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MiR-1207过表达通过激活Wnt/β-连环蛋白信号通路促进卵巢癌中癌干细胞样特性。

MiR-1207 overexpression promotes cancer stem cell-like traits in ovarian cancer by activating the Wnt/β-catenin signaling pathway.

作者信息

Wu Geyan, Liu Aibin, Zhu Jinrong, Lei Fangyong, Wu Shu, Zhang Xin, Ye Liping, Cao Lixue, He Shanyang

机构信息

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.

出版信息

Oncotarget. 2015 Oct 6;6(30):28882-94. doi: 10.18632/oncotarget.4921.

Abstract

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.

摘要

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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a76/4745698/38232e608268/oncotarget-06-28882-g001.jpg

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