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BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

HNRNP G and HTRA2-BETA1 regulate estrogen receptor alpha expression with potential impact on endometrial cancer

Authors: Marc Hirschfeld, Yi Qin Ouyang, Markus Jaeger, Thalia Erbes, Marzenna Orlowska-Volk, Axel zur Hausen, Elmar Stickeler

Published in: BMC Cancer | Issue 1/2015

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Abstract

Background

Estrogen receptor alpha (ERa/ESR1) expression is regulated by alternative splicing. Its most frequently detectable exon7 skipping isoform (ERaD7) is a dominant negative variant. Elevated expression of ERaD7 was already detected in endometrial cancer (EC), while its potential prognostic significance has not been characterized so far. Exon7 contains potential binding sites for the two functional splicing regulatory opponents, HNRNPG and HTRA2-BETA1 known to trigger opposite effects on EC outcome.
This study served to elucidate the influence of HNRNPG and HTRA2-BETA1 on ERa exon7 splicing regulation and the impact of ERaD7 concentration on type 1 EC outcome.

Methods

Functional in vitro experiments for HNRNPG and HTRA2-BETA1 in regard to the regulatory impact on endogenous and exogenous ERaD7 splicing were performed. Additionally, real-time PCR determined mRNA levels of ERaD7, HNRNPG and HTRA2-BETA1 in 116 type 1 EC patients.

Results

HNRNPG and HTRA2-BETA1 were found to be specific regulators of ERa exon7 splicing. While HTRA2-BETA1 promoted exon7 inclusion, HNRNPG antagonized this effect by inducing exon7 skipping (p = 0.004). ERaD7 was detected in 71 out of 116 type 1 EC specimens. Statistical analyses revealed an inverse correlation between ERaD7 mRNA levels and tumor grading (p = 0.029), FIGO stage (p = 0.033) as well as lymph node metastases (p = 0.032), respectively. Furthermore, higher ERaD7 expression could be correlated to an improved disease-specific survival (p = 0.034).

Conclusions

Our study demonstrates antagonistic regulatory effects of HNRNPG and HTRA2-BETA1 on ERa exon7 splicing with potential impact on type 1 EC clinical outcome due to the consecutively variable expression levels of the ERa isoform D7.
Appendix
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Literature
1.
Stanojevic Z, Djordjevic B, Todorovska I, Lilic V, Zivadinovic R, Dunjic O. Risk factors and adjuvant chemotherapy in the treatment of endometrial cancer. J BUON. 2008;13(1):23–30.PubMed
2.
3.
Liu J, Mao Q, Liu Y, Hao X, Zhang S, Zhang J. Analysis of miR-205 and miR-155 expression in the blood of breast cancer patients. Chin J Cancer Res. 2013;25(1):46–54.PubMedPubMedCentral
4.
5.
Shabani N, Kuhn C, Kunze S, Schulze S, Mayr D, Dian D, et al. Prognostic significance of oestrogen receptor alpha (ERalpha) and beta (ERbeta), progesterone receptor A (PR-A) and B (PR-B) in endometrial carcinomas. Eur J Cancer. 2007;43(16):2434–44.CrossRefPubMed
6.
Krasner C. Aromatase inhibitors in gynecologic cancers. J Steroid Biochem Mol Biol. 2007;106(1–5):76–80.CrossRefPubMed
7.
Garcia Pedrero JM, Zuazua P, Martinez-Campa C, Lazo PS, Ramos S. The naturally occurring variant of estrogen receptor (ER) ERDeltaE7 suppresses estrogen-dependent transcriptional activation by both wild-type ERalpha and ERbeta. Endocrinology. 2003;144(7):2967–76.CrossRefPubMed
8.
Jazaeri O, Shupnik MA, Jazaeri AA, Rice LW. Expression of estrogen receptor alpha mRNA and protein variants in human endometrial carcinoma. Gynecol Oncol. 1999;74(1):38–47.CrossRefPubMed
9.
Fujimoto J, Ichigo S, Hirose R, Hori M, Tamaya T. Expression of estrogen receptor exon 5 splicing variant (ER E5SV) mRNA in gynaecological cancers. J Steroid Biochem Mol Biol. 1997;60(1–2):25–30.CrossRefPubMed
10.
Fuqua SA, Fitzgerald SD, Allred DC, Elledge RM, Nawaz Z, McDonnell DP, et al. Inhibition of estrogen receptor action by a naturally occurring variant in human breast tumors. Cancer Res. 1992;52(2):483–6.PubMed
11.
Marshburn PB, Zhang J, Bahrani-Mostafavi Z, Mostafavi BZ, Marroum MC, Mougeot JL, et al. Estrogen receptor-alpha messenger RNA variants that lack exon 5 or exon 7 are coexpressed with wild-type form in human endometrium during all phases of the menstrual cycle. Am J Obstet Gynecol. 2004;191(2):626–33. discussion 633–624.CrossRefPubMed
12.
Horvath G, Leser G, Hahlin M, Henriksson M. Exon deletions and variants of human estrogen receptor mRNA in endometrial hyperplasia and adenocarcinoma. Int J Gynecol Cancer. 2000;10(2):128–36.CrossRefPubMed
13.
Wong J, Weickert CS. Transcriptional interaction of an estrogen receptor splice variant and ErbB4 suggests convergence in gene susceptibility pathways in schizophrenia. J Biol Chem. 2009;284(28):18824–32.CrossRefPubMedPubMedCentral
14.
Ouyang YQ, zur Hausen A, Orlowska-Volk M, Jager M, Bettendorf H, Hirschfeld M, et al. Expression levels of hnRNP G and hTra2-beta1 correlate with opposite outcomes in endometrial cancer biology. Int J Cancer. 2011;128(9):2010–9.CrossRefPubMed
15.
Venables JP. Unbalanced alternative splicing and its significance in cancer. Bioessays. 2006;28(4):378–86.CrossRefPubMed
16.
Tavassoéli FA, Devilee P. WHO: World Health Organization. Pathology and Genetics of Tumours of the Breast and Female Genital Organs: Tumours of the Breast and Female Genital Organs. Lyon: IARC press; 2003.
17.
18.
Daoud R, Mies G, Smialowska A, Olah L, Hossmann KA, Stamm S. Ischemia induces a translocation of the splicing factor tra2-beta 1 and changes alternative splicing patterns in the brain. J Neurosci. 2002;22(14):5889–99.PubMed
19.
Witek A, Paul-Samojedny M, Stojko R, Seifert B, Mazurek U. Coexpression index of estrogen receptor alpha mRNA isoforms in simple, complex hyperplasia without atypia, complex atypical hyperplasia and adenocarcinoma. Gynecol Oncol. 2007;106(2):407–12.CrossRefPubMed
20.
Barone I, Brusco L, Fuqua SA. Estrogen receptor mutations and changes in downstream gene expression and signaling. Clin Cancer Res. 2010;16(10):2702–8.CrossRefPubMedPubMedCentral
21.
Gaub MP, Bellard M, Scheuer I, Chambon P, Sassone-Corsi P. Activation of the ovalbumin gene by the estrogen receptor involves the fos-jun complex. Cell. 1990;63(6):1267–76.CrossRefPubMed
22.
Ray A, Prefontaine KE, Ray P. Down-modulation of interleukin-6 gene expression by 17 beta-estradiol in the absence of high affinity DNA binding by the estrogen receptor. J Biol Chem. 1994;269(17):12940–6.PubMed
23.
Webb P, Lopez GN, Uht RM, Kushner PJ. Tamoxifen activation of the estrogen receptor/AP-1 pathway: potential origin for the cell-specific estrogen-like effects of antiestrogens. Mol Endocrinol. 1995;9(4):443–56.PubMed
24.
Weigel NL, Zhang Y. Ligand-independent activation of steroid hormone receptors. J Mol Med (Berl). 1998;76(7):469–79.CrossRef
25.
Horvath G, Leser G, Helou K, Henriksson M. Function of the exon 7 deletion variant estrogen receptor alpha protein in an estradiol-resistant, tamoxifen-sensitive human endometrial adenocarcinoma grown in nude mice. Gynecol Oncol. 2002;84(2):271–9.CrossRefPubMed
26.
Nazarali SA, Narod SA. Tamoxifen for women at high risk of breast cancer. Breast Cancer (Dove Med Press). 2014;6:29–36.
27.
Gotteland M, Desauty G, Delarue JC, Liu L, May E. Human estrogen receptor messenger RNA variants in both normal and tumor breast tissues. Mol Cell Endocrinol. 1995;112(1):1–13.CrossRefPubMed
28.
Perez I, Lin CH, McAfee JG, Patton JG. Mutation of PTB binding sites causes misregulation of alternative 3’ splice site selection in vivo. RNA. 1997;3(7):764–78.PubMedPubMedCentral
29.
30.
Chan RC, Black DL. The polypyrimidine tract binding protein binds upstream of neural cell-specific c-src exon N1 to repress the splicing of the intron downstream. Mol Cell Biol. 1997;17(8):4667–76.CrossRefPubMedPubMedCentral
31.
Spellman R, Rideau A, Matlin A, Gooding C, Robinson F, McGlincy N, et al. Regulation of alternative splicing by PTB and associated factors. Biochem Soc Trans. 2005;33(Pt 3):457–60.CrossRefPubMed
32.
33.
Valcarcel J, Gebauer F. Post-transcriptional regulation: the dawn of PTB. Curr Biol. 1997;7(11):R705–8.CrossRefPubMed
34.
Martinez-Contreras R, Cloutier P, Shkreta L, Fisette JF, Revil T, Chabot B. hnRNP proteins and splicing control. Adv Exp Med Biol. 2007;623:123–47.CrossRefPubMed
35.
Hofmann Y, Lorson CL, Stamm S, Androphy EJ, Wirth B. Htra2-beta 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2). Proc Natl Acad Sci U S A. 2000;97(17):9618–23.CrossRefPubMedPubMedCentral
36.
Tacke R, Tohyama M, Ogawa S, Manley JL. Human Tra2 proteins are sequence-specific activators of pre-mRNA splicing. Cell. 1998;93(1):139–48.CrossRefPubMed
37.
Nasim MT, Chernova TK, Chowdhury HM, Yue BG, Eperon IC. HnRNP G and Tra2beta: opposite effects on splicing matched by antagonism in RNA binding. Hum Mol Genet. 2003;12(11):1337–48.CrossRefPubMed
38.
Heinrich B, Zhang Z, Raitskin O, Hiller M, Benderska N, Hartmann AM, et al. Heterogeneous nuclear ribonucleoprotein G regulates splice site selection by binding to CC(A/C)-rich regions in pre-mRNA. J Biol Chem. 2009;284(21):14303–15.CrossRefPubMedPubMedCentral
Metadata
Title
HNRNP G and HTRA2-BETA1 regulate estrogen receptor alpha expression with potential impact on endometrial cancer
Authors
Marc Hirschfeld
Yi Qin Ouyang
Markus Jaeger
Thalia Erbes
Marzenna Orlowska-Volk
Axel zur Hausen
Elmar Stickeler
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1088-1

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