Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, PR China.
J Chemother. 2023 May;35(3):250-258. doi: 10.1080/1120009X.2022.2082348. Epub 2022 Aug 16.
Thyroid cancer is a prevalent human endocrine tumour. Surgical resection is a primary approach for well-differentiated thyroid cancers. Currently, the combination of chemotherapy with subsequent irradiation is a therapeutic strategy for the late stage or metastatic thyroid cancer. Yet, drug resistance and side-effects greatly limit widely clinical applications of chemotherapeutic drugs. The long non-coding RNA IQCH antisense RNA 1 (IQCH-AS1) is correlated with survival and diagnosis of cancer patients. Currently, the precise roles of IQCH-AS1 in thyroid cancer and the chemosensitivity of doxorubicin remain unclear. Here, we report IQCH-AS1 was significantly down-regulated in thyroid cancer tissues and cell lines. Overexpression of IQCH-AS1 effectively sensitized thyroid cancer cells to doxorubicin. From the established doxorubicin-resistant thyroid cancer cell line, 8505 C Doxo R, we detected that IQCH-AS1 was remarkedly suppressed in doxorubicin-resistant cells. Bioinformatics analysis, RNA pull-down and luciferase assays illustrated that IQCH-AS1 functioned as a ceRNA of miR-196a-5p which showed an oncogenic role in thyroid cancer. Overexpression of miR-196a-5p, which was upregulated in 8505 C Doxo R cells, significantly de-sensitized thyroid cancer cells to doxorubicin. Furthermore, PPP2R1B, which encode the protein phosphatase 2 A regulatory subunit A, was directly targeted by miR-196a-5p in thyroid cancer cells. Rescue experiments validated that recovery of miR-196a-5p in IQCH-AS1-overexpressing 8508 C doxorubicin resistant cells successfully reversed the IQCH-AS1-promoted doxorubicin sensitization targeting PPP2R1B. Summarily, our study revealed new functions and molecular targets of the lncRNA-IQCH-AS1-mediated chemosensitivity of thyroid cancer, contributing to the development of anti-chemoresistant strategies against thyroid cancer.
甲状腺癌是一种常见的人类内分泌肿瘤。手术切除是分化良好的甲状腺癌的主要治疗方法。目前，化疗联合后续放疗是晚期或转移性甲状腺癌的治疗策略。然而，药物耐药性和副作用极大地限制了化疗药物的广泛临床应用。长链非编码 RNA IQCH 反义 RNA 1（IQCH-AS1）与癌症患者的生存和诊断相关。目前，IQCH-AS1 在甲状腺癌中的精确作用和多柔比星的化疗敏感性尚不清楚。在这里，我们报告 IQCH-AS1 在甲状腺癌组织和细胞系中显著下调。IQCH-AS1 的过表达有效地使甲状腺癌细胞对多柔比星敏感。从建立的多柔比星耐药甲状腺癌细胞系 8505C Doxo R 中，我们检测到多柔比星耐药细胞中 IQCH-AS1 显著抑制。生物信息学分析、RNA 下拉和荧光素酶测定表明，IQCH-AS1 作为 miR-196a-5p 的 ceRNA 发挥作用，miR-196a-5p 在甲状腺癌中具有致癌作用。在 8505C Doxo R 细胞中上调的 miR-196a-5p 的过表达显著使甲状腺癌细胞对多柔比星失敏。此外，PPP2R1B 编码蛋白磷酸酶 2A 调节亚基 A，是甲状腺癌细胞中 miR-196a-5p 的直接靶标。挽救实验验证了在 IQCH-AS1 过表达的 8508C 多柔比星耐药细胞中 miR-196a-5p 的恢复成功地逆转了 IQCH-AS1 靶向 PPP2R1B 促进的多柔比星敏化。总之，我们的研究揭示了 lncRNA-IQCH-AS1 介导的甲状腺癌细胞化疗敏感性的新功能和分子靶点，为开发针对甲状腺癌的抗化疗耐药策略做出了贡献。
