Department of Pharmacy, Ege University, Turkey.
Department of Neurosurgery, Acibadem Maslak Hospital, Istanbul, Turkey.
Gene. 2020 May 20;739:144518. doi: 10.1016/j.gene.2020.144518. Epub 2020 Feb 28.
Glioblastomas (GBMs) are primary brain tumors with extremely bad prognosis and therefore; discovery of novel regulators of their pathology is of immense importance. LncRNAs (long noncoding RNAs) regulate nuclear structure, embryonic pluripotency, cell differentiation, development and carcinogenesis. Many lncRNAs have weak evolutionary conservation; however, a nuclear lncRNA, MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), is exceptionally conserved and is among the most abundant lncRNAs in benign tissues. The majority of cell culture studies and clinico-epidemiological studies demonstrated that MALAT1 acts a tumor promoter in GBMs and inhibition of MALAT1 suppressed tumor growth in various preclinical models of GBM. MALAT1 involves in stemness of GBM cells by regulating SOX2, nestin and members of WNT pathway. MALAT1 induces protective autophagy and suppresses apoptosis in GBM cells via sponging miRNA-101 and increases temozolomide chemoresistance via enhancing epithelial-mesenchymal transition, suppressing miR-203 and promoting thymidilate synthase. Moreover, knockdown of MALAT1 expression enhances blood-brain tumor barrier permeability via miR-140, which may provide a double benefit of MALAT1 suppression by increasing the delivery of chemotherapy agents into the GBM tissues. On the other hand, there also exist some cell culture and animal studies showing that MALAT1 acts as a tumor suppressor in GBMs by suppression of ERK/MAPK and MMP2 signaling and by repression of miR-155 with subsequent increase of FBXW7. Whether protective or detrimental, MALAT1 seems to be an important component of GBM pathogenesis and hence; novels studies are needed in versatile models, including many different primary GBM cultures, orthotopic and xenogreft in vivo models and transgenic mice.
胶质母细胞瘤（GBM）是一种预后极差的原发性脑肿瘤，因此，发现其病理的新型调节因子具有重要意义。lncRNA（长非编码 RNA）调节核结构、胚胎多能性、细胞分化、发育和癌变。许多 lncRNA 进化保守性较弱；然而，一种核 lncRNA，MALAT1（转移相关肺腺癌转录本 1），则异常保守，是良性组织中最丰富的 lncRNA 之一。大多数细胞培养研究和临床流行病学研究表明，MALAT1 在 GBM 中作为肿瘤促进物发挥作用，抑制 MALAT1 可抑制各种 GBM 临床前模型中的肿瘤生长。MALAT1 通过调节 SOX2、巢蛋白和 WNT 通路成员来参与 GBM 细胞的干性。MALAT1 通过海绵 miRNA-101 诱导 GBM 细胞保护性自噬并抑制细胞凋亡，通过增强上皮-间充质转化、抑制 miR-203 和促进胸苷酸合成酶来增加替莫唑胺化疗耐药性。此外，MALAT1 表达的敲低通过 miR-140 增强血脑肿瘤屏障通透性，这可能通过增加化疗药物进入 GBM 组织的递送提供 MALAT1 抑制的双重益处。另一方面，也有一些细胞培养和动物研究表明，MALAT1 通过抑制 ERK/MAPK 和 MMP2 信号以及抑制 miR-155 及其随后增加 FBXW7 来作为 GBM 中的肿瘤抑制物发挥作用。无论保护还是有害，MALAT1 似乎都是 GBM 发病机制的重要组成部分，因此，需要在各种模型中进行新的研究，包括许多不同的原发性 GBM 培养物、原位和异种移植体内模型以及转基因小鼠。
