Dehydroepiandrosterone-induces MiR-21 Transcription in HepG2 Cells Through Estrogen Receptor β and Androgen Receptor

Overview

Journal Mol Cell Endocrinol

Specialties Cell Biology
Endocrinology
Molecular Biology

Date 2014 May 22

PMID 24845419

Citations 17

Authors

Yun Teng

Lacey M Litchfield

Margarita M Ivanova

Russell A Prough

Barbara J Clark

Carolyn M Klinge

Affiliations

Soon will be listed here.

Abstract

Although oncomiR miR-21 is highly expressed in liver and overexpressed in hepatocellular carcinoma (HCC), its regulation is uncharacterized. We examined the effect of physiologically relevant nanomolar concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) on miR-21 expression in HepG2 human hepatoma cells. 10nM DHEA and DHEA-S increase pri-miR-21 transcription in HepG2 cells. Dietary DHEA increased miR-21 in vivo in mouse liver. siRNA and inhibitor studies suggest that DHEA-S requires desulfation for activity and that DHEA-induced pri-miR-21 transcription involves metabolism to androgen and estrogen receptor (AR and ER) ligands. Activation of ERβ and AR by DHEA metabolites androst-5-ene-3,17-dione (ADIONE), androst-5-ene-3β,17β-diol (ADIOL), dihydrotestosterone (DHT), and 5α-androstane-3β,17β-diol (3β-Adiol) increased miR-21 transcription. DHEA-induced miR-21 increased cell proliferation and decreased Pdcd4 protein, a bona fide miR-21. Estradiol (E2) inhibited miR-21 expression via ERα. DHEA increased ERβ and AR recruitment to the miR-21 promoter within the VMP1/TMEM49 gene, with possible significance in hepatocellular carcinoma.

Citing Articles

Identification and validation of PANoptosis-related LncRNAs prognosis system in hepatocellular carcinoma.

Shu Q, Zhu J, Mo J, Wei X, Zhu Z, Chen X Sci Rep. 2025; 15(1):6030.

PMID: 39972122 PMC: 11840146. DOI: 10.1038/s41598-025-90498-y.

The Estrogen-Autophagy Axis: Insights into Cytoprotection and Therapeutic Potential in Cancer and Infection.

Zhao Y, Klionsky D, Wang X, Huang Q, Deng Z, Xiang J Int J Mol Sci. 2024; 25(23).

PMID: 39684286 PMC: 11641569. DOI: 10.3390/ijms252312576.

Sex difference in liver diseases: How preclinical models help to dissect the sex-related mechanisms sustaining NAFLD and hepatocellular carcinoma.

Smiriglia A, Lorito N, Serra M, Perra A, Morandi A, Kowalik M iScience. 2023; 26(12):108363.

PMID: 38034347 PMC: 10682354. DOI: 10.1016/j.isci.2023.108363.

The role of NLRP3 inflammasome in hepatocellular carcinoma.

Zhao H, Zhang Y, Zhang Y, Chen C, Liu H, Yang Y Front Pharmacol. 2023; 14:1150325.

PMID: 37153780 PMC: 10157400. DOI: 10.3389/fphar.2023.1150325.

Interaction between Non-Coding RNAs and Androgen Receptor with an Especial Focus on Prostate Cancer.

Taheri M, Khoshbakht T, Jamali E, Kallenbach J, Ghafouri-Fard S, Baniahmad A Cells. 2021; 10(11).

PMID: 34831421 PMC: 8619311. DOI: 10.3390/cells10113198.

References

Inaki K, Hillmer A, Ukil L, Yao F, Woo X, Vardy L . Transcriptional consequences of genomic structural aberrations in breast cancer. Genome Res. 2011; 21(5):676-87. PMC: 3083084. DOI: 10.1101/gr.113225.110. View

Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo Y . MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res. 2008; 18(3):350-9. DOI: 10.1038/cr.2008.24. View

Liu D, Dillon J . Dehydroepiandrosterone activates endothelial cell nitric-oxide synthase by a specific plasma membrane receptor coupled to Galpha(i2,3). J Biol Chem. 2002; 277(24):21379-88. DOI: 10.1074/jbc.M200491200. View

Tan J, Sharief Y, Hamil K, Gregory C, Zang D, Sar M . Dehydroepiandrosterone activates mutant androgen receptors expressed in the androgen-dependent human prostate cancer xenograft CWR22 and LNCaP cells. Mol Endocrinol. 1997; 11(4):450-9. DOI: 10.1210/mend.11.4.9906. View

Purohit A, Woo L, Potter B . Steroid sulfatase: a pivotal player in estrogen synthesis and metabolism. Mol Cell Endocrinol. 2011; 340(2):154-60. DOI: 10.1016/j.mce.2011.06.012. View

Rainey W, Nakamura Y . Regulation of the adrenal androgen biosynthesis. J Steroid Biochem Mol Biol. 2007; 108(3-5):281-6. PMC: 2699571. DOI: 10.1016/j.jsbmb.2007.09.015. View

Rijk J, Bovee T, Peijnenburg A, Groot M, Rietjens I, Nielen M . Bovine liver slices: A multifunctional in vitro model to study the prohormone dehydroepiandrosterone (DHEA). Toxicol In Vitro. 2012; 26(6):1014-21. DOI: 10.1016/j.tiv.2012.04.012. View

Yeh S, Chen P . Gender disparity of hepatocellular carcinoma: the roles of sex hormones. Oncology. 2010; 78 Suppl 1:172-9. DOI: 10.1159/000315247. View

Androsavich J, Chau B, Bhat B, Linsley P, Walter N . Disease-linked microRNA-21 exhibits drastically reduced mRNA binding and silencing activity in healthy mouse liver. RNA. 2012; 18(8):1510-26. PMC: 3404372. DOI: 10.1261/rna.033308.112. View

10.

Mizokami A, Koh E, Fujita H, Maeda Y, Egawa M, Koshida K . The adrenal androgen androstenediol is present in prostate cancer tissue after androgen deprivation therapy and activates mutated androgen receptor. Cancer Res. 2004; 64(2):765-71. DOI: 10.1158/0008-5472.can-03-0130. View

11.

Dougherty S, Mazhawidza W, Bohn A, Robinson K, Mattingly K, Blankenship K . Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells. Endocr Relat Cancer. 2006; 13(1):113-34. PMC: 1472635. DOI: 10.1677/erc.1.01118. View

12.

Traish A, Kang H, Saad F, Guay A . Dehydroepiandrosterone (DHEA)--a precursor steroid or an active hormone in human physiology. J Sex Med. 2011; 8(11):2960-82. DOI: 10.1111/j.1743-6109.2011.02523.x. View

13.

Shimizu I . Impact of oestrogens on the progression of liver disease. Liver Int. 2003; 23(1):63-9. DOI: 10.1034/j.1600-0676.2003.00811.x. View

14.

Paris O, Ferraro L, Grober O, Ravo M, De Filippo M, Giurato G . Direct regulation of microRNA biogenesis and expression by estrogen receptor beta in hormone-responsive breast cancer. Oncogene. 2012; 31(38):4196-206. DOI: 10.1038/onc.2011.583. View

15.

White N, Fatoohi E, Metias M, Jung K, Stephan C, Yousef G . Metastamirs: a stepping stone towards improved cancer management. Nat Rev Clin Oncol. 2010; 8(2):75-84. DOI: 10.1038/nrclinonc.2010.173. View

16.

Pinthus J, Bryskin I, Trachtenberg J, Lu J, Singh G, Fridman E . Androgen induces adaptation to oxidative stress in prostate cancer: implications for treatment with radiation therapy. Neoplasia. 2007; 9(1):68-80. PMC: 1803036. DOI: 10.1593/neo.06739. View

17.

Miller K, Al-Rayyan N, Ivanova M, Mattingly K, Ripp S, Klinge C . DHEA metabolites activate estrogen receptors alpha and beta. Steroids. 2012; 78(1):15-25. PMC: 3529809. DOI: 10.1016/j.steroids.2012.10.002. View

18.

Wu H, Tweedie D, Milewich L, Frenkel R, Estabrook R, Prough R . Induction of microsomal NADPH-cytochrome P-450 reductase and cytochrome P-450IVA1 (P-450LA omega) by dehydroepiandrosterone in rats: a possible peroxisomal proliferator. Cancer Res. 1989; 49(9):2337-43. View

19.

Ribas J, Lupold S . The transcriptional regulation of miR-21, its multiple transcripts, and their implication in prostate cancer. Cell Cycle. 2010; 9(5):923-9. PMC: 3462654. DOI: 10.4161/cc.9.5.10930. View

20.

Petrovic N, Mandusic V, Stanojevic B, Lukic S, Todorovic L, Roganovic J . The difference in miR-21 expression levels between invasive and non-invasive breast cancers emphasizes its role in breast cancer invasion. Med Oncol. 2014; 31(3):867. DOI: 10.1007/s12032-014-0867-x. View