Department of Gynecology, Shanghai Changning Maternity and Infant Health Hospital, Shanghai, China.
Environ Toxicol. 2023 Sep;38(9):2155-2164. doi: 10.1002/tox.23852. Epub 2023 Jun 19.
Cervical cancer (CC) is a deadly gynecological tumor worldwide. Otubain 2 (OTUB2) has been recently identified as an oncogene in human malignancies. However, its expression and function remain unclear. This work aims to explore the role of OTUB2 in CC progression. Herein, The Cancer Genome Atlas data revealed that OTUB2 expression was significantly upregulated in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and gradually increased with CESC progression; moreover, OTUB2 expression predicted poor outcomes of CESC patients. Then, RT-qPCR and Western blotting were applied to determine mRNA and protein expression in CC and normal cells. Our results confirmed that OTUB2 was highly expressed in CC cell lines. As indicated by CCK-8, Transwell, and flow cytometry results, OTUB2 silencing attenuated proliferative and metastatic capacities of CC cells but promoted CC cell apoptosis. Then, RBM15, an N6-methyladenosine (m A) methyltransferase "writer," was also demonstrated to be upregulated in CESC and CC cells. Mechanistically, m A RNA immunoprecipitation (Me-RIP) results showed that RBM15 inhibition reduced the m A methylation level of OTUB2 in CC cells, leading to the decline of OTUB2 expression. In addition, OTUB2 inhibition deactivated the AKT/mTOR signaling in CC cells. Furthermore, SC-79 (AKT/mTOR activator) partially abated the inhibitory effects of OTUB2 knockdown on the AKT/mTOR signaling pathway and the malignant phenotypes of CC cells. In summary, this work showed that RBM15-mediated m A modification led to OTUB2 upregulation, thereby promoting malignant behaviors of CC cells via the AKT/mTOR signaling pathway.
宫颈癌（CC）是一种致命的妇科肿瘤。Otubain 2（OTUB2）最近被鉴定为人类恶性肿瘤中的癌基因。然而，其表达和功能仍不清楚。本研究旨在探讨 OTUB2 在 CC 进展中的作用。本研究通过癌症基因组图谱数据发现，OTUB2 在宫颈鳞状细胞癌和宫颈内膜腺癌（CESC）中表达显著上调，且随着 CESC 进展逐渐增加；此外，OTUB2 表达预示着 CESC 患者预后不良。然后，应用 RT-qPCR 和 Western blot 检测 CC 和正常细胞中的 mRNA 和蛋白表达。我们的结果证实 OTUB2 在 CC 细胞系中高表达。CCK-8、Transwell 和流式细胞术结果表明，OTUB2 沉默抑制了 CC 细胞的增殖和迁移能力，但促进了 CC 细胞凋亡。然后，RBM15，一种 N6-甲基腺苷（m A）甲基转移酶“writer”，也被证明在 CESC 和 CC 细胞中上调。机制上，m A RNA 免疫沉淀（Me-RIP）结果表明，RBM15 抑制降低了 CC 细胞中 OTUB2 的 m A 甲基化水平，导致 OTUB2 表达下降。此外，OTUB2 抑制使 CC 细胞中的 AKT/mTOR 信号失活。此外，SC-79（AKT/mTOR 激活剂）部分减轻了 OTUB2 敲低对 AKT/mTOR 信号通路和 CC 细胞恶性表型的抑制作用。总之，本研究表明，RBM15 介导的 m A 修饰导致 OTUB2 上调，从而通过 AKT/mTOR 信号通路促进 CC 细胞的恶性行为。
