Long non-coding RNA H19 is aberrantly expressed in multiple malignancies and its expression levels correlate with recurrence, metastasis, and patient survival. Despite numerous reports documenting the role of H19 in carcinogenesis, its contribution to cervical cancer development is still largely unknown. In this study, I observed that H19 expression was elevated in cervical cancer cell lines and could be detected in extracellular vesicles in the culture medium. In addition, I demonstrated, by overexpression and knockdown experiments, that H19 promoted cell proliferation and multicellular tumor spheroid formation without significantly affecting apoptosis and cell migration. Finally, treatment with transforming growth factor beta and hypoxia-mimetic CoCl2 could modulate H19 levels in a cell line-specific manner. These findings indicate that H19 promotes both anchorage-specific and -independent growth of cervical cancer cell lines and may serve as a potential target for cancer diagnosis and therapy.
JemalABrayFCenterMMFerlayJWardEFormanD. Global cancer statistics. CA Cancer J Clin2011; 61: 69–90.
2.
Centers for Disease C, Prevention. FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep2010; 59: 626–9.
3.
McCormackPLJouraEA. Quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine (Gardasil(R)): a review of its use in the prevention of premalignant genital lesions, genital cancer and genital warts in women. Drugs2010; 70: 2449–74.
4.
JinXWLipoldLMcKenzieMSikonA. Cervical cancer screening: what’s new and what’s coming?Cleve Clin J Med2013; 80: 153–60.
5.
ZielinskiGDSnijdersPJRozendaalLVoorhorstFJvan der LindenHCRunsinkAPde SchipperFAMeijerCJ. HPV presence precedes abnormal cytology in women developing cervical cancer and signals false negative smears. Br J Cancer2001; 85: 398–404.
6.
LinCJLaiHCWangKHHsiungCALiuHWDingDCHsiehCYChuTY. Testing for methylated PCDH10 or WT1 is superior to the HPV test in detecting severe neoplasms (CIN3 or greater) in the triage of ASC-US smear results. Am J Obstet Gynecol2011; 204: 21 e1–7.
7.
DerrienTJohnsonRBussottiGTanzerADjebaliSTilgnerHGuernecGMartinDMerkelAKnowlesDGLagardeJVeeravalliLRuanXRuanYLassmannTCarninciPBrownJBLipovichLGonzalezJMThomasMDavisCAShiekhattarRGingerasTRHubbardTJNotredameCHarrowJGuigoR. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res2012; 22: 1775–89.
8.
JeonYSarmaKLeeJT. New and Xisting regulatory mechanisms of X chromosome inactivation. Curr Opin Genet Dev2012; 22: 62–71.
9.
MattickJSAmaralPPDingerMEMercerTRMehlerMF. RNA regulation of epigenetic processes. Bioessays2009; 31: 51–9.
10.
WapinskiOChangHY. Long noncoding RNAs and human disease. Trends Cell Biol2011; 21: 354–61.
11.
OromUADerrienTBeringerMGumireddyKGardiniABussottiGLaiFZytnickiMNotredameCHuangQGuigoRShiekhattarR. Long noncoding RNAs with enhancer-like function in human cells. Cell2010; 143: 46–58.
12.
ZongXTripathiVPrasanthKV. RNA splicing control: yet another gene regulatory role for long nuclear noncoding RNAs. RNA Biol2011; 8: 968–77.
13.
DornGW2ndMatkovichSJ. Menage a Trois: intimate relationship among a microRNA, long noncoding RNA, and mRNA. Circ Res2014; 114: 1362–5.
14.
ClarkMBMattickJS. Long noncoding RNAs in cell biology. Semin Cell Dev Biol2011; 22: 366–76.
15.
RandoTAChangHY. Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell2012; 148: 46–57.
16.
ServissJTJohnssonPGranderD. An emerging role for long non-coding RNAs in cancer metastasis. Front Genet2014; 5: 234–234.
17.
JiPDiederichsSWangWBoingSMetzgerRSchneiderPMTidowNBrandtBBuergerHBulkEThomasMBerdelWEServeHMuller-TidowC. MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene2003; 22: 8031–41.
18.
SchmidtLHSpiekerTKoschmiederSSchaffersSHumbergJJungenDBulkEHascherAWittmerDMarraAHillejanLWiebeKBerdelWEWiewrodtRMuller-TidowC. The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth. J Thorac Oncol2011; 6: 1984–92.
19.
QiuMTHuJWYinRXuL. Long noncoding RNA: an emerging paradigm of cancer research. Tumour Biol2013; 34: 613–20.
20.
SunMXiaRJinFXuTLiuZDeWLiuX. Downregulated long noncoding RNA MEG3 is associated with poor prognosis and promotes cell proliferation in gastric cancer. Tumour Biol2014; 35: 1065–73.
21.
FeigenbergTGofritONPizovGHochbergABenshushanA. Expression of the h19 oncofetal gene in premalignant lesions of cervical cancer: a potential targeting approach for development of nonsurgical treatment of high-risk lesions. ISRN Obstet Gynecol2013; 2013: 137509–137509.
22.
TanosVPrusDAyeshSWeinsteinDTykocinskiMLDe-GrootNHochbergAArielI. Expression of the imprinted H19 oncofetal RNA in epithelial ovarian cancer. Eur J Obstet Gynecol Reprod Biol1999; 85: 7–11.
23.
MatoukIRavehEOhanaPLailRAGershtainEGilonMDe GrootNCzerniakAHochbergA. The increasing complexity of the oncofetal h19 gene locus: functional dissection and therapeutic intervention. Int J Mol Sci2013; 14: 4298–316.
24.
PachnisVBelayewATilghmanSM. Locus unlinked to alpha-fetoprotein under the control of the murine raf and Rif genes. Proc Natl Acad Sci USA1984; 81: 5523–7.
25.
TsangWPNgEKNgSSJinHYuJSungJJKwokTT. Oncofetal H19-derived miR-675 regulates tumor suppressor RB in human colorectal cancer. Carcinogenesis2010; 31: 350–8.
26.
LuoMLiZWangWZengYLiuZQiuJ. Long non-coding RNA H19 increases bladder cancer metastasis by associating with EZH2 and inhibiting E-cadherin expression. Cancer Lett2013; 333: 213–21.
27.
MatoukIJDeGrootNMezanSAyeshSAbu-lailRHochbergAGalunE. The H19 non-coding RNA is essential for human tumor growth. PLoS One2007; 2: e845–e845.
28.
ZhuMChenQLiuXSunQZhaoXDengRWangYHuangJXuMYanJYuJ. lncRNA H19/miR-675 axis represses prostate cancer metastasis by targeting TGFBI. FEBS J2014; 281: 3766–75.
29.
SteenmanMJRainierSDobryCJGrundyPHoronILFeinbergAP. Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms’ tumour. Nat Genet1994; 7: 433–9.
30.
FichorovaRNRheinwaldJGAndersonDJ. Generation of papillomavirus-immortalized cell lines from normal human ectocervical, endocervical, and vaginal epithelium that maintain expression of tissue-specific differentiation proteins. Biol Reprod1997; 57: 847–55.
31.
IemprideeTReuschJARichingAJohannsenECDovatSKenneySCMertzJE. Epstein-Barr virus utilizes Ikaros in regulating its latent-lytic switch in B cells. J Virol2014; 88: 4811–27.
32.
KeNWangXXuXAbassiYA. The xCELLigence system for real-time and label-free monitoring of cell viability. Methods Mol Biol2011; 740: 33–43.
33.
NugitrangsonPPuthongSIemprideeTPimtongWPornpakakulSChanchaoC. In vitro and in vivo characterization of the anticancer activity of Thai stingless bee (Tetragonula laeviceps) cerumen. Exp Biol Med (Maywood)2016; 241: 166–76.
34.
GhazalSMcKinnonBZhouJMuellerMMenYYangLMuellerMFlanneryCHuangYTaylorHS. H19 lncRNA alters stromal cell growth via IGF signaling in the endometrium of women with endometriosis. EMBO Mol Med2015; 7: 996–1003.
35.
ZhuZSongLHeJSunYLiuXZouX. Ectopic expressed long non-coding RNA H19 contributes to malignant cell behavior of ovarian cancer. Int J Clin Exp Pathol2015; 8: 10082–91.
36.
GuoGKangQChenQChenZWangJTanLChenJL. High expression of long non-coding RNA H19 is required for efficient tumorigenesis induced by Bcr-Abl oncogene. FEBS Lett2014; 588: 1780–6.
37.
MatoukIJHalleDRavehEGilonMSorinVHochbergA. The role of the oncofetal H19 lncRNA in tumor metastasis: orchestrating the EMT-MET decision. Oncotarget2016; 7: 3748–65.
PardaliKMoustakasA. Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer. Biochim Biophys Acta2007; 1775: 21–62.
40.
WuDYotndaP. Induction and testing of hypoxia in cell culture. J Vis Exp2011; 54: e2899–e2899.
41.
ZhouXYinCDangYYeFZhangG. Identification of the long non-coding RNA H19 in plasma as a novel biomarker for diagnosis of gastric cancer. Sci Rep2015; 5: 11516–11516.
42.
LiHYuBLiJSuLYanMZhuZLiuB. Overexpression of lncRNA H19 enhances carcinogenesis and metastasis of gastric cancer. Oncotarget2014; 5: 2318–29.
43.
LuoMLiZWangWZengYLiuZQiuJ. Upregulated H19 contributes to bladder cancer cell proliferation by regulating ID2 expression. FEBS J2013; 280: 1709–16.
44.
BerteauxNLottinSMonteDPinteSQuatannensBCollJHondermarckHCurgyJJDugimontTAdriaenssensE. H19 mRNA-like noncoding RNA promotes breast cancer cell proliferation through positive control by E2F1. J Biol Chem2005; 280: 29625–36.
45.
DufauIFrongiaCSicardFDedieuLCordelierPAusseilFDucommunBValetteA. Multicellular tumor spheroid model to evaluate spatio-temporal dynamics effect of chemotherapeutics: application to the gemcitabine/CHK1 inhibitor combination in pancreatic cancer. BMC Cancer2012; 12: 15–15.
46.
SutherlandRM. Cell and environment interactions in tumor microregions: the multicell spheroid model. Science1988; 240: 177–84.
47.
RavehEMatoukIJGilonMHochbergA. The H19 Long non-coding RNA in cancer initiation, progression and metastasis – a proposed unifying theory. Mol Cancer2015; 14: 184–184.
48.
YanLZhouJGaoYGhazalSLuLBelloneSYangYLiuNZhaoXSantinADTaylorHHuangY. Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation. Oncogene2015; 34: 3076–84.
49.
ShiYWangYLuanWWangPTaoTZhangJQianJLiuNYouY. Long non-coding RNA H19 promotes glioma cell invasion by deriving miR-675. PLoS One2014; 9: e86295–e86295.
50.
MatoukIJMezanSMizrahiAOhanaPAbu-LailRFelligYDegrootNGalunEHochbergA. The oncofetal H19 RNA connection: hypoxia, p53 and cancer. Biochim Biophys Acta2010; 1803: 443–51.
