期刊
INTERNATIONAL JOURNAL OF CANCER
卷 137, 期 10, 页码 2296-2309出版社
WILEY
DOI: 10.1002/ijc.29606
关键词
tumor suppression; miR-302/367 regulated gene expression; epigenetic regulation of the tumor cell state
类别
资金
- LOEWE Center for Cell and Gene Therapy (State of Hessen at the Goethe University, Frankfurt)
- LOEWE Center for Cell and Gene Therapy (Georg-Speyer-Haus)
- German Federal Ministry of Health (BMG)
- Ministry of Higher Education, Research and the Arts of the State of Hessen (HMWK
- Georg-Speyer-Haus)
- Grants-in-Aid for Scientific Research [15K08408, 25871006] Funding Source: KAKEN
Cellular transformation is initiated by the activation of oncogenes and a closely associated developmental reprogramming of the epigenetic landscape. Transcription factors, regulators of chromatin states and microRNAs influence cell fates in development and stabilize the phenotypes of normal, differentiated cells and of cancer cells. The miR-302/367 cluster, predominantly expressed in human embryonic stem cells (hESs), can promote the cellular reprogramming of human and mouse cells and contribute to the generation of iPSC. We have used the epigenetic reprogramming potential of the miR-302/367 cluster to deprogram tumor cells, that is, hift their gene expression pattern towards an alternative program associated with more benign cellular phenotypes. Induction of the miR-302/367 cluster in extensively mutated U87MG glioblastoma cells drastically suppressed the expression of transformation related proteins, for example, the reprogramming factors OCT3/4, SOX2, KLF4 and c-MYC, and the transcription factors POU3F2, SALL2 and OLIG2, required for the maintenance of glioblastoma stem-like tumor propagating cells. It also diminished PI3K/AKT and STAT3 signaling, impeded colony formation in soft agar and cell migration and suppressed pro-inflammatory cytokine secretion. At the same time, the miR-302/367 cluster restored the expression of neuronal markers of differentiation. Most notably, miR-302/367 cluster expressing cells lose their ability to form tumors and to establish liver metastasis in nude mice. The induction of the miR-302/367 cluster in U87MG glioblastoma cells suppresses the expression of multiple transformation related genes, abolishes the tumor and metastasis formation potential of these cells and can potentially become a new approach for cancer therapy.
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