Wu Geyan, Liu Aibin, Zhu Jinrong, Lei Fangyong, Wu Shu, Zhang Xin, Ye Liping, Cao Lixue, He Shanyang
Department of Obstetrics and Gynecology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510700, PR China.
State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China.
Oncotarget. 2015 Oct 6;6(30):28882-94. doi: 10.18632/oncotarget.4921.
Wnt/β-catenin signaling pathway is strictly controlled by multiple negative regulators. However, how tumor cells override the negative regulatory effects to maintain constitutive activation of Wnt/β-catenin signaling, which is commonly observed in various cancers, remains puzzling. In current study, we reported that overexpression of miR-1207 in ovarian cancer activated Wnt/β-catenin signaling by directly targeting and suppressing secreted Frizzled-related protein 1 (SFRP1), AXIN2 and inhibitor of β-catenin and TCF-4 (ICAT), which are vital negative regulators of the Wnt/β-catenin pathway. We found that the expression of miR-1207 was ubiquitously upregulated in both ovarian cancer tissues and cells, which inversely correlated with patient overall survival. Furthermore, overexpression of miR-1207 enhanced, while silencing miR-1207 reduced, stem cell-like traits of ovarian cancer cells in vitro and in vivo, including tumor sphere formation capability and proportion of SP+ and CD133+ cells. Importantly, upregulating miR-1207 promoted, while silencing miR-1207 inhibited, the tumorigenicity of ovarian cancer cells. Hence, our results suggest that miR-1207 plays a vital role in promoting the cancer stem cell-like phenotype in ovarian cancer and might represent a potential target for anti-ovarian cancer therapy.
Wnt/β-连环蛋白信号通路受到多种负调控因子的严格控制。然而,肿瘤细胞如何克服负调控作用以维持Wnt/β-连环蛋白信号通路的组成性激活,这在各种癌症中普遍存在,仍然是一个谜。在本研究中,我们报道卵巢癌中miR-1207的过表达通过直接靶向并抑制分泌型卷曲相关蛋白1(SFRP1)、AXIN2以及β-连环蛋白和TCF-4抑制剂(ICAT)来激活Wnt/β-连环蛋白信号通路,这些都是Wnt/β-连环蛋白通路至关重要的负调控因子。我们发现miR-1207在卵巢癌组织和细胞中均普遍上调,且与患者总生存期呈负相关。此外,miR-1207的过表达增强了卵巢癌细胞在体外和体内的干细胞样特性,包括肿瘤球形成能力以及SP+和CD133+细胞的比例,而沉默miR-1207则降低了这些特性。重要的是,上调miR-1207促进了卵巢癌细胞的致瘤性,而沉默miR-1207则抑制了其致瘤性。因此,我们的结果表明miR-1207在促进卵巢癌的癌干细胞样表型中起着至关重要的作用,可能是抗卵巢癌治疗的一个潜在靶点。