Transcriptomic study of dormant gastrointestinal cancer stem cells

Nishikawa,Shimpei; Dewi,Dyah  Laksmi; Ishii,Hideshi; Konno,Masamitsu; Haraguchi,Naotsugu; Kano,Yoshihiro; Fukusumi,Takahito; Ohta,Katsuya; Noguchi,Yuko; Ozaki,Miyuki; Sakai,Daisuke; Satoh,Taroh; Doki,Yuichiro; Mori,Masaki

doi:10.3892/ijo.2012.1531

Transcriptomic study of dormant gastrointestinal cancer stem cells

Authors:
- Shimpei Nishikawa
- Dyah Laksmi Dewi
- Hideshi Ishii
- Masamitsu Konno
- Naotsugu Haraguchi
- Yoshihiro Kano
- Takahito Fukusumi
- Katsuya Ohta
- Yuko Noguchi
- Miyuki Ozaki
- Daisuke Sakai
- Taroh Satoh
- Yuichiro Doki
- Masaki Mori
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Affiliations: Department of Frontier Science for Cancer and Chemotherapy, Osaka University, Graduate School of Medicine, Suita, Osaka 565-0871, Japan, Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Suita, Osaka 565-0871, Japan
Published online on: June 25, 2012 https://doi.org/10.3892/ijo.2012.1531
Pages: 979-984

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Abstract

We previously discovered the coexistence of dormant and proliferating cancer stem cells (CSCs) in gastrointestinal cancer, which leads to chemoradiation resistance. CD13-/CD90+ proliferating liver CSCs are sensitive to chemotherapy, and CD13+/CD90- dormant CSCs have a limited proliferation ability, survive in hypoxic areas with reduced oxidative stress, and relapse and metastasize to other organs. In such CD13+ dormant cells, non-homologous end-joining, an error-prone repair mechanism, is dominant after DNA damage, whereas high-fidelity homologous recombination is apparent in CD13- proliferating cells, suggesting the significance of dormancy as an essential protective mechanism of therapy resistance. However, this mechanism may also play a role in the generation and accumulation of heterogeneity during cancer progression, although the exact mechanism remains to be understood. Through transcriptomic study, we elucidated the underlying epigenetic mechanism for malignant behavior of dormant CSCs, i.e., simultaneous activation of several pathways including EZH2- and TP53-related proteins in response to microRNA101, suggesting that a pharmacogenomic approach would open an era to novel molecular targeting cancer therapy.

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1.	Reya T, Morrison SJ, Clarke MF and Weissman IL: Stem cells, cancer, and cancer stem cells. Nature. 414:105–111. 2001. View Article : Google Scholar : PubMed/NCBI
2.	Visvader JE and Lindeman GJ: Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 10:755–768. 2008. View Article : Google Scholar : PubMed/NCBI
3.	Dewi DL, Ishii H, Kano Y, et al: Cancer stem cell theory in gastrointestinal malignancies: recent progress and upcoming challenges. J Gastroenterol. 46:1145–1157. 2011. View Article : Google Scholar : PubMed/NCBI
4.	Li L and Clevers H: Coexistence of quiescent and active adult stem cells in mammals. Science. 327:542–545. 2010. View Article : Google Scholar : PubMed/NCBI
5.	Haraguchi N, Ishii H, Mimori K, et al: CD13 is a therapeutic target in human liver cancer stem cells. J Clin Invest. 120:3326–3339. 2010. View Article : Google Scholar : PubMed/NCBI
6.	Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K and Linn S: Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem. 73:39–85. 2004. View Article : Google Scholar : PubMed/NCBI
7.	Nishikawa S, Ishii H, Haraguchi N, et al: Genotoxic therapy stimulates error-prone DNA repair in dormant hepatocellular cancer stem cells. Exp Ther Med. (In press).
8.	Haraguchi N, Ishii H, Nagano H, Doki Y and Mori M: The future prospects and subject of the liver cancer stem cells study for the clinical application. Gastroenterology. Feb 23–2011.(Epub ahead of print).
9.	Kim HM, Haraguchi N, Ishii H, et al: Increased CD13 expression reduces reactive oxygen species, promoting survival of liver cancer stem cells via an epithelial-mesenchymal transition-like phenomenon. Ann Surg Oncol. Aug 31–2011.(Epub ahead of print).
10.	Yang ZF, Ho DW, Ng MN, et al: Significance of CD90⁺ cancer stem cells in human liver cancer. Cancer Cell. 13:153–166. 2008.
11.	Weinstock DM, Richardson CA, Elliott B and Jasin M: Modeling oncogenic translocations: distinct roles for double-strand break repair pathways in translocation formation in mammalian cells. DNA Repair (Amst). 5:1065–1074. 2006. View Article : Google Scholar
12.	Ishii H, Iwatsuki M, Ieta K, Ohta D, Haraguchi N, Mimori K and Mori M: Cancer stem cells and chemoradiation resistance. Cancer Sci. 99:1871–1877. 2008. View Article : Google Scholar
13.	Chen H, Rossier C and Antonarakis SE: Cloning of a human homolog of the Drosophila enhancer of zeste gene (EZH2) that maps to chromosome 21q22.2. Genomics. 38:30–37. 1996. View Article : Google Scholar : PubMed/NCBI
14.	Varambally S, Cao Q, Mani RS, et al: Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science. 322:1695–1699. 2008. View Article : Google Scholar : PubMed/NCBI
15.	Friedman JM, Liang G, Liu CC, et al: The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2. Cancer Res. 69:2623–2629. 2009. View Article : Google Scholar : PubMed/NCBI
16.	Cao P, Deng Z, Wan M, Huang W, et al: MicroRNA-101 negatively regulates Ezh2 and its expression is modulated by androgen receptor and HIF-1alpha/HIF-1beta. Mol Cancer. 9:1082010. View Article : Google Scholar : PubMed/NCBI
17.	Wang HJ, Ruan HJ, He XJ, et al: MicroRNA-101 is down-regulated in gastric cancer and involved in cell migration and invasion. Eur J Cancer. 46:2295–2303. 2010. View Article : Google Scholar : PubMed/NCBI
18.	Bao B, Ali S, Banerjee S, Wang Z, et al: Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res. 72:335–345. 2012. View Article : Google Scholar : PubMed/NCBI
19.	Zhang JG, Guo JF, Liu DL, Liu Q and Wang JJ: MicroRNA-101 exerts tumor-suppressive functions in non-small cell lung cancer through directly targeting enhancer of zeste homolog 2. J Thorac Oncol. 6:671–678. 2011. View Article : Google Scholar : PubMed/NCBI
20.	Smits M, Nilsson J, Mir SE, et al: miR-101 is down-regulated in glioblastoma resulting in EZH2-induced proliferation, migration, and angiogenesis. Oncotarget. 1:710–720. 2010.PubMed/NCBI
21.	Banerjee R, Mani RS, Russo N, et al: The tumor suppressor gene rap1GAP is silenced by miR-101-mediated EZH2 overexpression in invasive squamous cell carcinoma. Oncogene. 30:4339–4349. 2011. View Article : Google Scholar : PubMed/NCBI
22.	Moskwa P, Buffa FM, Pan Y, et al: miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol Cell. 41:210–220. 2011. View Article : Google Scholar : PubMed/NCBI
23.	Liu Z, Liu J, Segura MF, et al: MiR182 overexpression in tumorigenesis of high-grade ovarian papillary serous carcinoma. J Pathol. Feb 9–2012.(Epub ahead of print).
24.	Segura MF, Hanniford D, Menendez S, et al: Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor. Proc Natl Acad Sci USA. 106:1814–1819. 2009. View Article : Google Scholar : PubMed/NCBI
25.	Dewi DL, Ishii H, Haraguchi N, et al: Reprogramming of gastrointestinal cancer cells. Cancer Sci. 103:393–399. 2012. View Article : Google Scholar