Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Cripto Enhances Proliferation and Survival of Mesenchymal Stem Cells by Up-Regulating JAK2/STAT3 Pathway in a GRP78-Dependent Manner

  • Yun, SeungPil (Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, The Johns Hopkins University School of Medicine) ;
  • Yun, Chul Won (Medical Science Research Institute, Soonchunhyang University, Seoul Hospital) ;
  • Lee, Jun Hee (Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine) ;
  • Kim, SangMin (Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Department of Neurology, The Johns Hopkins University School of Medicine) ;
  • Lee, Sang Hun (Medical Science Research Institute, Soonchunhyang University, Seoul Hospital)
  • Received : 2017.05.01
  • Accepted : 2017.06.09
  • Published : 2018.09.01
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Abstract

Cripto is a small glycosylphosphatidylinositol-anchored signaling protein that can detach from the anchored membrane and stimulate proliferation, migration, differentiation, vascularization, and angiogenesis. In the present study, we demonstrated that Cripto positively affected proliferation and survival of mesenchymal stem cells (MSCs) without affecting multipotency. Cripto also increased expression of phosphorylated janus kinase 2 (p-JAK2), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), 78 kDa glucose-regulated protein (GRP78), c-Myc, and cyclin D1. Notably, treatment with an anti-GRP78 antibody blocked these effects. In addition, pretreatment with STAT3 short interfering RNA (siRNA) inhibited the increase in p-JAK2, c-Myc, cyclin D1, and BCL3 levels caused by Cripto and attenuated the pro-survival action of Cripto on MSCs. We also found that incubation with Cripto protected MSCs from apoptosis caused by hypoxia or $H_2O_2$ exposure, and the level of caspase-3 decreased by the Cripto-induced expression of B-cell lymphoma 3-encoded protein (BCL3). These effects were sensitive to down-regulation of BCL3 expression by BCL3 siRNA. Finally, we showed that Cripto enhanced expression levels of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF). In summary, our results demonstrated that Cripto activated a novel biochemical cascade that potentiated MSC proliferation and survival. This cascade relied on phosphorylation of JAK2 and STAT3 and was regulated by GRP78. Our findings may facilitate clinical applications of MSCs, as these cells may benefit from positive effects of Cripto on their survival and biological properties.

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References

  1. Ahmed, S. U. and Milner, J. (2009) Basal cancer cell survival involves JNK2 suppression of a novel JNK1/c-Jun/Bcl-3 apoptotic network. PLoS ONE 4, e7305. https://doi.org/10.1371/journal.pone.0007305
  2. Akira, S., Nishio, Y., Inoue, M., Wang, X. J., Wei, S., Matsusaka, T., Yoshida, K., Sudo, T., Naruto, M. and Kishimoto, T. (1994) Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77, 63-71. https://doi.org/10.1016/0092-8674(94)90235-6
  3. Andersson, O., Korach-Andre, M., Reissmann, E., Ibanez, C. F. and Bertolino, P. (2008) Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity. Proc. Natl. Acad. Sci. U.S.A. 105, 7252-7256. https://doi.org/10.1073/pnas.0800272105
  4. Ball, L. M., Bernardo, M. E., Roelofs, H., Lankester, A., Cometa, A., Egeler, R. M., Locatelli, F. and Fibbe, W. E. (2007) Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood 110, 2764-2767. https://doi.org/10.1182/blood-2007-04-087056
  5. Bernardo, M. E., Ball, L. M., Cometa, A. M., Roelofs, H., Zecca, M., Avanzini, M. A., Bertaina, A., Vinti, L., Lankester, A., Maccario, R., Ringden, O., Le Blanc, K., Egeler, R. M., Fibbe, W. E. and Locatelli, F. (2011) Co-infusion of ex vivo-expanded, parental MSCs prevents life-threatening acute GVHD, but does not reduce the risk of graft failure in pediatric patients undergoing allogeneic umbilical cord blood transplantation. Bone Marrow Transplant. 46, 200-207. https://doi.org/10.1038/bmt.2010.87
  6. Bianco, C., Adkins, H. B., Wechselberger, C., Seno, M., Normanno, N., De Luca, A., Sun, Y., Khan, N., Kenney, N., Ebert, A., Williams, K. P., Sanicola, M. and Salomon, D. S. (2002) Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells. Mol. Cell. Biol. 22, 2586-2597. https://doi.org/10.1128/MCB.22.8.2586-2597.2002
  7. Caplan, A. I. (1991) Mesenchymal stem cells. J. Orthop. Res. 9, 641-650. https://doi.org/10.1002/jor.1100090504
  8. Cohen, G. M. (1997) Caspases: the executioners of apoptosis. Biochem. J. 326, 1-16. https://doi.org/10.1042/bj3260001
  9. da Silva Meirelles, L., Fontes, A. M., Covas, D. T. and Caplan, A. I. (2009) Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 20, 419-427. https://doi.org/10.1016/j.cytogfr.2009.10.002
  10. Ding, D. C., Shyu, W. C., Lin, S. Z. and Li, H. (2006) Current concepts in adult stem cell therapy for stroke. Curr. Med. Chem. 13, 3565-3574. https://doi.org/10.2174/092986706779026237
  11. Ding, D. C., Shyu, W. C., Lin, S. Z. and Li, H. (2007) The role of endothelial progenitor cells in ischemic cerebral and heart diseases. Cell Transplant. 16, 273-284. https://doi.org/10.3727/000000007783464777
  12. Dudka, A. A., Sweet, S. M. and Heath, J. K. (2010) Signal transducers and activators of transcription-3 binding to the fibroblast growth factor receptor is activated by receptor amplification. Cancer Res. 70, 3391-3401. https://doi.org/10.1158/0008-5472.CAN-09-3033
  13. Gonzalez-Gronow, M., Selim, M. A., Papalas, J. and Pizzo, S. V. (2009) GRP78: a multifunctional receptor on the cell surface. Antioxid. Redox. Signal. 11, 2299-2306. https://doi.org/10.1089/ars.2009.2568
  14. Gorin, C., Rochefort, G. Y., Bascetin, R., Ying, H., Lesieur, J., Sadoine, J., Beckouche, N., Berndt, S., Novais, A., Lesage, M., Hosten, B., Vercellino, L., Merlet, P., Le-Denmat, D., Marchiol, C., Letourneur, D., Nicoletti, A., Vital, S. O., Poliard, A., Salmon, B., Muller, L., Chaussain, C. and Germain, S. (2016) Priming dental pulp stem cells with fibroblast growth factor-2 increases angiogenesis of implanted tissue-engineered constructs through hepatocyte growth factor and vascular endothelial growth factor secretion. Stem Cells Transl. Med. 5, 392-404. https://doi.org/10.5966/sctm.2015-0166
  15. Gray, P. C. and Vale, W. (2012) Cripto/GRP78 modulation of the TGF-${\beta}$ pathway in development and oncogenesis. FEBS Lett. 586, 1836-1845. https://doi.org/10.1016/j.febslet.2012.01.051
  16. Han, Y. S., Lee, J. H., Yoon, Y. M., Yun, C. W., Noh, H. and Lee, S. H. (2016) Hypoxia-induced expression of cellular prion protein improves the therapeutic potential of mesenchymal stem cells. Cell Death Dis. 7, e2395. https://doi.org/10.1038/cddis.2016.310
  17. Kelber, J. A., Panopoulos, A. D., Shani, G., Booker, E. C., Belmonte, J. C., Vale, W. W. and Gray, P. C. (2009) Blockade of Cripto binding to cell surface GRP78 inhibits oncogenic Cripto signaling via MAPK/PI3K and Smad2/3 pathways. Oncogene 28, 2324-2336. https://doi.org/10.1038/onc.2009.97
  18. Klauzinska, M., Castro, N. P., Rangel, M. C., Spike, B. T., Gray, P. C., Bertolette, D., Cuttitta, F. and Salomon, D. (2014) The multifaceted role of the embryonic gene Cripto-1 in cancer, stem cells and epithelial-mesenchymal transition. Semin. Cancer Biol. 29, 51-58. https://doi.org/10.1016/j.semcancer.2014.08.003
  19. Kohlmeier, L., Arminger, G., Bartolomeycik, S., Bellach, B., Rehm, J. and Thamm, M. (1992) Pet birds as an independent risk factor for lung cancer: case-control study. BMJ 305, 986-989. https://doi.org/10.1136/bmj.305.6860.986
  20. Le Blanc, K., Frassoni, F., Ball, L., Locatelli, F., Roelofs, H., Lewis, I., Lanino, E., Sundberg, B., Bernardo, M. E., Remberger, M., Dini, G., Egeler, R. M., Bacigalupo, A., Fibbe, W. and Ringden, O. (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371, 1579-1586. https://doi.org/10.1016/S0140-6736(08)60690-X
  21. Lee, J. H., Ryu, J. M., Han, Y. S., Zia, M. F., Kwon, H. Y., Noh, H., Han, H. J. and Lee, S. H. (2016a) Fucoidan improves bioactivity and vasculogenic potential of mesenchymal stem cells in murine hind limb ischemia associated with chronic kidney disease. J. Mol. Cell. Cardiol. 97, 169-179. https://doi.org/10.1016/j.yjmcc.2016.05.011
  22. Lee, S. C., Jeong, H. J., Lee, S. K. and Kim, S. J. (2016b) Hypoxic conditioned medium from human adipose-derived stem cells promotes mouse liver regeneration through JAK/STAT3 signaling. Stem Cells Transl. Med. 5, 816-825. https://doi.org/10.5966/sctm.2015-0191
  23. Lee, S. H., Lee, J. H., Han, Y. S., Ryu, J. M., Yoon, Y. M. and Han, H. J. (2015a) Hypoxia accelerates vascular repair of endothelial colony-forming cells on ischemic injury via STAT3-BCL3 axis. Stem Cell Res. Ther. 6, 139. https://doi.org/10.1186/s13287-015-0128-8
  24. Lee, S. H., Lee, K. B., Lee, J. H., Kang, S., Kim, H. G., Asahara, T. and Kwon, S. M. (2015b) Selective interference targeting of lnk in umbilical cord-derived late endothelial progenitor cells improves vascular repair, following hind limb ischemic injury, via regulation of JAK2/STAT3 signaling. Stem Cells 33, 1490-1500. https://doi.org/10.1002/stem.1938
  25. Li, J. and Lee, A. S. (2006) Stress induction of GRP78/BiP and its role in cancer. Curr. Mol. Med. 6, 45-54. https://doi.org/10.2174/156652406775574523
  26. Li, Z., Zhang, L., Zhao, Y., Li, H., Xiao, H., Fu, R., Zhao, C., Wu, H. and Li, Z. (2013) Cell-surface GRP78 facilitates colorectal cancer cell migration and invasion. Int. J. Biochem. Cell Biol. 45, 987-994. https://doi.org/10.1016/j.biocel.2013.02.002
  27. Luo, S., Mao, C., Lee, B. and Lee, A. S. (2006) GRP78/BiP is required for cell proliferation and protecting the inner cell mass from apoptosis during early mouse embryonic development. Mol. Cell. Biol. 26, 5688-5697. https://doi.org/10.1128/MCB.00779-06
  28. Minchiotti, G. (2005) Nodal-dependant Cripto signaling in ES cells: from stem cells to tumor biology. Oncogene 24, 5668-5675. https://doi.org/10.1038/sj.onc.1208917
  29. Misra, U. K., Payne, S. and Pizzo, S. V. (2011) Ligation of prostate cancer cell surface GRP78 activates a proproliferative and antiapoptotic feedback loop: a role for secreted prostate-specific antigen. J. Biol. Chem. 286, 1248-1259. https://doi.org/10.1074/jbc.M110.129767
  30. Ni, M., Zhang, Y. and Lee, A. S. (2011) Beyond the endoplasmic reticulum: atypical GRP78 in cell viability, signalling and therapeutic targeting. Biochem. J. 434, 181-188. https://doi.org/10.1042/BJ20101569
  31. Niu, G., Wright, K. L., Huang, M., Song, L., Haura, E., Turkson, J., Zhang, S., Wang, T., Sinibaldi, D., Coppola, D., Heller, R., Ellis, L. M., Karras, J., Bromberg, J., Pardoll, D., Jove, R. and Yu, H. (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21, 2000-2008. https://doi.org/10.1038/sj.onc.1205260
  32. Papageorgiou, I., Nicholls, P. K., Wang, F., Lackmann, M., Makanji, Y., Salamonsen, L. A., Robertson, D. M. and Harrison, C. A. (2009) Expression of nodal signalling components in cycling human endometrium and in endometrial cancer. Reprod. Biol. Endocrinol. 7, 122. https://doi.org/10.1186/1477-7827-7-122
  33. Pittenger, M. F., Mackay, A. M., Beck, S. C., Jaiswal, R. K., Douglas, R., Mosca, J. D., Moorman, M. A., Simonetti, D. W., Craig, S. and Marshak, D. R. (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284, 143-147. https://doi.org/10.1126/science.284.5411.143
  34. Sato, M., Yao, V. J., Arap, W. and Pasqualini, R. (2010) GRP78 signaling hub a receptor for targeted tumor therapy. Adv. Genet. 69, 97-114.
  35. Shani, G., Fischer, W. H., Justice, N. J., Kelber, J. A., Vale, W. and Gray, P. C. (2008) GRP78 and Cripto form a complex at the cell surface and collaborate to inhibit transforming growth factor ${\beta}$ signaling and enhance cell growth. Mol. Cell. Biol. 28, 666-677. https://doi.org/10.1128/MCB.01716-07
  36. Shen, M. M. (2007) Nodal signaling: developmental roles and regulation. Development 134, 1023-1034. https://doi.org/10.1242/dev.000166
  37. Spike, B. T., Kelber, J. A., Booker, E., Kalathur, M., Rodewald, R., Lipianskaya, J., La, J., He, M., Wright, T., Klemke, R., Wahl, G. M. and Gray, P. C. (2014) CRIPTO/GRP78 signaling maintains fetal and adult mammary stem cells ex vivo. Stem Cell Reports 2, 427-439. https://doi.org/10.1016/j.stemcr.2014.02.010
  38. Tan, Y., Huang, N., Zhang, X., Hu, J., Cheng, S., Pi, L. and Cheng, Y. (2016) KIAA0247 suppresses the proliferation, angiogenesis and promote apoptosis of human glioma through inactivation of the AKT and Stat3 signaling pathway. Oncotarget 7, 87100-87113.
  39. Xu, G. Y. and Tang, X. J. (2017) Troxerutin (TXN) potentiated 5-Fluorouracil (5-Fu) treatment of human gastric cancer through suppressing STAT3/NF-${\kappa}B$ and Bcl-2 signaling pathways. Biomed. Pharmacother. 92, 95-107. https://doi.org/10.1016/j.biopha.2017.04.059
  40. Xue, C., Xie, J., Zhao, D., Lin, S., Zhou, T., Shi, S., Shao, X., Lin, Y., Zhu, B. and Cai, X. (2017) The JAK/STAT3 signalling pathway regulated angiogenesis in an endothelial cell/adipose-derived stromal cell co-culture, 3D gel model. Cell Prolif. 50, e12307. https://doi.org/10.1111/cpr.12307
  41. Yao, X., Liu, H., Zhang, X., Zhang, L., Li, X., Wang, C. and Sun, S. (2015) Cell surface GRP78 accelerated breast cancer cell proliferation and migration by activating STAT3. PLoS ONE 10, e0125634. https://doi.org/10.1371/journal.pone.0125634
  42. Zhang, J. G., Zhao, J. and Xin, Y. (2010) Significance and relationship between Cripto-1 and p-STAT3 expression in gastric cancer and precancerous lesions. World J. Gastroenterol. 16, 571-577. https://doi.org/10.3748/wjg.v16.i5.571
  43. Zhang, X. X., Li, H. D., Zhao, S., Zhao, L., Song, H. J., Wang, G., Guo, Q. J., Luan, Z. D. and Su, R. J. (2013) The cell surface GRP78 facilitates the invasion of hepatocellular carcinoma cells. Biomed. Res. Int. 2013, 917296.
  44. Zhou, J., Ning, Z., Wang, B., Yun, E. J., Zhang, T., Pong, R. C., Fazli, L., Gleave, M., Zeng, J., Fan, J., Wang, X., Li, L., Hsieh, J. T., He, D. and Wu, K. (2015) DAB2IP loss confers the resistance of prostate cancer to androgen deprivation therapy through activating STAT3 and inhibiting apoptosis. Cell Death Dis. 6, e1955. https://doi.org/10.1038/cddis.2015.289

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