BMP-2 induces motility and invasiveness by promoting colon cancer stemness through STAT3 activation
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Bone morphogenetic proteins (BMPs) have been involved in metastatic progression and tumorigenesis of many cancer types. However, it remains unclear how BMP-2 contributes to the initiation and development of these cancers. Here, we investigated the role of BMP-2 in colon cancer stem cell (CSC) development from colon cancer cells. We also determined the effects of BMP-2 on CSC development and epithelial-mesenchymal transition (EMT) in human colon cancer cell lines HCT-116 and SW620. We found that BMP-2 enhanced sphere formation of colon cancer cells without serum. Also, BMP-2-induced spheres displayed up-regulation of stemness markers (CD133+ and EpCAM+) and increased drug resistance, hallmarks of CSCs. Importantly, expression of EMT activators p-Smad1/5 and Snail and N-cadherin was increased in the spheres’ cells, indicating that BMP-2 signaling might result in CSC self-renewal and EMT. Furthermore, siRNA-mediated knockdown of signal transducer and activator of transcription 3 (STAT3) in HCT-116 cells reversed BMP-2-induced EMT and stem cell formation. Taken together, our results suggest that the BMP-2 induced STAT3-mediated induction of colon cancer cell metastasis requires an EMT and/or changes in CSC markers.
KeywordsColon cancer Bone morphogenetic proteins Cancer stem cells Epithelial-mesenchymal transition Signal transducer and activator of transcription 3
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF2012R1A1A2042905) and supported by Korea University Grant (K1421591).
Conflicts of interest
- 25.Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa JJ, Renauld JC. Interleukin-22 (il-22) activates the jak/stat, erk, jnk, and p38 map kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from il-10. J Biol Chem. 2002;277:33676–82.CrossRefPubMedGoogle Scholar
- 30.Liao A, Wang W, Sun D, Jiang Y, Tian S, Li J, Yang X, Shi R. Bone morphogenetic protein 2 mediates epithelial-mesenchymal transition via akt and erk signaling pathways in gastric cancer. Tumour Biol. 2015;36:2773–78.Google Scholar
- 33.Piccirillo SG, Vescovi AL. Bone morphogenetic proteins regulate tumorigenicity in human glioblastoma stem cells. Ernst Schering Found Symp Proc. 2006;5:59–81.Google Scholar
- 41.Ghosh-Choudhury N, Abboud SL, Nishimura R, Celeste A, Mahimainathan L, Choudhury GG. Requirement of bmp-2-induced phosphatidylinositol 3-kinase and akt serine/threonine kinase in osteoblast differentiation and smad-dependent bmp-2 gene transcription. J Biol Chem. 2002;277:33361–8.CrossRefPubMedGoogle Scholar
- 42.Kashyap V, Rezende NC, Scotland KB, Shaffer SM, Persson JL, Gudas LJ, et al. Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the nanog, oct4, and sox2 pluripotency transcription factors with polycomb repressive complexes and stem cell micrornas. Stem Cells Dev. 2009;18:1093–108.CrossRefPubMedPubMedCentralGoogle Scholar