Foshan Stomatological Hospital, School of Medicine, Foshan University, Foshan, China.
Department of Oral and Maxillofacial Surgery, ZhuJiang Hospital, Southern Medical University, Guangzhou, China.
J Cell Mol Med. 2023 Dec;27(24):4133-4144. doi: 10.1111/jcmm.17998. Epub 2023 Oct 20.
Cisplatin (CDDP) chemoresistance is one of the predominant factors in oral squamous cell carcinoma (OSCC) treatment failure. Uncovering the mechanisms underlying CDDP resistance is of great importance in OSCC therapy. Circular RNAs (circRNAs) are a newly discovered class of noncoding RNAs, which are reported to participate in the progression of various diseases, including cancer. However, the function of circRNAs in CDDP resistance in OSCC remains unclear. Quantitative reverse transcription PCR was used to search for different circRNAs between OSCC cell lines and CDDP-resistant cell lines. The results showed that circ-ILF2 expression was higher in CDDP-resistant OSCC cell lines. The stability of circ-ILF2 was also confirmed using RNase R and actinomycin D assays. Functional experiments, including cytotoxicity, apoptosis and growth rate assays, showed that upregulation of circ-ILF2 contributes to CDDP resistance. Luciferase reporter-gene, RNA pull-down and quantitative real-time PCR (RT-qPCR) assays showed that circ-ILF2 functions as a microRNA sponge for miR-1252. Luciferase reporter assays, RNA pull-down, RT-qPCR and Western blotting showed that miR-1252 directly targeted and regulated the expression of KLF8. Circ-ILF2 plays an important role in CDDP resistance in OSCC. Circ-ILF2 exerts its function through the miR-1252/KLF8 pathway. In addition, tumour-associated macrophages (TAM) play important roles in cancer progressions, our results showed that circ-ILF2 in OSCC cells induced the M2 polarization of macrophages which provided new thoughts on immunotherapy. Our results suggest that circ-ILF2 may represent a potential therapeutic target in CDDP-resistant OSCC.
顺铂（CDDP）耐药性是口腔鳞状细胞癌（OSCC）治疗失败的主要因素之一。揭示CDDP 耐药的机制在 OSCC 治疗中非常重要。环状 RNA（circRNA）是一类新发现的非编码 RNA，据报道参与多种疾病的进展，包括癌症。然而，circRNA 在 OSCC 中 CDDP 耐药中的作用尚不清楚。定量逆转录 PCR 用于在 OSCC 细胞系和 CDDP 耐药细胞系之间搜索不同的 circRNA。结果表明，CDDP 耐药 OSCC 细胞系中 circ-ILF2 的表达更高。使用 RNase R 和放线菌素 D 测定也证实了 circ-ILF2 的稳定性。包括细胞毒性、细胞凋亡和生长速率测定在内的功能实验表明，circ-ILF2 的上调有助于 CDDP 耐药。荧光素酶报告基因、RNA 下拉和定量实时 PCR（RT-qPCR）测定表明，circ-ILF2 作为 miR-1252 的 microRNA 海绵发挥作用。荧光素酶报告基因测定、RNA 下拉、RT-qPCR 和 Western blot 表明，miR-1252 直接靶向并调节 KLF8 的表达。circ-ILF2 在 OSCC 中的 CDDP 耐药中起重要作用。circ-ILF2 通过 miR-1252/KLF8 通路发挥作用。此外，肿瘤相关巨噬细胞（TAM）在癌症进展中起重要作用，我们的结果表明，OSCC 细胞中的 circ-ILF2 诱导巨噬细胞的 M2 极化，为免疫治疗提供了新的思路。我们的结果表明，circ-ILF2 可能代表 CDDP 耐药 OSCC 的潜在治疗靶点。
