Up-Regulation of PI 3-Kinases and the Activation of PI3K-Akt Signaling Pathway in Cancer Stem-Like Cells Through DNA Hypomethylation Mediated by the Cancer.

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Up-Regulation of PI 3-Kinases and the Activation of PI3K-Akt Signaling Pathway in Cancer Stem-Like Cells Through DNA Hypomethylation Mediated by the Cancer Microenvironment Aung Ko Ko Oo, Anna Sanchez Calle, Neha Nair, Hafizah Mahmud, Arun Vaidyanath, Junya Yamauchi, Aprilliana Cahya Khayrani, Juan Du, Md Jahangir Alam, Akimasa Seno, Akifumi Mizutani, Hiroshi Murakami, Yoshiaki Iwasaki, Ling Chen, Tomonari Kasai, Masaharu Seno Translational Oncology Volume 11, Issue 3, Pages 653-663 (June 2018) DOI: 10.1016/j.tranon.2018.03.001 Copyright © 2018 Terms and Conditions

Figure 1 Characterization of miPS-LLCcm cells converted from miPSCs. (A) Summarized scheme of conversion of miPSCs. (B) Converted miPSCs in adherent culture (top) and in suspension culture (bottom). (C) Tumors and metastatic nodules in lungs generated by subcutaneously transplanted miPSCs, miPS-LLCcm cells and Ptdc cells into the Balb/c-nu mouse. Arrows in lung indicate the positions of nodules. The histogram showed the average number of lung nodules for each of the three cells. (D) The sizes of tumors growing in 4-6 weeks. (E) Ptdc cells in adherent culture (top) and sphere formation in suspension culture (bottom) with the expression of GFP. (F) LMN cells in adherent culture (top) and sphere formation in suspension culture (bottom) with the expression of GFP. (G) Comparison of the expression levels of stemness markers by rt-qPCR. a, miPSCs; b, miPS-LLCcm cells; c, Ptdc cells; d, LMN cells. Translational Oncology 2018 11, 653-663DOI: (10.1016/j.tranon.2018.03.001) Copyright © 2018 Terms and Conditions

Figure 2 Histological analyses of allografts of miPS-LLCcm cells. (A) High nuclear to cytoplasmic ratio (a) and with the mass of undifferentiated cells (asterisks in (b)), granular epithelial structure (arrows in (c)) and micrometastasis (arrows in (d)). (B) Metastatic nodules-like tumor in the lung pulmonary tissue (left), in the lung tissue (middle), and in the chest (right). (C) Teratoma from untreated miPSCs showing the three germ layers: squamous epithelial tissue (asterisks) in ectoderm (left), muscle tissue in mesoderm (middle) and gland-like structures (asterisks) in endoderm (right). (A-C) H&E staining. Translational Oncology 2018 11, 653-663DOI: (10.1016/j.tranon.2018.03.001) Copyright © 2018 Terms and Conditions

Figure 3 The localization and expression of CSC markers. (A) IHC analysis showing the expression of CD44 and ALDH1 in the tumor of the miPS-LLCcm cells. (B) The comparison of the expression of CD44 and ALDH1 the Ptdc and LMN cells with miPS-LLCcm by rt-qPCR analysis. ***P < .001, **P < .01, *P < .05. Translational Oncology 2018 11, 653-663DOI: (10.1016/j.tranon.2018.03.001) Copyright © 2018 Terms and Conditions

Figure 4 The localization and expression of EMT markers in miPS-LLCcm derived tumors. (A) Immuno-histochemical (IHC) analysis showed that ductal epithelial structure expressed MUC1 (left) and the undifferentiated mass of cells expressed the GFP (right). Comparison of the expression of (B) epithelial and mesenchymal markers (E-cadherin and N-cadherin) and (C) EMT markers in a, miPS-LLCcm cells; b, Ptdc cells and c, LMN cells. Translational Oncology 2018 11, 653-663DOI: (10.1016/j.tranon.2018.03.001) Copyright © 2018 Terms and Conditions

Figure 5 Results of hypomethylation analyses. Identification of DMRs and KEGG pathway analysis. (A) Relative DNA methylation levels of miPS-LLCcm cells, Ptdc cells and LMN cells compared to miPSCs. miPSCs vs. miPS-LLCcm cells (left), miPSCs vs. Ptdc cells (middle) and miPSCs vs. LMN cells (right). (B-D) Numbers of DMRs hypo- and hyper-methylated in each chromosome are depicted and KEGG pathways nominated with the number of hypomethylated genes. (B) miPSCs vs. miPS-LLCcm cells, (C) miPSCs vs. Ptdc cells and (D) miPSCs vs. LMN cells. Translational Oncology 2018 11, 653-663DOI: (10.1016/j.tranon.2018.03.001) Copyright © 2018 Terms and Conditions

Figure 6 Evaluation of the candidate signaling pathway nominated by the KEGG analysis. (A) rt-qPCR analyses of the candidate hypomethylated genes; (B) rt-qPCR analyses of Pik3cg (top) and Pik3ca (bottom); ***P < .001, **P < .01, *P < .05. (a, miPSCs; b, miPS-LLCcm cells; c, Ptdc cells; d, LMN cells). (C) Immunoblotting analysis of AKT activation and the expression of Pik3r5. Translational Oncology 2018 11, 653-663DOI: (10.1016/j.tranon.2018.03.001) Copyright © 2018 Terms and Conditions