Qingdao Hospital of Traditional Chinese Medicine, Qingdao Haici Hospital, No. 4, Renmin Road, Shibei District, Qingdao, 266034, China.
The Qingdao Center Hospital, Qingdao, China.
World J Surg Oncol. 2022 Aug 17;20(1):260. doi: 10.1186/s12957-022-02724-w.
Cluster of differentiation 147 (CD147) overexpression plays a key role in the proliferation, differentiation, invasion, metastasis, and prognosis of hepatocellular carcinoma (HCC). The aim of this study was to explore the relationship between rs6757 and the HCC risk in the South Chinese population, and the functional significance of rs6757 by affecting the efficacy of microRNA-3976 (miR-3976) binding to the CD147 3'-UTR.
We performed a retrospective case-control study to analyze the association between rs6757 and the risk of HCC. We chose candidate microRNAs with the potential of interacting with rs6757 through a series of silico analyses. A luciferase reporter gene assay was implemented to detect the binding extent of microRNAs to each polymorphic allele of rs6757.
An obvious association between rs6757 and the risk of HCC was detected in C vs. T (OR = 1.826, 95% CI [1.263-2.642]), CC vs. TT (OR = 4.513, 95% CI [1.510-13.489]), dominant genetic model (OR = 1.824, 95% CI [1.120-2.965]), and recessive genetic model (OR = 3.765, 95% CI [1.286-11.020]). Bioinformatics analysis indicated that miR-3976 binding sites containing the rs6757-T allele had lower free energies than those with the C allele, the lower free energies, the higher affinities. Luciferase activity was remarkably decreased by miR-3976 binding to the CD147 3'-UTR bearing rs6757 T allele, which could be reversed by miR-3976 inhibitors. Furthermore, miR-3976 reduced the luciferase expression in a manner of dose-dependent when cotransfected with constructs with the CD147-TT-pSICHECK2.
The research we have done suggests that rs6757 confers the CD147 allele-specific translational suppression by miR-3976, which provides a theoretical basis for antineoplastic therapy targeting CD147.
簇分化抗原 147（CD147）过表达在肝细胞癌（HCC）的增殖、分化、侵袭、转移和预后中起着关键作用。本研究旨在探讨 rs6757 与华南人群 HCC 风险的关系，以及 rs6757 通过影响 microRNA-3976（miR-3976）与 CD147 3'-UTR 的结合效力对 HCC 风险的功能意义。
我们进行了一项回顾性病例对照研究，以分析 rs6757 与 HCC 风险之间的关系。我们通过一系列的计算机分析选择了具有与 rs6757 相互作用潜力的候选 microRNAs。通过荧光素酶报告基因检测分析检测 microRNAs 与 rs6757 每个多态性等位基因的结合程度。
rs6757 与 HCC 风险之间存在明显关联，C 对 T（OR = 1.826，95%CI [1.263-2.642]）、CC 对 TT（OR = 4.513，95%CI [1.510-13.489]）、显性遗传模型（OR = 1.824，95%CI [1.120-2.965]）和隐性遗传模型（OR = 3.765，95%CI [1.286-11.020]）。生物信息学分析表明，含有 rs6757-T 等位基因的 miR-3976 结合位点的自由能低于含有 C 等位基因的结合位点，自由能越低，亲和力越高。miR-3976 与携带 rs6757T 等位基因的 CD147 3'-UTR 结合后，荧光素酶活性显著降低，而 miR-3976 抑制剂可逆转这一现象。此外，当与携带 CD147-TT-pSICHECK2 的构建体共转染时，miR-3976 以剂量依赖的方式显著降低了荧光素酶的表达。
我们的研究表明，rs6757 通过 miR-3976 赋予 CD147 等位基因特异性翻译抑制作用，为靶向 CD147 的抗肿瘤治疗提供了理论依据。
