Guo Li, Li Yingwei, Zhao Chen, Peng Jiali, Song Kun, Chen Long, Zhang Ping, Ma Hanlin, Yuan Cunzhong, Yan Shi, Fang Yan, Kong Beihua
Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Obstetrics and Gynecology, Qingdao Municipal Hospital, Shandong University, Qingdao, China.
Front Oncol. 2020 Sep 4;10:524128. doi: 10.3389/fonc.2020.524128. eCollection 2020.
The high frequency of somatic copy number alterations, as opposed to point mutations, is considered a unique feature of ovarian cancer. Amplification-dependent overexpression of RecQ protein-like 4 (RECQL4), which participates in DNA replication and repair, mediates the development of various cancers, but its pathobiological and clinical roles are poorly understood. Here, using bioinformatics analysis, RECQL4 amplification was found to occur in 27% of ovarian cancer samples in the TCGA cohort. RECQL4 was found to be upregulated and associated with a poor prognosis based on the immunohistochemistry staining of ovarian cancer. Functionally, RECQL4 overexpression increased proliferation and invasion of ovarian cancer cells. RECQL4 silencing had the opposite effects. In addition, RECQL4 knockdown enhanced the sensitivity of ovarian cancer cells to cisplatin and PARP inhibitor (PARPi). Further mechanistic investigations revealed that MAFB was a downstream target of RECQL4. The oncogenic effect of RECQL4 was attenuated after MAFB knockdown. Moreover, RECQL4 overexpression was negatively regulated by the tumor suppressor miR-10a-5p. Collectively, these findings indicate that genomic amplification and low expression of miR-10a-5p contribute to RECQL4 overexpression in ovarian cancer. This is the first study to reveal the oncogenic functions and clinical significance of RECQL4 in ovarian cancer.
与点突变相反，体细胞拷贝数改变的高频率被认为是卵巢癌的一个独特特征。参与DNA复制和修复的类RecQ蛋白4（RECQL4）的扩增依赖性过表达介导了各种癌症的发展，但其病理生物学和临床作用仍知之甚少。在这里，通过生物信息学分析，发现TCGA队列中27%的卵巢癌样本发生了RECQL4扩增。基于卵巢癌的免疫组织化学染色，发现RECQL4上调并与不良预后相关。在功能上，RECQL4过表达增加了卵巢癌细胞的增殖和侵袭。RECQL4沉默则产生相反的效果。此外，RECQL4敲低增强了卵巢癌细胞对顺铂和聚ADP核糖聚合酶抑制剂（PARPi）的敏感性。进一步的机制研究表明，MAFB是RECQL4的下游靶点。MAFB敲低后，RECQL4的致癌作用减弱。此外，RECQL4过表达受到肿瘤抑制因子miR-10a-5p的负调控。总的来说，这些发现表明基因组扩增和miR-10a-5p的低表达导致了卵巢癌中RECQL4的过表达。这是第一项揭示RECQL4在卵巢癌中的致癌功能和临床意义的研究。
