Activation of estrogen receptors with E2 downregulates peroxisome proliferator-activated receptor γ in hepatocellular carcinoma

Lin,Yueh-Min; Velmurugan,Bharath  Kumar; Yeh,Yu-Lan; Tu,Chuan   Chou; Ho,Tsung-Jung; Lai,Tung  Yuan; Tsai,Chih-Hao; Tsai,Fuu  Jen; Tsai,Chang-Hai; Huang,Chih-Yang

doi:10.3892/or.2013.2793

Activation of estrogen receptors with E2 downregulates peroxisome proliferator-activated receptor γ in hepatocellular carcinoma

Authors:
- Yueh-Min Lin
- Bharath Kumar Velmurugan
- Yu-Lan Yeh
- Chuan Chou Tu
- Tsung-Jung Ho
- Tung Yuan Lai
- Chih-Hao Tsai
- Fuu Jen Tsai
- Chang-Hai Tsai
- Chih-Yang Huang
View Affiliations

Affiliations: Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan, R.O.C., Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, R.O.C., Institute of Medical and Molecular Toxicology, Chung Shan University, Taichung, Taiwan, R.O.C., School of Chinese Medicine, China Medical University, Taichung, Taiwan, R.O.C., Department of Traditional Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, R.O.C., Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan, R.O.C., Department of Healthcare Administration, Asia University, Taichung, Taiwan, R.O.C.
Published online on: October 10, 2013 https://doi.org/10.3892/or.2013.2793
Pages: 3027-3031

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality and occurs more often in men than in women; however, little is known about its underlying molecular mechanisms. The present study investigated the effect of estrogen receptor (ER)α and ERβ on peroxisome proliferator-activated receptor γ (PPARγ) expression in Hep3B cells. We examined PPARγ, ERα and ERβ mRNA and protein expression by RT-PCR and western blotting. In order to determine whether PPARγ plays a central role in HCC, we screened for PPARγ expression in liver cancer patient tissues and differentially differentiated HCC cell lines (HA22T, Huh-7, Hep3B and HepG2). We found that PPARγ expression was highly expressed in liver cancer tissues and in Hep3B cells. Furthermore, overexpression of ERα and ERβ was found to decrease PPARγ expression at the transcriptional as well as at the translational level in a ligand-dependent manner. In summary, the present study demonstrated that both ERα and β were sufficient to inhibit PPARγ and provide a valuable therapeutic option for the treatment of HCC patients.

View Figures

View References

1	Greten TF, Papendorf F, Bleck JS, et al: Survival rate in patients with hepatocellular carcinoma: a retrospective analysis of 389 patients. Br J Cancer. 92:1862–1868. 2005. View Article : Google Scholar : PubMed/NCBI
2	El-Serag HB: Hepatocellular carcinoma: recent trends in the United States. Gastroenterology. 127:S27–S34. 2004. View Article : Google Scholar : PubMed/NCBI
3	Weng CJ, Chau CF, Hsieh YS, Yang SF and Yen GC: Lucidenic acid inhibits PMA-induced invasion of human hepatoma cells through inactivating MAPK/ERK signal transduction pathway and reducing binding activities of NF-κB and AP-1. Carcinogenesis. 29:147–156. 2008.PubMed/NCBI
4	El-Serag HB, Mason AC and Key C: Trends in survival of patients with hepatocellular carcinoma between 1977 and 1996 in the United States. Hepatology. 33:62–65. 2001. View Article : Google Scholar : PubMed/NCBI
5	Vacca M, Degirolamo C, Massafra V, et al: Nuclear receptors in regenerating liver and hepatocellular carcinoma. Mol Cell Endocrinol. 368:108–119. 2012. View Article : Google Scholar : PubMed/NCBI
6	Koeffler HP: Peroxisome proliferator-activated receptor γ and cancers. Clin Cancer Res. 9:1–9. 2003.
7	Vanden Heuvel JP: Peroxisome proliferator-activated receptors (PPARS) and carcinogenesis. Toxicol Sci. 47:1–8. 1999.PubMed/NCBI
8	Panigrahy D, Singer S, Shen LQ, et al: PPARγ ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J Clin Invest. 110:923–932. 2002.
9	Toyoda M, Takagi H, Horiguchi N, et al: A ligand for peroxisome proliferator activated receptor γ inhibits cell growth and induces apoptosis in human liver cancer cells. Gut. 50:563–567. 2002.
10	Wang X and Kilgore MW: Signal cross-talk between estrogen receptor alpha and beta and the peroxisome proliferator-activated receptor gamma1 in MDA-MB-231 and MCF-7 breast cancer cells. Mol Cell Endocrinol. 194:123–133. 2002. View Article : Google Scholar
11	Foryst-Ludwig A, Clemenz M, Hohmann S, et al: Metabolic actions of estrogen receptor beta (ERβ) are mediated by a negative cross-talk with PPARγ. PLoS Genet. 4:e10001082008.
12	Wu X, Subramaniam M, Grygo SB, et al: Estrogen receptor-beta sensitizes breast cancer cells to the anti-estrogenic actions of endoxifen. Breast Cancer Res. 13:R272011. View Article : Google Scholar : PubMed/NCBI
13	Ng IO, Ng M and Fan ST: Better survival in women with resected hepatocellular carcinoma is not related to tumor proliferation or expression of hormone receptors. Am J Gastroenterol. 92:1355–1358. 1997.PubMed/NCBI
14	Jonas S, Bechstein WO, Heinze T, et al: Female sex hormone receptor status in advanced hepatocellular carcinoma and outcome after surgical resection. Surgery. 121:456–461. 1997. View Article : Google Scholar : PubMed/NCBI
15	Kennelly R, Kavanagh DO, Hogan AM and Winter DC: Oestrogen and the colon: potential mechanisms for cancer prevention. Lancet Oncol. 9:385–391. 2008. View Article : Google Scholar : PubMed/NCBI
16	Yu J, Shen B, Chu ES, et al: Inhibitory role of peroxisome proliferator-activated receptor gamma in hepatocarcinogenesis in mice and in vitro. Hepatology. 51:2008–2019. 2010. View Article : Google Scholar : PubMed/NCBI
17	Borbath I and Horsmans Y: The role of PPARγ in hepatocellular carcinoma. PPAR Res. 2008:2095202008.
18	Li MY, Deng H, Zhao JM, Dai D and Tan XY: Peroxisome proliferator-activated receptor gamma ligands inhibit cell growth and induce apoptosis in human liver cancer BEL-7402 cells. World J Gastroenterol. 9:1683–1688. 2003.PubMed/NCBI
19	Lovat PE, Oliverio S, Ranalli M, et al: GADD153 and 12-lipoxygenase mediate fenretinide-induced apoptosis of neuroblastoma. Cancer Res. 62:5158–5167. 2002.PubMed/NCBI
20	Galbiati E, Caruso PL, Amari G, et al: Pharmacological actions of a novel, potent, tissue-selective benzopyran estrogen. J Pharmacol Exp Ther. 303:196–203. 2002. View Article : Google Scholar : PubMed/NCBI
21	Chen GG, Lee JF, Wang SH, Chan UP, Ip PC and Lau WY: Apoptosis induced by activation of peroxisome-proliferator activated receptor-gamma is associated with Bcl-2 and NF-kappaB in human colon cancer. Life Sci. 70:2631–2646. 2002. View Article : Google Scholar : PubMed/NCBI
22	Terashita Y, Sasaki H, Haruki N, et al: Decreased peroxisome proliferator-activated receptor gamma gene expression is correlated with poor prognosis in patients with esophageal cancer. Jpn J Clin Oncol. 32:238–243. 2002. View Article : Google Scholar : PubMed/NCBI
23	Cui Y, Miyoshi K, Claudio E, et al: Loss of the peroxisome proliferation-activated receptor gamma (PPARγ) does not affect mammary development and propensity for tumor formation but leads to reduced fertility. J Biol Chem. 277:17830–17835. 2002.
24	Yu J, Qiao L, Zimmermann L, et al: Troglitazone inhibits tumor growth in hepatocellular carcinoma in vitro and in vivo. Hepatology. 43:134–143. 2006. View Article : Google Scholar : PubMed/NCBI
25	Li MY, Hsin MK, Yip J, Mok TS, Underwood MJ and Chen GG: PPARgamma activation extinguishes smoking carcinogen by inhibiting NNK-mediated proliferation. Am J Respir Cell Mol Biol. 42:113–122. 2010. View Article : Google Scholar : PubMed/NCBI
26	Badawi AF and Badr MZ: Expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor-γ and levels of prostaglandin E₂ and 15-deoxy-Δ^12,14-prostaglandin J₂ in human breast cancer and metastasis. Int J Cancer. 103:84–90. 2003.
27	Sakamoto A, Yokoyama Y, Umemoto M, et al: Clinical implication of expression of cyclooxygenase-2 and peroxisome proliferator activated-receptor gamma in epithelial ovarian tumours. Br J Cancer. 91:633–638. 2004.PubMed/NCBI
28	Upla P, Marjomaki V, Kankaanpaa P, et al: Clustering induces a lateral redistribution of α2β1 integrin from membrane rafts to caveolae and subsequent protein kinase C-dependent internalization. Mol Biol Cell. 15:625–636. 2004.
29	Bonofiglio D, Gabriele S, Aquila S, et al: Estrogen receptor α binds to peroxisome proliferator-activated receptor response element and negatively interferes with peroxisome proliferator-activated receptor γ signaling in breast cancer cells. Clin Cancer Res. 11:6139–6147. 2005.