LINC00978 通过 AKR1B1 调节代谢重排促进胶质母细胞瘤的恶性转化。

LINC00978 regulates metabolic rewiring to promote the malignancy of glioblastoma through AKR1B1.

机构信息

Department of Neurosurgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China; Hypothalamic Pituitary Research Center, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China.

Department of Radiology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China.

出版信息

Cancer Lett. 2023 Jul 28;567:216277. doi: 10.1016/j.canlet.2023.216277. Epub 2023 Jun 17.

DOI:10.1016/j.canlet.2023.216277

PMID:37336288

Abstract

Glioma is a fatal primary brain tumor. Improved glioma treatment effectiveness depends on a better understanding of its underlying mechanisms. Glioblastoma (GBM), was classified as high-grade glioma with the most lethality and therapeutic resistance. Herein, we reported LINC00978 overexpressed in high-grade gliomas. Down-regulation of LINC00978 in glioblastoma cells inhibited cell proliferation, invasion, migration, and induced apoptosis. In vivo experiments confirmed that the CamK-A siRNA of LINC00978 could effectively inhibit the proliferation of glioblastoma cells. The main pathway and genes regulated by LINC00978 were detected using RNA sequencing to elucidate the molecular mechanism. The results suggest that LINC00978 regulates the expression of genes related to metabolic pathways, including aldo-keto reductase family 1 member B (AKR1B1), which mediates the cytotoxicity of 2-deoxyglucose. LINC00978 positively regulated AKR1B1 expression, and 2-deoxyglucose induced AKR1B1 expression via a LINC00978-dependent mechanism. This research has revealed that LINC00978 promotes the sensitivity of glioblastoma cells to 2DG. LINC00978 is highly expressed in most high-grade glioma patients. Thus, understanding the anticancer mechanism identified in this study may contribute to treating the majority of glioma patients. This study clarified the function and molecular mechanism of LINC00978 in glioblastoma and provided a study basis for LINC00978 to guide the clinical treatment of glioblastoma.

摘要

神经胶质瘤是一种致命的原发性脑肿瘤。提高神经胶质瘤的治疗效果取决于对其潜在机制的更好理解。胶质母细胞瘤（GBM）被归类为高级别神经胶质瘤，具有最高的致死率和治疗抵抗性。在此，我们报道了 LINC00978 在高级别神经胶质瘤中过表达。下调神经胶质瘤细胞中的 LINC00978 抑制细胞增殖、侵袭和迁移，并诱导细胞凋亡。体内实验证实，LINC00978 的 CamK-A siRNA 可有效抑制神经胶质瘤细胞的增殖。通过 RNA 测序检测 LINC00978 调节的主要通路和基因，以阐明其分子机制。结果表明，LINC00978 调节与代谢途径相关的基因表达，包括醛酮还原酶家族 1 成员 B（AKR1B1），其介导 2-脱氧葡萄糖的细胞毒性。LINC00978 正向调节 AKR1B1 的表达，2-脱氧葡萄糖通过 LINC00978 依赖的机制诱导 AKR1B1 的表达。这项研究揭示了 LINC00978 促进神经胶质瘤细胞对 2DG 的敏感性。LINC00978 在大多数高级别神经胶质瘤患者中高表达。因此，了解本研究中确定的抗癌机制可能有助于治疗大多数神经胶质瘤患者。本研究阐明了 LINC00978 在神经胶质瘤中的功能和分子机制，为 LINC00978 指导神经胶质瘤的临床治疗提供了研究基础。