Dong Ruifen, Liu Xiaolin, Zhang Qing, Jiang Zhijun, Li Yingwei, Wei Yuyan, Li Yinuo, Yang Qifeng, Liu Jinsong, Wei Jian-Jun, Shao Changshun, Liu Zhaojian, Kong Beihua
Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong, China.
Department of Breast Surgery, Qilu Hospital, Shandong University, Jinan, Shandong, China.
Oncotarget. 2014 Nov 15;5(21):10816-29. doi: 10.18632/oncotarget.2522.
High-grade serous ovarian carcinoma (HGSOC), the most common and aggressive subtype of epithelial ovarian cancer, is characterized by TP53 mutations and genetic instability. Using miRNA profiling analysis, we found that miR-145, a p53 regulated miRNA, was frequently down-regulated in HGSOC. miR-145 down-regulation was further validated in a large cohort of HGSOCs by qPCR. Overexpression of miR-145 in ovarian cancer cells significantly suppressed proliferation, migration and invasion in vitro and inhibited tumor growth and metastasis in vivo. Metadherin (MTDH) was subsequently identified as a direct target of miR-145, and was found to be significantly up-regulated in HGSOC. Furthermore, overexpression of MTDH rescued the inhibitory effects of miR-145 in ovarian cancer cells. Finally, we found that high level of MTDH expression correlated with poor prognosis of HGSOC. Therefore, lack of suppression of MTDH by miR-145 when p53 is dysfunctional leads to increased tumor growth and metastasis of HGSOC. Our study established a new link between p53, miR-145 and MTDH in the regulation of tumor growth and metastasis in HGSOC.
高级别浆液性卵巢癌（HGSOC）是上皮性卵巢癌最常见且侵袭性最强的亚型，其特征为TP53突变和基因不稳定。通过miRNA谱分析，我们发现miR-145（一种p53调控的miRNA）在HGSOC中经常下调。通过qPCR在大量HGSOC队列中进一步验证了miR-145的下调。在卵巢癌细胞中过表达miR-145可显著抑制体外增殖、迁移和侵袭，并在体内抑制肿瘤生长和转移。随后鉴定出Metadherin（MTDH）是miR-145的直接靶点，并发现其在HGSOC中显著上调。此外，MTDH的过表达挽救了miR-145对卵巢癌细胞的抑制作用。最后，我们发现高水平的MTDH表达与HGSOC的不良预后相关。因此，当p53功能失调时，miR-145对MTDH的抑制缺失会导致HGSOC的肿瘤生长和转移增加。我们的研究在HGSOC的肿瘤生长和转移调控中建立了p53、miR-145和MTDH之间的新联系。
