Department of Obstetrics and Gynecology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan.
Int J Oncol. 2014 Mar;44(3):669-77. doi: 10.3892/ijo.2013.2230. Epub 2013 Dec 23.
A small subset of cells with CD133 expression is thought to have increased chemoresistance and tumorigenicity, features of cancer stem cells (CSCs); the molecular mechanisms by which these properties arise remain unclear. We characterized CD133+ endometrial cancer cells based on microarray analyses of Ishikawa cells. Of the genes upregulated in CD133+ cells compared with CD133- cells, we noted several key factors involved in the aggressive behavior of cells, including ABCG2 and matrix metalloproteinase (MMP). Flow cytometric analyses identified a side-cell population (SP) with CSC features in Ishikawa cells, and they were found to be more enriched in CD133+ cells than CD133- cells. In particular, CD133+/SP cells exhibited higher proliferative and colony‑forming activity than CD133+/non-SP cells. Matrigel invasion assay revealed that CD133+ cells have enhanced invasive capacity with elevated MT1-MMP expression. siRNA‑based knockdown of MT1-MMP largely abolished the invasive capacity of CD133+ cells, but not CD133- cells due to low levels of constitutive MT1-MMP1 expression. These findings demonstrate that increased chemoresistance and tumorigenic potential of CD133+ cells are at least partly attributed to an enriched SP fraction as well as increased MMP-1 expression. These results will be of assistance in the establishment of molecular target therapy to CSCs in endometrial cancer.
一小部分具有 CD133 表达的细胞被认为具有增加的化疗耐药性和致瘤性，这些特性是癌症干细胞（CSC）的特征；这些特性产生的分子机制尚不清楚。我们基于 Ishikawa 细胞的基因表达谱分析，对具有 CD133 表达的子宫内膜癌细胞进行了特征描述。与 CD133-细胞相比，在 CD133+细胞中上调的基因中，我们注意到了几个涉及细胞侵袭行为的关键因子，包括 ABCG2 和基质金属蛋白酶（MMP）。流式细胞术分析鉴定出 Ishikawa 细胞中具有 CSC 特征的侧细胞群（SP），并且它们在 CD133+细胞中比 CD133-细胞更为丰富。特别是，CD133+/SP 细胞表现出比 CD133+/非-SP 细胞更高的增殖和集落形成活性。Matrigel 侵袭实验表明，CD133+细胞具有增强的侵袭能力，并且 MT1-MMP 表达升高。基于 siRNA 的 MT1-MMP 敲低在很大程度上消除了 CD133+细胞的侵袭能力，但由于 MT1-MMP1 的组成型表达水平较低，CD133-细胞不受影响。这些发现表明，CD133+细胞增加的化疗耐药性和致瘤潜能至少部分归因于富集的 SP 亚群以及 MMP-1 表达增加。这些结果将有助于建立针对子宫内膜癌 CSC 的分子靶向治疗。
