Induction of LGR5 by H2O2 treatment is associated with cell proliferation via the JNK signaling pathway in colon cancer cells

Kim,Sung-Hee; Kim,Kyung-Hee; Yoo,Byong-Chul; Ku,Ja-Lok

doi:10.3892/ijo.2012.1596

November 2012 Volume 41 Issue 5

Full Size Image

Cover Legend PDF

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

November 2012 Volume 41 Issue 5

Full Size Image

Cover Legend PDF

Article

Induction of LGR5 by H2O2 treatment is associated with cell proliferation via the JNK signaling pathway in colon cancer cells

Authors:
- Sung-Hee Kim
- Kyung-Hee Kim
- Byong-Chul Yoo
- Ja-Lok Ku
View Affiliations / Copyright

Affiliations: Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-744, Republic of Korea, Colorectal Cancer Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi 411-764, Republic of Korea
Pages: 1744-1750
|
Published online on: August 22, 2012

https://doi.org/10.3892/ijo.2012.1596
Expand metrics +

Abstract

Recently, the leucine-rich repeat G protein-coupled receptor 5 (LGR5/GPR49) was identified as a potential marker of intestinal stem cells in human. The LGR5 is known as a Wnt signaling target gene, and its expression pattern is related with β-catenin mutation. H2O2 is a member of reactive oxygen species (ROS) and regulates metabolism, aging, apoptosis and the intensity of growth factor signaling. In addition, it acts as a negative or positive regulator of Wnt signaling. However, the effect of H2O2 on Wnt signaling and its target gene LGR5 is not clear. In this study, we investigated the effects of ROS on cancer stem cells, in colorectal cancer cells. Colorectal cancer cells were treated with exogenous H2O2, after which cellular responses and the expression of LGR5 were examined. In SNU-C2A cells, proliferation increased following treatment with 50-300 µM of H2O2, whereas cell viability significantly decreased after treatment with 600-900 µM of H2O2. Expression of heme oxygenase (HO)-1 and jun, which aid in the reduction of oxidative stress, were induced in the low dose H2O2-treated SNU-C2A cells. The LGR5 expression level was significantly increased following 50-300 µM H2O2 treatment; in addition, β-catenin was increased in H2O2-treated colon cancer cells. However, the increased β-catenin was detected not in the nucleus but in the cytoplasm, which means that β-catenin was stabilized in the cytoplasm and not translocated into the nucleus where it could function as a transcription factor for the expression of LGR5. In addition, there was no direct interaction between LGR5 and β-catenin. In this study, we found that LGR5 expression increased when cancer cells were treated with a low dose of H2O2. Our results indicate that the LGR5 increase resulted via activation of the JNK signaling pathway. The induction of LGR5 expression influenced cell proliferation in colorectal cancer cells.

View Figures

View References

1.	Barker N and Clevers H: Tracking down the stem cells of the intestine: strategies to identify adult stem cells. Gastroenterology. 133:1755–1760. 2007. View Article : Google Scholar : PubMed/NCBI
2.	Barker N, van Es JH, Kuipers J, et al: Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 449:1003–1007. 2007. View Article : Google Scholar : PubMed/NCBI
3.	Becker L, Huang Q and Mashimo H: Immunostaining of Lgr5, an intestinal stem cell marker, in normal and premalignant human gastrointestinal tissue. Sci World J. 8:1168–1176. 2008. View Article : Google Scholar : PubMed/NCBI
4.	Barker N and Clevers H: Leucine-rich repeat-containing G-protein-coupled receptors as markers of adult stem cells. Gastroenterology. 138:1681–1696. 2010. View Article : Google Scholar : PubMed/NCBI
5.	Dalerba P, Cho RW and Clarke MF: Cancer stem cells: models and concepts. Annu Rev Med. 58:267–284. 2007. View Article : Google Scholar : PubMed/NCBI
6.	Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al: Identification and expansion of human colon-cancer-initiating cells. Nature. 445:111–115. 2007. View Article : Google Scholar : PubMed/NCBI
7.	Corbeil D, Röper K, Hellwig A, et al: The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions. J Biol Chem. 275:5512–5520. 2000. View Article : Google Scholar : PubMed/NCBI
8.	Burkert J, Wright NA and Alison MR: Stem cells and cancer: an intimate relationship. J Pathol. 209:287–297. 2006. View Article : Google Scholar : PubMed/NCBI
9.	Bao S, Wu Q, McLendon RE, et al: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 444:756–760. 2006. View Article : Google Scholar : PubMed/NCBI
10.	Li X, Lewis MT, Huang J, et al: Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 100:672–679. 2008. View Article : Google Scholar : PubMed/NCBI
11.	Phillips TM, McBride WH and Pajonk F: The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst. 98:1777–1785. 2006.
12.	Diehn M, Cho RW, Lobo NA, et al: Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 458:780–783. 2009. View Article : Google Scholar : PubMed/NCBI
13.	Fridovich I: The biology of oxygen radicals. Science. 201:875–880. 1978. View Article : Google Scholar : PubMed/NCBI
14.	Yamamoto Y, Sakamoto M, Fujii G, et al: Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepato-cellular carcinomas with beta-catenin mutations. Hepatology. 37:528–533. 2003. View Article : Google Scholar : PubMed/NCBI
15.	Fan XS, Wu HY, Yu HP, Zhou Q, Zhang YF and Huang Q: Expression of Lgr5 in human colorectal carcinogenesis and its potential correlation with beta-catenin. Int J Colorectal Dis. 25:583–590. 2010. View Article : Google Scholar : PubMed/NCBI
16.	Shin SY, Kim CG, Jho EH, et al: Hydrogen peroxide negatively modulates Wnt signaling through downregulation of beta-catenin. Cancer Lett. 212:225–231. 2004. View Article : Google Scholar : PubMed/NCBI
17.	Funato Y, Michiue T, Asashima M and Miki H: The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-beta-catenin signalling through dishevelled. Nat Cell Biol. 8:501–508. 2006. View Article : Google Scholar : PubMed/NCBI
18.	Oh JH, Ku JL, Yoon KA, et al: Establishment and characterization of 12 human colorectal-carcinoma cell lines. Int J Cancer. 81:902–910. 1999. View Article : Google Scholar : PubMed/NCBI
19.	Park IJ, Hwang JT, Kim YM, Ha J and Park OJ: Differential modulation of AMPK signaling pathways by low or high levels of exogenous reactive oxygen species in colon cancer cells. Ann NY Acad Sci. 1091:102–109. 2006. View Article : Google Scholar : PubMed/NCBI
20.	Boulares AH, Yakovlev AG, Ivanova V, Stoica BA, Wang G, Iyer S and Smulson M: Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis. J Biol Chem. 274:22932–22940. 1999. View Article : Google Scholar : PubMed/NCBI
21.	Busserolles J, Megias J, Terencio MC and Alcaraz MJ: Heme oxygenase-1 inhibits apoptosis in Caco-2 cells via activation of Akt pathway. Int J Biochem Cell Biol. 38:1510–1517. 2006. View Article : Google Scholar : PubMed/NCBI
22.	Aggeli IK, Gaitanaki C and Beis I: Involvement of JNKs and p38-MAPK/MSK1 pathways in H₂O₂-induced upregulation of heme oxygenase-1 mRNA in H9c2 cells. Cell Signal. 18:1801–1812. 2006. View Article : Google Scholar : PubMed/NCBI
23.	Myatt SS, Brosens JJ and Lam EW: Sense and sensitivity: FOXO and ROS in cancer development and treatment. Antioxid Redox Signal. 14:675–687. 2011. View Article : Google Scholar : PubMed/NCBI
24.	Liu SL, Lin X, Shi DY, Cheng J, Wu CQ and Zhang YD: Reactive oxygen species stimulated human hepatoma cell proliferation via cross-talk between PI3-K/PKB and JNK signaling pathways. Arch Biochem Biophys. 406:173–182. 2002. View Article : Google Scholar : PubMed/NCBI
25.	Aguilera C, Nakagawa K, Sancho R, Chakraborty A, Hendrich B and Behrens A: c-Jun N-terminal phosphorylation antagonises recruitment of the Mbd3/NuRD repressor complex. Nature. 469:231–235. 2011. View Article : Google Scholar : PubMed/NCBI
26.	Reya T and Clevers H: Wnt signalling in stem cells and cancer. Nature. 434:843–850. 2005. View Article : Google Scholar : PubMed/NCBI
27.	Zeilstra J, Joosten SP, Dokter M, Verwiel E, Spaargaren M and Pals ST: Deletion of the WNT target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis. Cancer Res. 68:3655–3661. 2008.PubMed/NCBI
28.	Giorgio M, Trinei M, Migliaccio E and Pelicci PG: Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals? Nat Rev Mol Cell Biol. 8:722–728. 2007. View Article : Google Scholar : PubMed/NCBI
29.	Lee YK, Lee MS, Kim YM and Park OJ: Effects of cotreatment of 12-O-tetradecanoylphorbol-13-acetate and H₂O₂ on apoptotic regulation via AMP-activated protein kinase-cyclooxygenase-2 signals. Ann NY Acad Sci. 1171:564–569. 2009. View Article : Google Scholar : PubMed/NCBI
30.	Sancho R, Nateri AS, De Vinuesa AG, et al: JNK signalling modulates intestinal homeostasis and tumourigenesis in mice. EMBO J. 28:1843–1854. 2009. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Induction of LGR5 by H2O2 treatment is associated with cell proliferation via the JNK signaling pathway in colon cancer cells

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Related Articles