miRNA microarray analysis revealed that miR-196a-5p was significantly upregulated in CD44(+) cells than CD44(−) cells. Suppression of miR-196a-5p led to decreased colony formation and invasion of GCSCs. miR-196a-5p decreased the expression of Smad4 by targeting 3′-UTR of the mRNA. The expression of Smad4 in gastric cancer tissues was correlated with differentiation state of tumors, TNM stage and depth of invasion. The stimulation of epithelial-mesenchymal transition (EMT) by miR-196a-5p in cancer stem-like cells was abolished by overexpression of Smad4. Collectively, these data demonstrate that miR-196a-5p has a key role in EMT and invasion by targeting Smad4 in GCSCs. miR-196a-5p may serve as a potential target for gastric cancer therapy.