Guo Fan, Lu Ruijiao, Kong Weina, Anwar Miyessar, Feng Yangchun
Department of Medical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, No 789 Suzhou Road, Urumqi, China.
Postdoctoral Research Workstation of Tumor Hospital affiliated to Xinjiang Medical University, Urumqi, China.
Cancer Cell Int. 2024 Jan 10;24(1):25. doi: 10.1186/s12935-024-03214-7.
Cervical cancer (CC) is a potential clinical application of PD-1/PD-L1 inhibitor. We aimed to study the mechanism of DNA mismatch repair (MMR) system regulating the expression of PD-L1 in CC through DNA methyltransferase (DNMTs).
We collected pathological specimens from 118 cases of CC to analyze the relationship between PD-L1 expression and DNMTs in different MMR states. RNA interference (RNAi) technique was used to simulate the formation of CC cell line with MMR deficiency (dMMR) state, and subcutaneous tumor formation experiment was carried out in nude mice to verify the relationship between PD-L1 expression and DNMTs in MMR state.
The PD-L1 positive rate in 118 cases of CC was 58.47%, while the microsatellite instability (MSI) status accounted for 5.93%. There was a significant difference in the expression of PD-L1 between patients within the dMMR and MMR proficient (pMMR) groups (χ = 21.405, P < 0.001). Subcutaneous inoculation after infection of Siha cells led to successful tumorigenesis in nude mice, accompanied by a significant increase in the level of PD-L1 expression in the mouse tumors, while the expression level of MLH1 and MSH2 protein decreased significantly. We also found that PD-L1 expression was closely related to the expression of DNMTs.
PD-L1 is universal expressed on the surface of CC cells, dMMR status enhances the expression of PD-L1 on the surface of CC cells, dMMR states of CC are related to the demethylation status of the PD-L1 gene promoter region.
宫颈癌（CC）是PD-1/PD-L1抑制剂的潜在临床应用对象。我们旨在研究DNA错配修复（MMR）系统通过DNA甲基转移酶（DNMTs）调节CC中PD-L1表达的机制。
收集118例CC的病理标本，分析不同MMR状态下PD-L1表达与DNMTs之间的关系。采用RNA干扰（RNAi）技术模拟MMR缺陷（dMMR）状态的CC细胞系形成，并在裸鼠中进行皮下肿瘤形成实验，以验证MMR状态下PD-L1表达与DNMTs之间的关系。
118例CC中PD-L1阳性率为58.47%，微卫星不稳定性（MSI）状态占5.93%。dMMR组与MMR proficient（pMMR）组患者之间PD-L1表达存在显著差异（χ=21.405，P<0.001）。Siha细胞感染后皮下接种导致裸鼠成功成瘤，同时小鼠肿瘤中PD-L1表达水平显著升高，而MLH1和MSH2蛋白表达水平显著降低。我们还发现PD-L1表达与DNMTs的表达密切相关。
PD-L1在CC细胞表面普遍表达，dMMR状态增强CC细胞表面PD-L1的表达，CC的dMMR状态与PD-L1基因启动子区域的去甲基化状态有关。
