Wang Cuicui, Kong Fanfei, Ma Jian, Miao Jianing, Su Peng, Yang Hui, Li Qing, Ma Xiaoxin
Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning Province, 110000, PR China.
Key Laboratory of Gynecological Oncology of Liaoning Province, Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Shenyang, Liaoning Province, 110000, PR China.
Cell Death Discov. 2022 Jun 8;8(1):279. doi: 10.1038/s41420-022-01045-x.
Long noncoding RNAs (lncRNAs) play important regulatory roles in a variety of pathological processes involving cancer. However, the exact molecular mechanisms of lncRNA regulation in endometrial carcinoma (EC) remain poorly defined. The aim of this study was to illustrate the mechanism of LINC00958 in regulating the function of IGF2BP3, an RNA binding protein involved in mRNA stability, and their clinical implications in EC. First, we investigated the clinical role of IGF2BP3 in EC and demonstrated its prognostic value. Loss-of-function and gain-of-function studies showed that IGF2BP3 promoted EC cell proliferation, migration and invasion. Then, we carried out RNA immunoprecipitation sequencing (RIP-seq) analysis, RNA pulldown and immunofluorescence-RNA fluorescence in situ hybridization to identify LINC00958 that interacted with IGF2BP3 in the cytoplasm of EC cells. Rescue experiments indicated that knockdown of LINC00958 partially offset the EC cell progression mediated by IGF2BP3. After that, RNA sequencing was used to screen out the downstream genes of IGF2BP3 and LINC00958. The results revealed that IGF2BP3 upregulated E2F3 expression by interacting with LINC00958. Furthermore, RNA stability assays demonstrated that silencing LINC00958 partially rescued the IGF2BP3-mediated promoting effect on the mRNA stability of E2F3. Collectively, this study suggests that LINC00958, as an oncogene, assists IGF2BP3 in stabilizing E2F3 mRNA and ultimately promotes EC progression, providing a promising therapeutic target for patients with EC.
长链非编码RNA（lncRNAs）在包括癌症在内的多种病理过程中发挥着重要的调节作用。然而，lncRNA在子宫内膜癌（EC）中的具体调控分子机制仍不清楚。本研究旨在阐明LINC00958在调节IGF2BP3功能中的机制，IGF2BP3是一种参与mRNA稳定性的RNA结合蛋白，以及它们在EC中的临床意义。首先，我们研究了IGF2BP3在EC中的临床作用，并证明了其预后价值。功能丧失和功能获得研究表明，IGF2BP3促进EC细胞增殖、迁移和侵袭。然后，我们进行了RNA免疫沉淀测序（RIP-seq）分析、RNA下拉实验以及免疫荧光-RNA荧光原位杂交，以鉴定在EC细胞胞质中与IGF2BP3相互作用的LINC00958。挽救实验表明，敲低LINC00958部分抵消了IGF2BP3介导的EC细胞进展。之后，利用RNA测序筛选出IGF2BP3和LINC00958的下游基因。结果显示，IGF2BP3通过与LINC00958相互作用上调E2F3表达。此外，RNA稳定性分析表明，沉默LINC00958部分挽救了IGF2BP3介导的对E2F3 mRNA稳定性的促进作用。总的来说，本研究表明，LINC00958作为一种癌基因，协助IGF2BP3稳定E2F3 mRNA，最终促进EC进展，为EC患者提供了一个有前景的治疗靶点。
