Department of Neurosurgery, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, 92354, USA.
Cell Death Dis. 2018 Nov 15;9(12):1139. doi: 10.1038/s41419-018-1183-8.
Temozolomide (TMZ) and radiation therapy combination for glioblastoma (GB) patients has been considered as the most effective therapy after surgical procedure. However, the overall clinical prognosis remains unsatisfactory due to intrinsic or developing resistance to TMZ. Recently, increasing evidence suggested that long noncoding RNAs (lncRNAs) play a critical role in various biological processes of tumors, and have been implicated in resistance to various drugs. However, the role of lncRNAs in TMZ resistance is poorly understood. Here, we found that the expression of lncRNA AC003092.1 was markedly decreased in TMZ resistance (TR) of GB cells (U87TR and U251TR) compared with their parental cells (U87 and U251). In patients with glioma, low levels of lncRNA AC003092.1 were correlated with increased TMZ resistance, higher risk of relapse, and poor prognosis. Overexpression of lncRNA AC003092.1 enhances TMZ sensitivity, facilitates cell apoptosis, and inhibits cell proliferation in TMZ-resistant GB cells. In addition, we identified that lncRNA AC003092.1 regulates TMZ chemosensitivity through TFPI-2-mediated cell apoptosis in vitro and in vivo. Mechanistically, further investigation revealed that lncRNA AC003092.1 regulates TFPI-2 expression through miR-195 in GB. Taken together, these data suggest that lncRNA AC003092.1 could inhibit the function of miR-195 by acting as an endogenous CeRNA, leading to increased expression of TFPI-2; this promotes TMZ-induced apoptosis, thereby making GB cells more sensitive to TMZ. Our findings indicate that overexpression of lncRNA AC003092.1 may be a potential therapy to overcome TMZ resistance in GB patients.
替莫唑胺（TMZ）联合放射治疗已被认为是胶质母细胞瘤（GB）患者手术后最有效的治疗方法。然而，由于内在或对 TMZ 的耐药性，总体临床预后仍不理想。最近，越来越多的证据表明，长链非编码 RNA（lncRNA）在肿瘤的各种生物学过程中发挥着关键作用，并与各种药物的耐药性有关。然而，lncRNA 在 TMZ 耐药中的作用尚不清楚。在这里，我们发现 lncRNA AC003092.1 的表达在 TMZ 耐药（TR）的 GB 细胞（U87TR 和 U251TR）中明显低于其亲本细胞（U87 和 U251）。在胶质瘤患者中，lncRNA AC003092.1 水平较低与 TMZ 耐药增加、复发风险增加和预后不良相关。lncRNA AC003092.1 的过表达增强了 TMZ 耐药的 GB 细胞的 TMZ 敏感性，促进细胞凋亡，抑制细胞增殖。此外，我们还发现，lncRNA AC003092.1 通过 TFPI-2 介导的细胞凋亡在体外和体内调节 TMZ 化疗敏感性。机制上，进一步的研究表明，lncRNA AC003092.1 通过在 GB 中调节 miR-195 来调节 TFPI-2 的表达。总之，这些数据表明，lncRNA AC003092.1 可以通过作为内源性 CeRNA 抑制 miR-195 的功能，导致 TFPI-2 表达增加；这促进 TMZ 诱导的细胞凋亡，从而使 GB 细胞对 TMZ 更敏感。我们的研究结果表明，lncRNA AC003092.1 的过表达可能是克服 GB 患者 TMZ 耐药的潜在治疗方法。
