Yu Dayeon, Shin Hyun-Soo, Lee Yeo Song, Lee Yong Chan
1] Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea [2] Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
1] Division of Nephrology, Department of Internal Medicine, Ewha Medical Research Center, Seoul, Korea [2] Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Korea.
Lab Invest. 2014 Dec;94(12):1370-81. doi: 10.1038/labinvest.2014.125. Epub 2014 Oct 6.
Cancer stem cells have the capacity to form new tumors and are thus considered to be a cause of metastasis and tumor recurrence. However, many of the mechanisms determining cancer stem cell characteristics are still unknown. MicroRNAs (miRNAs) are possible modulators of cancer stem cell generation and may be involved in the retention of cancer stem cell characteristics. The aim of this study was to examine the miRNA expression profiles regulating the cancer stem-like cell characteristics in gastric cancer. We sorted gastric cancer stem-like cells using the stem cell marker CD44 by fluorescence-activated cell sorting. CD44(+) cells formed more and larger spheres compared with CD44(-) cells. Cancer stem cell markers were overexpressed in CD44(+) cells. CD44(+) cells showed increased expression of mesenchymal cell markers, whereas epithelial markers were downregulated. In miRNA microarray, the miR-106b family comprising miR-106b, miR-93, and miR-25 was significantly upregulated in CD44(+) cells than in CD44(-) cells. Smad7, which inhibits transforming growth factor-β (TGF-β)/Smad signaling as a target of the miR-106b family, was downregulated in CD44(+) cells. Furthermore, expression of TGF-β/Smad signal molecules was activated in CD44(+) cells, in accordance with the action of the miR-106b family. Inhibition of miR-106b showed suppression of the TGF-β/Smad signaling pathway and decreased self-renewal capacity and cell invasiveness. Our study suggests that CD44(+) gastric cancer cells show cancer stem cell properties with epithelial-mesenchymal transition (EMT). Increased miR-106b family expression regulated cancer stem-like cell properties, particularly EMT characteristics, through the TGF-β/Smad signaling pathway in CD44(+) stem-like cells. Taken together, these results indicate that targeting miR-106b may be an effective form of cancer therapy in gastric cancer through the modulation of cancer stem cell characteristics.
癌症干细胞具有形成新肿瘤的能力，因此被认为是转移和肿瘤复发的一个原因。然而，许多决定癌症干细胞特性的机制仍然未知。微小RNA（miRNA）可能是癌症干细胞生成的调节因子，并且可能参与癌症干细胞特性的维持。本研究的目的是检测调节胃癌中癌症干细胞样细胞特性的miRNA表达谱。我们通过荧光激活细胞分选术使用干细胞标志物CD44对胃癌干细胞样细胞进行分选。与CD44（-）细胞相比，CD44（+）细胞形成更多更大的球体。癌症干细胞标志物在CD44（+）细胞中过表达。CD44（+）细胞中间充质细胞标志物的表达增加，而上皮标志物下调。在miRNA微阵列中，由miR-106b、miR-93和miR-25组成的miR-106b家族在CD44（+）细胞中比在CD44（-）细胞中显著上调。作为miR-106b家族靶点的抑制转化生长因子-β（TGF-β）/Smad信号的Smad7在CD44（+）细胞中下调。此外，根据miR-106b家族的作用，TGF-β/Smad信号分子的表达在CD44（+）细胞中被激活。抑制miR-106b显示TGF-β/Smad信号通路受到抑制，自我更新能力和细胞侵袭性降低。我们的研究表明，CD44（+）胃癌细胞表现出具有上皮-间质转化（EMT）的癌症干细胞特性。miR-106b家族表达的增加通过CD44（+）干细胞样细胞中的TGF-β/Smad信号通路调节癌症干细胞样细胞特性，特别是EMT特性。综上所述，这些结果表明，通过调节癌症干细胞特性，靶向miR-106b可能是胃癌治疗的一种有效形式。
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