Neurosurgery Department, the Affiliated Hospital of Southwest Medical University, 646000, Luzhou, P. R. China.
Sichuan Clinical Research Center for Neurosurgery, 646000, Luzhou, P. R. China.
Cell Death Dis. 2022 Feb 18;13(2):160. doi: 10.1038/s41419-021-04471-4.
Long non-coding RNAs (lncRNAs) have been manifested to manipulate diverse biological processes, including tumor-induced immune tolerance. Thus, we aimed in this study to identify the expression pattern of lncRNA homeobox A cluster antisense RNA 2 (HOXA-AS2) in glioma and decipher its role in immune tolerance and glioma progression. We found aberrant upregulation of lncRNA HOXA-AS2, lysine demethylase 2A (KDM2A), and jagged 1 (JAG1) and a downregulation of microRNA-302a (miR-302a) in glioma specimens. Next, RNA immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter gene assay demonstrated that lncRNA HOXA-AS2 upregulated KDM2A expression by preventing miR-302a from binding to its 3'untranslated region. The functional experiments suggested that lncRNA HOXA-AS2 could promote regulatory T (T) cell proliferation and immune tolerance, which might be achieved through inhibition of miR-302a and activation of KDM2A/JAG1 axis. These findings were validated in a tumor xenograft mouse model. To conclude, lncRNA HOXA-AS2 facilitates KDM2A/JAG1 expression to promote T cell proliferation and immune tolerance in glioma by binding to miR-302a. These findings may aid in the development of novel antitumor targets.
长链非编码 RNA（lncRNA）已被证明可调节多种生物过程，包括肿瘤诱导的免疫耐受。因此，我们旨在本研究中鉴定 lncRNA 同源盒 A 簇反义 RNA 2（HOXA-AS2）在神经胶质瘤中的表达模式，并阐明其在免疫耐受和神经胶质瘤进展中的作用。我们发现神经胶质瘤标本中 lncRNA HOXA-AS2、赖氨酸去甲基酶 2A（KDM2A）和 jagged 1（JAG1）异常上调，microRNA-302a（miR-302a）下调。接下来，RNA 免疫沉淀、染色质免疫沉淀和双荧光素酶报告基因分析表明，lncRNA HOXA-AS2 通过阻止 miR-302a 与其 3'非翻译区结合而上调 KDM2A 的表达。功能实验表明，lncRNA HOXA-AS2 可促进调节性 T（T）细胞增殖和免疫耐受，这可能是通过抑制 miR-302a 和激活 KDM2A/JAG1 轴实现的。这些发现在肿瘤异种移植小鼠模型中得到了验证。总之，lncRNA HOXA-AS2 通过与 miR-302a 结合，促进 KDM2A/JAG1 的表达，从而促进胶质瘤中 T 细胞的增殖和免疫耐受。这些发现可能有助于开发新的抗肿瘤靶标。
