Jing Li-Ping, Li Meng, Xia Xi-Yan, Zheng Xin, Chen Jia-Yu, He Jing, Zhuang Xue-Wei
Clinical Laboratory Department, Liaoning Cancer Hospital & Institute, 110042, Shenyang, Liaoning, China.
Department of Laboratory, Shandong Provincial Third Hospital, Shandong University, 250031, Jinan, Shandong, China.
Heliyon. 2024 May 17;10(11):e31487. doi: 10.1016/j.heliyon.2024.e31487. eCollection 2024 Jun 15.
Cervical cancer is one of the most common malignancies in women worldwide. As a RING type ubiquitin ligase, SIAH2 has been reported to promote the progression of a variety of tumors by interacting with and targeting multiple chaperones and substrates. The aim of this study was to further identify the role and the related molecular mechanisms involved of SIAH2 in cervical carcinogenesis.
Cellular assays showed that knockdown of SIAH2 inhibited the proliferation, migration and invasion of human cervical cancer cells C33A and SiHa, induced apoptosis, and increased the sensitivity to cisplatin treatment. Knockdown of SIAH2 also inhibited the epithelial-mesenchymal transition and activation of the Akt/mTOR signaling pathway in cervical cancer cells, which were detected by Western blot. Mechanistically, SIAH2, as a ubiquitin ligase, induced the ubiquitination degradation of GSK3β degradation by using coIP. The results of complementation experiments further demonstrated that GSK3β overexpression rescued the increase of cell proliferation and invasion caused by SIAH2 overexpression. Specific expression of SIAH2 appeared in precancerous and cervical cancer tissues compared to inflammatory cervical lesions tissues using immunohistochemical staining. The more SIAH2 was expressed as the degree of cancer progressed. SIAH2 was significantly highly expressed in cervical cancer tissues (44/55, 80 %) compared with precancerous tissues (18/69, 26.1 %). Moreover, the expression level of SIAH2 in cervical cancer tissues was significantly correlated with the degree of cancer differentiation, and cervical cancer tissues with higher SIAH2 expression levels were less differentiated.
Targeting SIAH2 may be beneficial to the treatment of cervical cancer.
宫颈癌是全球女性中最常见的恶性肿瘤之一。作为一种RING型泛素连接酶，据报道SIAH2通过与多种伴侣蛋白和底物相互作用并将其作为靶点来促进多种肿瘤的进展。本研究的目的是进一步确定SIAH2在宫颈癌发生中的作用及相关分子机制。
细胞实验表明，敲低SIAH2可抑制人宫颈癌细胞C33A和SiHa的增殖、迁移和侵袭，诱导细胞凋亡，并增加对顺铂治疗的敏感性。敲低SIAH2还可抑制宫颈癌细胞的上皮-间质转化以及Akt/mTOR信号通路的激活，这通过蛋白质免疫印迹法检测得出。机制上，SIAH2作为一种泛素连接酶，通过免疫共沉淀法诱导GSK3β的泛素化降解。互补实验结果进一步证明，GSK3β过表达可挽救由SIAH2过表达引起的细胞增殖和侵袭增加。与炎性宫颈病变组织相比，免疫组织化学染色显示SIAH2在癌前和宫颈癌组织中呈特异性表达。随着癌症进展程度增加，SIAH2表达越多。与癌前组织（18/69，26.1%）相比，SIAH2在宫颈癌组织中显著高表达（44/55，80%）。此外，SIAH2在宫颈癌组织中的表达水平与癌症分化程度显著相关，SIAH2表达水平较高的宫颈癌组织分化程度较低。
靶向SIAH2可能对宫颈癌治疗有益。
