生物通报道：来自中国科技大学，以及台湾阳明大学的两个研究组分别在Cell出版社旗下著名期刊Molecular Cell杂志上发表文章，揭示了miR142-3p对胶质母细胞瘤的表观遗传调控作用，以及长片段非编码RNA通过调控肿瘤细胞瓦伯格效应促进肿瘤生长的作用机制。

在第一篇文章：Epigenetic Regulation of the miR142-3p/Interleukin-6 Circuit in Glioblastoma中，邱士华教授领导的研究组发现了一种小分子RNA：miR142-3p对胶质母细胞瘤的表观遗传调控作用。

表观遗传调控在胶质母细胞瘤GBM的肿瘤发生过程中扮演了重要角色，这种肿瘤是最常见的脑胶质瘤之一，占胶质瘤的25%以上，也是最恶性的一种。大多发生于成人，特别是30～50岁间，而且胶质母细胞瘤呈浸润性生长，病程迅速进展，手术切除后常很快复发。

在这篇文章中，研究人员发现白细胞介素-6（IL- 6）能通过诱导DNA甲基转移酶1介导miR142-3p启动子的超甲基化，抑制miR142-3p的表达，促进GBM的进程。而且有趣的是， miR142-3p也抑制IL-6的分泌。

临床上，研究人员发现IL - 6，HMGA2和Sox2蛋白表达增加，miR142-3p启动子超甲基化的GBM患者生存率低。这些研究实验数据都表明IL-6/miR142-3p反馈环路相关的GBM恶性肿瘤调控也许是一个重要的治疗靶点。

此外来自中国科技大学的研究人员揭示了长片段非编码RNA通过调控肿瘤细胞瓦伯格（Warburg）效应促进肿瘤生长的作用机制。

相对于正常细胞，肿瘤细胞的代谢方式在整体上发生了改变，其中一个显著的特征是，肿瘤细胞即使在有氧状态下也优先进行糖酵解，而不是通过产能效率更高的氧化磷酸化途径为细胞生长提供能量，这就是著名的Warburg效应(由上世纪20年代德国科学家Otto Warburg首先提出，为此他在1931年获得诺贝尔生理医学奖)。虽然低氧微环境可以促进肿瘤Warburg效应这一结论已被人们广泛接受，但是其具体的分子机制仍不明确，特别是长片段非编码RNA是否也参与调控低氧环境下肿瘤的Warburg效应没有报道。

这一研究组在研究中发现长片段非编码RNA分子—lincRNA-p21可以被低氧或低氧诱导因子HIF-1α诱导表达，诱导表达的lincRNA-p21通过分别结合HIF-1α和VHL、阻止HIF-1α-VHL复合物的形成、抑制VHL对HIF-1α的降解，从而提高HIF-1α的蛋白水平，最终形成一个正反馈循环，并促进肿瘤细胞的Warburg效应。更为重要的是，该研究运用小鼠肿瘤模型，证明了lincRNA-p21和HIF-1α形成的正反馈循环确实能够促进肿瘤的生长，暗示lincRNA-p21作为一个癌基因在体内发挥功能。这一创新性的研究结果首次阐明了长片段非编码RNA在调控肿瘤细胞Warburg效应中的重要作用，同时也提示lincRNA-p21可以作为肿瘤治疗的潜在靶点。

原文摘要：
Epigenetic Regulation of the miR142-3p/Interleukin-6 Circuit in Glioblastoma

Epigenetic regulation plays a critical role in glioblastoma (GBM) tumorigenesis. However, how microRNAs (miRNAs) and cytokines cooperate to regulate GBM tumor progression is still unclear. Here, we show that interleukin-6 (IL-6) inhibits miR142-3p expression and promotes GBM propagation by inducing DNA methyltransferase 1-mediated hypermethylation of the miR142-3p promoter. Interestingly, miR142-3p also suppresses IL-6 secretion by targeting the 3 UTR of IL-6. In addition, miR142-3p also targets the 3 UTR and suppresses the expression of high-mobility group AT-hook 2 (HMGA2), leading to inhibition of Sox2-related stemness. We further show that HMGA2 enhances Sox2 expression by directly binding to the Sox2 promoter. Clinically, GBM patients whose tumors present upregulated IL-6, HMGA2, and Sox2 protein expressions and hypermethylated miR142-3p promoter also demonstrate poor survival outcome. Orthotopic delivery of miR142-3p blocks IL-6/HMGA2/Sox2 expression and suppresses stem-like properties in GBM-xenotransplanted mice. Collectively, we discovered an IL-6/miR142-3p feedback-loop-dependent regulation of GBM malignancy that could be a potential therapeutic target.

Reciprocal Regulation of HIF-1α and LincRNA-p21 Modulates the Warburg Effect

Hypoxia has long been linked to the Warburg effect, yet the underlying mechanism remains largely unclear. It is also not known if lncRNAs are involved in the contribution of hypoxia to the Warburg effect. Here we show that lincRNA-p21 is a hypoxia-responsive lncRNA and is essential for hypoxia-enhanced glycolysis. Hypoxia/HIF-1α-induced lincRNA-p21 is able to bind HIF-1α and VHL and thus disrupts the VHL-HIF-1α interaction. This disassociation attenuates VHL-mediated HIF-1α ubiquitination and causes HIF-1α accumulation. These data indicate the existence of a positive feedback loop between HIF-1α and lincRNA-p21 that promotes glycolysis under hypoxia. The ability of lincRNA-p21 to promote tumor growth is validated in mouse xenograft models. Together, these findings suggest that lincRNA-p21 is an important player in the regulation of the Warburg effect and also implicate lincRNA-p21 as a valuable therapeutic target for cancer.

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