Tong Liping, Chu Ming, Yan Bingqing, Zhao Weiyi, Liu Shuang, Wei Wei, Lou Huihuang, Zhang Shengkun, Ma Shuai, Xu Juan, Wei Lanlan
Wu Lien-Teh institute, Department of Microbiology, Harbin Medical University, The Heilongjiang Key Laboratory of Immunity and Infection, Pathogen Biology, Harbin 150081, China.
Department of Neurosurgery, The First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
Oncotarget. 2017 Mar 14;8(11):17738-17749. doi: 10.18632/oncotarget.14717.
Cell invasion is crucial for high mortality and recurrence rate in glioma. Epithelial-mesenchymal transition (EMT) is an important step in cancer invasion. Metadherin (MTDH) contributes to EMT in several cancers, but the role and mechanism of MTDH in EMT-like process of glioma remain unknown. Here we demonstrate that MTDH was overexpressed in glioma tissues and cells and induced EMT-like change and invasion of glioma cells. Interestingly, MTDH could modulate the expression of a group of glioma-related miRNAs. In particular, MTDH upregulated miR-130b transcription via acting as a coactivator of NF-kB. MiR-130b promoted EMT-like change and invasion of glioma cells through targeting multiple EMT-related genes, including PTEN, PPP2CA and SMAD7. In addition, PTEN acted as the competing endogenous RNA (ceRNA) to affect PPP2CA and SMAD7 expression, and inhibited EMT-like change in glioma cells. Furthermore, miR-130b mediated EMT-like change induced by MTDH, and MTDH inhibited the expression levels of PTEN, PPP2CA and SMAD7. Taken together, we reveal a novel mechanism that MTDH induces EMT-like change and invasion of glioma via the regulation of miR-130b-ceRNAs, providing the first direct link between MTDH and miRNAs in cancer cells.
细胞侵袭对于胶质瘤的高死亡率和复发率至关重要。上皮-间质转化（EMT）是癌症侵袭中的重要步骤。Metadherin（MTDH）在多种癌症中促进EMT，但MTDH在胶质瘤类似EMT过程中的作用和机制尚不清楚。在此，我们证明MTDH在胶质瘤组织和细胞中过表达，并诱导胶质瘤细胞发生类似EMT的变化和侵袭。有趣的是，MTDH可以调节一组胶质瘤相关miRNA的表达。特别是，MTDH通过作为NF-κB的共激活因子上调miR-130b的转录。miR-130b通过靶向多个EMT相关基因促进胶质瘤细胞发生类似EMT的变化和侵袭，这些基因包括PTEN、PPP2CA和SMAD7。此外，PTEN作为竞争性内源性RNA（ceRNA）影响PPP2CA和SMAD7的表达，并抑制胶质瘤细胞中类似EMT的变化。此外，miR-130b介导MTDH诱导的类似EMT的变化，且MTDH抑制PTEN、PPP2CA和SMAD7的表达水平。综上所述，我们揭示了一种新机制，即MTDH通过调节miR-130b-ceRNAs诱导胶质瘤细胞发生类似EMT的变化和侵袭，这首次在癌细胞中建立了MTDH与miRNA之间的直接联系。
