Li Yingwei, Diao Yuchao, Wang Zixiang, Wang Shourong, Peng Jiali, Kong Beihua
Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China.
Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
Cell Death Discov. 2022 Jul 19;8(1):326. doi: 10.1038/s41420-022-01120-3.
Regulation of alternative splicing (AS) by the splicing factor 3b (SF3B) family plays an essential role in cancer. However, the biological function of SF3B family members in cervical cancer (CC) needs to be further elucidated. In this study, we found that splicing factor 3b subunit 4 (SF3B4) was highly expressed in CC by bioinformatics analysis using cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) data from The Cancer Genome Atlas (TCGA). Then, we demonstrated that high expression of SF3B4 promoted proliferation and invasion abilities of CC cells in vitro and in vivo and that reduced expression of SF3B4 performed the opposite effect. Further RNA-seq and AS analysis showed that sperm-associated antigen 5 (SPAG5) was a downstream target gene of SF3B4. Interestingly, SPAG5 expression was decreased after SF3B4 knockdown because of retained introns (RIs) and reduced maturation of SPAG5 pre-mRNA. Importantly, SPAG5 deficiency impaired the oncogenic effects of SF3B4 overexpression on CC cells. In conclusion, SF3B4 promotes CC progression by regulating the effective splicing of SPAG5. SF3B4 could be a promising target for CC.
剪接因子3b（SF3B）家族对可变剪接（AS）的调控在癌症中起着至关重要的作用。然而，SF3B家族成员在宫颈癌（CC）中的生物学功能仍有待进一步阐明。在本研究中，我们利用来自癌症基因组图谱（TCGA）的宫颈鳞状细胞癌和宫颈内膜腺癌（CESC）数据进行生物信息学分析，发现剪接因子3b亚基4（SF3B4）在CC中高表达。随后，我们证明SF3B4的高表达在体外和体内均促进了CC细胞的增殖和侵袭能力，而SF3B4表达降低则产生相反的效果。进一步的RNA测序和AS分析表明，精子相关抗原5（SPAG5）是SF3B4的下游靶基因。有趣的是，由于内含子保留（RIs）和SPAG5前体mRNA成熟度降低，SF3B4敲低后SPAG5表达下降。重要的是，SPAG5缺陷削弱了SF3B4过表达对CC细胞的致癌作用。总之，SF3B4通过调节SPAG5的有效剪接促进CC进展。SF3B4可能是CC的一个有前景的治疗靶点。
