Long non-coding RNA HOTTIP promotes hypoxia-induced epithelial-mesenchymal transition of malignant glioma by regulating the miR-101/ZEB1 axis

Hypoxia is a universal characteristic of solid tumor and involving cancer metastasis via epithelial-mesenchymal transition (EMT). Long non-coding RNAs (lncRNAs) are known to regulate carcinogenesis and metastasis of various cancers. The aim of this study was to identify the function role of lncRNAs in the hypoxia-induced EMT of malignant glioma. We used U87 and U251 cell lines were treated under hypoxia to induce EMT, then lncRNA microarray analyse was performed between U87-hypoxia and parental cell line. The relative expression of lncRNA and HIF-1 alpha were detected by qRT-PCR between glioma tissues without metastasis and that with metastasis. Hypoxia could induce EMT and increase HOTTIP expression in glioma cells. Among the different expressions of lncRNAs, HOTTIP was the most upregulated lncRNA in glioma cells treated by hypoxia. High levels of HOTTIP and HIF-1 alpha were correlated with glioma metastasis and poor patient prognosis. Knockdown of HIF-1 alpha and HOTTIP blocked hypoxia-induced EMT, and suppressed invasion and migration of glioma cells. Finally, HOTTIP sponged endogenous miR-101 and inhibited its activity, which resulted in increased ZEB1 expression and promoted process of EMT. HIF-1 alpha/HOTTIP/miR-101/ZEB1 axis plays essential role in hypoxia-induced EMT and metastasis of glioma, and HOTTIP may serve as a therapeutic target to reverse EMT and prevent glioma progression.