Ossifying fibroma tumor stem cells are maintained by epigenetic regulation of a TSP1/TGF-β/SMAD3 autocrine loop.

Haiyan Qin, Cunye Qu, Takayoshi Yamaza, Ruili Yang, Xia Lin, Xue Yan Duan, Kentaro Akiyama, Y. Liu, Qunzhou Zhang, Chider Chen, Yibu Chen, Hank Heng Qi, Xin Hua Feng, Anh D. Le, Songtao Shi

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Abnormal stem cell function makes a known contribution to many malignant tumors, but the role of stem cells in benign tumors is not well understood. Here, we show that ossifying fibroma (OF) contains a stem cell population that resembles mesenchymal stem cells (OFMSCs) and is capable of generating OF-like tumor xenografts. Mechanistically, OFMSCs show enhanced TGF-β signaling that induces aberrant proliferation and deficient osteogenesis via Notch and BMP signaling pathways, respectively. The elevated TGF-β activity is tightly regulated by JHDM1D-mediated epigenetic regulation of thrombospondin-1 (TSP1), forming a JHDM1D/TSP1/TGF-β/SMAD3 autocrine loop. Inhibition of TGF-β signaling in OFMSCs can rescue their abnormal osteogenic differentiation and elevated proliferation rate. Furthermore, chronic activation of TGF-β can convert normal MSCs into OF-like MSCs via establishment of this JHDM1D/TSP1/TGF-β/SMAD3 autocrine loop. These results reveal that epigenetic regulation of TGF-β signaling in MSCs governs the benign tumor phenotype in OF and highlight TGF-β signaling as a candidate therapeutic target.

Original languageEnglish
Pages (from-to)577-589
Number of pages13
JournalCell stem cell
Volume13
Issue number5
Publication statusPublished - Nov 7 2013

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Cell Biology

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  • Cite this

    Qin, H., Qu, C., Yamaza, T., Yang, R., Lin, X., Duan, X. Y., Akiyama, K., Liu, Y., Zhang, Q., Chen, C., Chen, Y., Qi, H. H., Feng, X. H., Le, A. D., & Shi, S. (2013). Ossifying fibroma tumor stem cells are maintained by epigenetic regulation of a TSP1/TGF-β/SMAD3 autocrine loop. Cell stem cell, 13(5), 577-589.