Epithelialization of mouse ovarian tumor cells originating in the fallopian tube stroma.
Epithelialization of mouse ovarian tumor cells originating in the fallopian tube stroma.
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DOI：
10.18632/oncotarget.11808
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发表时间：
2016-10-04
期刊：
影响因子：
--
通讯作者：
Ng SW
中科院分区：
文献类型：
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作者：
Hua Y;Choi PW;Trachtenberg AJ;Ng AC;Kuo WP;Ng SK;Dinulescu DM;Matzuk MM;Berkowitz RS;Ng SW
上皮性卵巢癌占所有卵巢癌的90%，是最致命的妇科恶性肿瘤。最近的研究表明，输卵管伞可能是高级别浆液性上皮性卵巢癌（HGSOC）的细胞来源。具有条件性Dicer-Pten双敲除（Dicer-Pten DKO）的小鼠HGSOC模型有趣地从输卵管基质发展原发性肿瘤。我们检查了由每个基因敲除贡献的Dicer-Pten DKO小鼠肿瘤细胞的生长和上皮表型。与表达全长E-cadherin的人卵巢上皮癌细胞不同，Dicer-Pten DKO间质瘤细胞表达切割的E-cadherin片段和金属蛋白酶2，一种上皮和间充质标志物的混合物。尽管Dicer-Pten DKO肿瘤细胞如预期的那样失去了成熟microRNA的表达，但由于PTEN功能的丧失，它们显示出高水平的tRNA片段表达和增强的AKT活化。将Dicer 1表达构建体引入DKO小鼠肿瘤细胞中显著降低了DNA合成和细胞生长速率，同时减少了粘附和ZO 1上皮染色。因此，很可能Dicer的缺失促进了输卵管基质细胞中的间充质-上皮转化，并且与Pten缺失一起，进一步促进了细胞增殖和上皮样肿瘤发生。
Epithelial ovarian carcinoma accounts for 90% of all ovarian cancer and is the most deadly gynecologic malignancy. Recent studies have suggested that fallopian tube fimbriae can be the origin of cells for high-grade serous subtype of epithelial ovarian carcinoma (HGSOC). A mouse HGSOC model with conditional Dicer-Pten double knockout (Dicer-Pten DKO) developed primary tumors, intriguingly, from the fallopian tube stroma. We examined the growth and epithelial phenotypes of the Dicer-Pten DKO mouse tumor cells contributable by each gene knockout. Unlike human ovarian epithelial cancer cells that expressed full-length E-cadherin, the Dicer-Pten DKO stromal tumor cells expressed cleaved E-cadherin fragments and metalloproteinase 2, a mixture of epithelial and mesenchymal markers. Although the Dicer-Pten DKO tumor cells lost the expression of mature microRNAs as expected, they showed high levels of tRNA fragment expression and enhanced AKT activation due to the loss of PTEN function. Introduction of a Dicer1-expressing construct into the DKO mouse tumor cells significantly reduced DNA synthesis and the cell growth rate, with concurrent diminished adhesion and ZO1 epithelial staining. Hence, it is likely that the loss of Dicer promoted mesenchymal-epithelial transition in fallopian tube stromal cells, and in conjunction with Pten loss, further promoted cell proliferation and epithelial-like tumorigenesis.