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Article

Exogenous Cripto-1 Suppresses Self-Renewal of Cancer Stem Cell Model

by
Md Jahangir Alam
1,2,
Ryota Takahashi
1,
Said M. Afify
1,3,
Aung Ko Ko Oo
1,
Kazuki Kumon
1,
Hend M. Nawara
1,
Aprilliana Cahya Khayrani
1,
Juan Du
1,
Maram H. Zahra
4,
Akimasa Seno
4,5,
David S. Salomon
6 and
Masaharu Seno
1,4,*
1
Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan
2
Department of Genetic Engineering and Biotechnology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
3
Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufia University, Shebin ElKoum-Menoufia 32511, Egypt
4
Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, Okayama 700-8530, Japan
5
Okayama University Research Laboratory of Stem Cell Engineering in Detroit, IBio, Wayne State University, Detroit, MI 48202, USA
6
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(11), 3345; https://doi.org/10.3390/ijms19113345
Submission received: 27 September 2018 / Revised: 19 October 2018 / Accepted: 20 October 2018 / Published: 26 October 2018
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Abstract

Cripto-1 is a glycophosphatidylinositol (GPI) anchored signaling protein of epidermal growth factor (EGF)-Cripto-1-FRL1-Cryptic (CFC) family and plays a significant role in the early developmental stages and in the different types of cancer cells, epithelial to mesenchymal transition and tumor angiogenesis. Previously, we have developed cancer stem cells (miPS-LLCcm) from mouse iPSCs by culturing them in the presence of conditioned medium of Lewis Lung Carcinoma (LLC) cells for four weeks. Nodal and Cripto-1 were confirmed to be expressed in miPS-LLCcm cells by quantitative reverse transcription PCR (rt-qPCR) implying that Cr-1 was required in maintaining stemness. To investigate the biological effect of adding exogenous soluble CR-1 to the cancer stem cells, we have prepared a C-terminally truncated soluble form of recombinant human CR-1 protein (rhsfCR-1), in which the GPI anchored moiety was removed by substitution of a stop codon through site-directed mutagenesis. rhsfCR-1 effectively suppressed the proliferation and sphere forming ability of miPS-LLCcm cells in a dose-dependent manner in the range of 0 to 5 µg/mL, due to the suppression of Nodal-Cripto-1/ALK4/Smad2 signaling pathway. Frequency of sphere-forming cells was dropped from 1/40 to 1/69 by rhsfCR-1 at 1 µg/mL. Moreover, rhsfCR-1 in the range of 0 to 1 µg/mL also limited the differentiation of miPS-LLCcm cells into vascular endothelial cells probably due to the suppression of self-renewal, which should reduce the number of cells with stemness property. As demonstrated by a soluble form of exogenous Cripto-1 in this study, the efficient blockade would be an attractive way to study Cripto-1 dependent cancer stem cell properties for therapeutic application.
Keywords: mouse iPS; miPS-LLCcm; Cripto-1; recombinant Cripto-1; self-renewal; cancer stem cells mouse iPS; miPS-LLCcm; Cripto-1; recombinant Cripto-1; self-renewal; cancer stem cells
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MDPI and ACS Style

Alam, M.J.; Takahashi, R.; Afify, S.M.; Oo, A.K.K.; Kumon, K.; Nawara, H.M.; Khayrani, A.C.; Du, J.; Zahra, M.H.; Seno, A.; et al. Exogenous Cripto-1 Suppresses Self-Renewal of Cancer Stem Cell Model. Int. J. Mol. Sci. 2018, 19, 3345. https://doi.org/10.3390/ijms19113345

AMA Style

Alam MJ, Takahashi R, Afify SM, Oo AKK, Kumon K, Nawara HM, Khayrani AC, Du J, Zahra MH, Seno A, et al. Exogenous Cripto-1 Suppresses Self-Renewal of Cancer Stem Cell Model. International Journal of Molecular Sciences. 2018; 19(11):3345. https://doi.org/10.3390/ijms19113345

Chicago/Turabian Style

Alam, Md Jahangir, Ryota Takahashi, Said M. Afify, Aung Ko Ko Oo, Kazuki Kumon, Hend M. Nawara, Aprilliana Cahya Khayrani, Juan Du, Maram H. Zahra, Akimasa Seno, and et al. 2018. "Exogenous Cripto-1 Suppresses Self-Renewal of Cancer Stem Cell Model" International Journal of Molecular Sciences 19, no. 11: 3345. https://doi.org/10.3390/ijms19113345

APA Style

Alam, M. J., Takahashi, R., Afify, S. M., Oo, A. K. K., Kumon, K., Nawara, H. M., Khayrani, A. C., Du, J., Zahra, M. H., Seno, A., Salomon, D. S., & Seno, M. (2018). Exogenous Cripto-1 Suppresses Self-Renewal of Cancer Stem Cell Model. International Journal of Molecular Sciences, 19(11), 3345. https://doi.org/10.3390/ijms19113345

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