Expression and clinical significance of estrogen‑regulated long non-coding RNAs in estrogen receptor α-positive ovarian cancer progression

Qiu,Jun-Jun; Ye,Le-Chi; Ding,Jing-Xin; Feng,Wei-Wei; Jin,Hong‑Yan; Zhang,Ying; Li,Qing; Hua,Ke-Qin

doi:10.3892/or.2014.3000

Expression and clinical significance of estrogen‑regulated long non-coding RNAs in estrogen receptor α-positive ovarian cancer progression

Authors:
- Jun-Jun Qiu
- Le-Chi Ye
- Jing-Xin Ding
- Wei-Wei Feng
- Hong‑Yan Jin
- Ying Zhang
- Qing Li
- Ke-Qin Hua
View Affiliations

Affiliations: Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, P.R. China, Department of General Surgery, Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China
Published online on: January 27, 2014 https://doi.org/10.3892/or.2014.3000
Pages: 1613-1622

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

Estrogen (E2) has long been implicated in epithelial ovarian cancer (EOC) progression. The effects of E2 on cancer progression can be mediated by numerous target genes, including coding RNAs and, more recently, non-coding RNAs (ncRNAs). Among the ncRNAs, long ncRNAs (lncRNAs) have emerged as new regulators in cancer progression; therefore, our aim was to determine whether the expression of any lncRNAs is regulated by E2 and, if so, whether a subset of these lncRNAs have some clinical significance in EOC progression. A microarray was performed to identify E2-regulated lncRNAs in E2 receptor (ER) α-positive EOC cells. Bioinformatics analyses of lncRNAs were conducted, focusing on gene ontology and pathway analyses. Quantitative real-time polymerase chain reactions were performed to confirm the expression of certain lncRNAs in ERα-positive EOC tissues. The correlation between certain lncRNA expression and clinicopathological factors as well as prognosis in ERα-positive EOC patients was then analyzed. We showed that 115 lncRNAs exhibited significant changes in E2-treated SKOV3 cells compared with untreated controls. Most of these lncRNAs were predicated to have potential to contribute to cancer progression. Notably, three candidates (TC0100223, TC0101686 and TC0101441) were aberrantly expressed in ERα-positive compared to ERα-negative EOC tissues, showing correlations with some malignant cancer phenotypes such as advanced FIGO stage and/or high histological grade. Furthermore, multivariate analysis indicated that TC0101441 was an independent prognostic factor for overall survival. Taken together, these results indicate for the first time that E2 can modulate lncRNA expression in ERα-positive EOC cells and that certain lncRNAs are correlated with advanced cancer progression and suggestive of a prognostic indicator in ERα-positive EOC patients. Knowledge of these E2-regulated lncRNAs could aid in the future understanding of the estrogenic effect on EOC progression and may assist in the clinical design of new target therapies based on a perspective of lncRNA.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar
3	Tsilidis KK, Allen NE, Key TJ, Dossus L, Kaaks R, Bakken K, Lund E, Fournier A, Dahm CC, Overvad K, Hansen L, Tjønneland A, Rinaldi S, Romieu I, Boutron-Ruault MC, Clavel-Chapelon F, Lukanova A, Boeing H, Schütze M, Benetou V, Palli D, Berrino F, Galasso R, Tumino R, Sacerdote C, Bueno-de-Mesquita HB, van Duijnhoven FJ, Braem MG, Onland-Moret NC, Gram IT, Rodríguez L, Duell EJ, Sánchez MJ, Huerta JM, Ardanaz E, Amiano P, Khaw KT, Wareham N and Riboli E: Menopausal hormone therapy and risk of ovarian cancer in the European prospective investigation into cancer and nutrition. Cancer Causes Control. 22:1075–1084. 2011. View Article : Google Scholar
4	Park SH, Cheung LW, Wong AS and Leung PC: Estrogen regulates snail and slug in the down-regulation of E-cadherin and induces metastatic potential of ovarian cancer cells through estrogen receptor alpha. Mol Endocrinol. 22:2085–2098. 2008. View Article : Google Scholar : PubMed/NCBI
5	Hua K, Din J, Cao Q, Feng W, Zhang Y, Yao L, Huang Y, Zhao Y and Feng Y: Estrogen and progestin regulate HIF-1α expression in ovarian cancer cell lines via the activation of Akt signaling transduction pathway. Oncol Rep. 21:893–898. 2009.
6	Hua K, Feng W, Cao Q, Zhou X, Lu X and Feng Y: Estrogen and progestin regulate metastasis through the PI3K/AKT pathway in human ovarian cancer. Int J Oncol. 33:959–967. 2008.PubMed/NCBI
7	Ding JX, Feng YJ, Yao LQ, Yu M, Jin HY and Yin LH: The reinforcement of invasion in epithelial ovarian cancer cells by 17β-estradiol is associated with upregulation of Snail. Gynecol Oncol. 103:623–630. 2006.PubMed/NCBI
8	Spillman MA, Manning NG, Dye WW, Sartorius CA, Post MD, Harrell JC, Jacobsen BM and Horwitz KB: Tissue-specific pathways for estrogen regulation of ovarian cancer growth and metastasis. Cancer Res. 70:8927–8936. 2010. View Article : Google Scholar : PubMed/NCBI
9	Laviolette LA, Garson K, Macdonald EA, Senterman MK, Courville K, Crane CA and Vanderhyden BC: 17β-estradiol accelerates tumor onset and decreases survival in a transgenic mouse model of ovarian cancer. Endocrinology. 151:929–938. 2010.
10	Twal WO, Czirok A, Hegedus B, Knaak C, Chintalapudi MR, Okagawa H, Sugi Y and Argraves WS: Fibulin-1 suppression of fibronectin regulated cell adhesion and motility. J Cell Sci. 114:4587–4598. 2001.PubMed/NCBI
11	Rochefort H, Chalbos D, Cunat S, Lucas A, Platet N and Garcia M: Estrogen regulated proteases and antiproteases in ovarian and breast cancer cells. J Steroid Biochem Mol Biol. 76:119–124. 2001. View Article : Google Scholar : PubMed/NCBI
12	Wilusz JE, Sunwoo H and Spector DL: Long noncoding RNAs: functional surprises from the RNA world. Genes Dev. 23:1494–1504. 2009. View Article : Google Scholar : PubMed/NCBI
13	Nagano T and Fraser P: No-nonsense functions for long noncoding RNAs. Cell. 145:178–181. 2011. View Article : Google Scholar : PubMed/NCBI
14	Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, Wang Y, Brzoska P, Kong B, Li R, West RB, van de Vijver MJ, Sukumar S and Chang HY: Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 464:1071–1076. 2010. View Article : Google Scholar : PubMed/NCBI
15	Tano K, Mizuno R, Okada T, Rakwal R, Shibato J, Masuo Y, Ijiri K and Akimitsu N: MALAT-1 enhances cell motility of lung adenocarcinoma cells by influencing the expression of motility-related genes. FEBS Lett. 584:4575–4580. 2010. View Article : Google Scholar : PubMed/NCBI
16	Matouk IJ, DeGroot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A and Galun E: The H19 non-coding RNA is essential for human tumor growth. PLoS One. 2:e8452007. View Article : Google Scholar : PubMed/NCBI
17	Du Y, Kong G, You X, Zhang S, Zhang T, Gao Y, Ye L and Zhang X: Elevation of highly up-regulated in liver cancer (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18. J Biol Chem. 287:26302–26311. 2012. View Article : Google Scholar : PubMed/NCBI
18	Huarte M, Guttman M, Feldser D, Garber M, Koziol MJ, Kenzelmann-Broz D, Khalil AM, Zuk O, Amit I, Rabani M, Attardi LD, Regev A, Lander ES, Jacks T and Rinn JL: A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response. Cell. 142:409–419. 2010. View Article : Google Scholar : PubMed/NCBI
19	Zhou Y, Zhang X and Klibanski A: MEG3 noncoding RNA: a tumor suppressor. J Mol Endocrinol. 48:R45–R53. 2012. View Article : Google Scholar : PubMed/NCBI
20	Silva JM, Boczek NJ, Berres MW, Ma X and Smith DI: LSINCT5 is over expressed in breast and ovarian cancer and affects cellular proliferation. RNA Biol. 8:496–505. 2011. View Article : Google Scholar : PubMed/NCBI
21	Rangel LB, Sherman-Baust CA, Wernyj RP, Schwartz DR, Cho KR and Morin PJ: Characterization of novel human ovarian cancer-specific transcripts (HOSTs) identified by serial analysis of gene expression. Oncogene. 22:7225–7232. 2003. View Article : Google Scholar : PubMed/NCBI
22	Xu W, Seok J, Mindrinos MN, Schweitzer AC, Jiang H, Wilhelmy J, Clark TA, Kapur K, Xing Y, Faham M, Storey JD, Moldawer LL, Maier RV, Tompkins RG, Wong WH, Davis RW and Xiao W: Human transcriptome array for high-throughput clinical studies. Proc Natl Acad Sci USA. 108:3707–3712. 2011. View Article : Google Scholar : PubMed/NCBI
23	Jia H, Osak M, Bogu GK, Stanton LW, Johnson R and Lipovich L: Genome-wide computational identification and manual annotation of human long noncoding RNA genes. RNA. 16:1478–1487. 2010. View Article : Google Scholar : PubMed/NCBI
24	Tafer H and Hofacker IL: RNAplex: a fast tool for RNA-RNA interaction search. Bioinformatics. 24:2657–2663. 2008. View Article : Google Scholar : PubMed/NCBI
25	Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC and Lempicki RA: DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 4:P32003. View Article : Google Scholar : PubMed/NCBI
26	Zhang C, Han L, Zhang A, Yang W, Zhou X, Pu P, Du Y, Zeng H and Kang C: Global changes of mRNA expression reveals an increased activity of the interferon-induced signal transducer and activator of transcription (STAT) pathway by repression of miR-221/222 in glioblastoma U251 cells. Int J Oncol. 36:1503–1512. 2010.PubMed/NCBI
27	Yang XY, Xi MR, Yang KX and Yu H: Prognostic value of estrogen receptor and progesterone receptor status in young Chinese ovarian carcinoma patients. Gynecol Oncol. 113:99–104. 2009. View Article : Google Scholar : PubMed/NCBI
28	Pujol P, Rey JM, Nirde P, Roger P, Gastaldi M, Laffargue F, Rochefort H and Maudelonde T: Differential expression of estrogen receptor-α and -β messenger RNAs as a potential marker of ovarian carcinogenesis. Cancer Res. 58:5367–5373. 1998.
29	Darb-Esfahani S, Wirtz RM, Sinn BV, Budczies J, Noske A, Weichert W, Faggad A, Scharff S, Sehouli J, Oskay-Ozcelik G, Zamagni C, De Iaco P, Martoni A, Dietel M and Denkert C: Estrogen receptor 1 mRNA is a prognostic factor in ovarian carcinoma: determination by kinetic PCR in formalin-fixed paraffin-embedded tissue. Endocr Relat Cancer. 16:1229–1239. 2009. View Article : Google Scholar : PubMed/NCBI
30	Yuan SX, Yang F, Yang Y, Tao QF, Zhang J, Huang G, Yang Y, Wang RY, Yang S, Huo XS, Zhang L, Wang F, Sun SH and Zhou WP: Long noncoding RNA associated with microvascular invasion in hepatocellular carcinoma promotes angiogenesis and serves as a predictor for hepatocellular carcinoma patients’ poor recurrence-free survival after hepatectomy. Hepatology. 56:2231–2241. 2012.PubMed/NCBI
31	Bussemakers MJ, van Bokhoven A, Verhaegh GW, Smit FP, Karthaus HF, Schalken JA, Debruyne FM, Ru N and Isaacs WB: DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res. 9:5975–5979. 1999.PubMed/NCBI
32	Srikantan V, Zou Z, Petrovics G, Xu L, Augustus M, Davis L, Livezey JR, Connell T, Sesterhenn IA, Yoshino K, Buzard GS, Mostofi FK, McLeod DG, Moul JW and Srivastava S: PCGEM1, a prostate-specific gene, is overexpressed in prostate cancer. Proc Natl Acad Sci USA. 97:12216–12221. 2000. View Article : Google Scholar