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

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Abstract

Previously, we have succeeded in converting induced pluripotent stem cells (iPSCs) into cancer stem cells (CSCs) by treating the iPSCs with conditioned medium of Lewis lung carcinoma (LLC) cells. The converted CSCs, named miPS-LLCcm cells, exhibited the self-renewal, differentiation potential, and potential to form malignant tumors with metastasis. In this study, we further characterized miPS-LLCcm cells both in vivo and in vitro. The tumors formed by subcutaneous injection showed the structures with pathophysiological features consisting of undifferentiated and malignant phenotypes generally found in adenocarcinoma. Metastasis in the lung was also observed as nodule structures. Excising from the tumors, primary cultured cells from the tumor and the nodule showed self-renewal, differentiation potential as well as tumor forming ability, which are the essential characters of CSCs. We then characterized the epigenetic regulation occurring in the CSCs. By comparing the DNA methylation level of CG rich regions, the differentially methylated regions (DMRs) were evaluated in all stages of CSCs when compared with the parental iPSCs. In DMRs, hypomethylation was found superior to hypermethylation in the miPS-LLCcm cells and its derivatives. The hypo- and hypermethylated genes were used to nominate KEGG pathways related with CSC. As a result, several categories were defined in the KEGG pathways from which most related with cancers, significant and high expression of components was PI3K-AKT signaling pathway. Simultaneously, the AKT activation was also confirmed in the CSCs. The PI3K-Akt signaling pathway should be an important pathway for the CSCs established by the treatment with conditioned medium of LLC cells.

Original languageEnglish
Pages (from-to)653-663
Number of pages11
JournalTranslational Oncology
Volume11
Issue number3
DOIs
Publication statusPublished - Jun 1 2018

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Tumor Microenvironment
Neoplastic Stem Cells
Phosphatidylinositol 3-Kinases
Up-Regulation
DNA
Induced Pluripotent Stem Cells
Lewis Lung Carcinoma
Neoplasms
Conditioned Culture Medium
Cultured Tumor Cells
Neoplasm Metastasis
DNA Methylation
Subcutaneous Injections
Epigenomics
Adenocarcinoma
Phenotype
Lung

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Oo, Aung Ko Ko; Calle, Anna Sanchez; Nair, Neha; Mahmud, Hafizah; Vaidyanath, Arun; Yamauchi, Junya; Khayrani, Aprilliana Cahya; Du, Juan; Alam, Md Jahangir; Seno, Akimasa; Mizutani, Akifumi; Murakami, Hiroshi; Iwasaki, Yoshiaki; Chen, Ling; Kasai, Tomonari; Seno, Masaharu.

In: Translational Oncology, Vol. 11, No. 3, 01.06.2018, p. 653-663.

Research output: Contribution to journalArticle

Oo, Aung Ko Ko ; Calle, Anna Sanchez ; Nair, Neha ; Mahmud, Hafizah ; Vaidyanath, Arun ; Yamauchi, Junya ; Khayrani, Aprilliana Cahya ; Du, Juan ; Alam, Md Jahangir ; Seno, Akimasa ; Mizutani, Akifumi ; Murakami, Hiroshi ; Iwasaki, Yoshiaki ; Chen, Ling ; Kasai, Tomonari ; Seno, Masaharu. / 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. In: Translational Oncology. 2018 ; Vol. 11, No. 3. pp. 653-663.
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abstract = "Previously, we have succeeded in converting induced pluripotent stem cells (iPSCs) into cancer stem cells (CSCs) by treating the iPSCs with conditioned medium of Lewis lung carcinoma (LLC) cells. The converted CSCs, named miPS-LLCcm cells, exhibited the self-renewal, differentiation potential, and potential to form malignant tumors with metastasis. In this study, we further characterized miPS-LLCcm cells both in vivo and in vitro. The tumors formed by subcutaneous injection showed the structures with pathophysiological features consisting of undifferentiated and malignant phenotypes generally found in adenocarcinoma. Metastasis in the lung was also observed as nodule structures. Excising from the tumors, primary cultured cells from the tumor and the nodule showed self-renewal, differentiation potential as well as tumor forming ability, which are the essential characters of CSCs. We then characterized the epigenetic regulation occurring in the CSCs. By comparing the DNA methylation level of CG rich regions, the differentially methylated regions (DMRs) were evaluated in all stages of CSCs when compared with the parental iPSCs. In DMRs, hypomethylation was found superior to hypermethylation in the miPS-LLCcm cells and its derivatives. The hypo- and hypermethylated genes were used to nominate KEGG pathways related with CSC. As a result, several categories were defined in the KEGG pathways from which most related with cancers, significant and high expression of components was PI3K-AKT signaling pathway. Simultaneously, the AKT activation was also confirmed in the CSCs. The PI3K-Akt signaling pathway should be an important pathway for the CSCs established by the treatment with conditioned medium of LLC cells.",
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AU - Calle, Anna Sanchez

AU - Nair, Neha

AU - Mahmud, Hafizah

AU - Vaidyanath, Arun

AU - Yamauchi, Junya

AU - Khayrani, Aprilliana Cahya

AU - Du, Juan

AU - Alam, Md Jahangir

AU - Seno, Akimasa

AU - Mizutani, Akifumi

AU - Murakami, Hiroshi

AU - Iwasaki, Yoshiaki

AU - Chen, Ling

AU - Kasai, Tomonari

AU - Seno, Masaharu

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