High-grade serous ovarian cancer (HGSOC) is one of the most common and lethal gynecological cancers. Long noncoding RNAs (lncRNAs) play important roles and act as prognostic biomarkers of ovarian cancer. However, few studies have focused on the prognostic prediction of lncRNAs solely in HGSOC. In this study, we identified candidate lncRNAs for a prognostic evaluation by examining reannotated lncRNA expression profiles and clinical data of 343 patients with HGSOC from The Cancer Genome Atlas. We built a 10-lncRNA signature using Cox-LASSO regression to predict the prognosis of patients with HGSOC. Trichotomized by the 10-lncRNA signature, high-risk patients experienced significantly shorter disease-free survival and overall survival (OS). Our novel 10-lncRNA signature showed superior predictive capacity compared to the other 2 published lncRNA signature models and clinicopathological parameters. We developed a nomogram for clinical use by integrating the 10-lncRNA signature and two clinicopathological risk factors to predict 1-, 3-, and 5-year OS. In addition, gene set enrichment analysis suggested that the group of high-risk patients was associated with mitotic spindle pathways. This model was also compatible with patients with or without BRCA1/2 mutations and had the potential to predict the response to platinum-based adjuvant chemotherapy. Our findings provide a novel 10-lncRNA prognostic signature for further clinical application in patients with HGSOC and indicate the underlying mechanisms of HGSOC progression.
Get full access to this article
View all access options for this article.
References
1.
AguilarB.J., ZhouH., and LuQ. (2017). Cdc42 signaling pathway inhibition as a therapeutic target in Ras-related cancers. Curr Med Chem, 24, 3485–3507.
2.
BastR.C.Jr., FeeneyM., LazarusH., NadlerL.M., ColvinR.B., and KnappR.C. (1981). Reactivity of a monoclonal antibody with human ovarian carcinoma. J Clin Invest, 68, 1331–1337.
3.
BelairC., SimS., KimK.Y., TanakaY., ParkI.H., and WolinS.L. (2019). The RNA exosome nuclease complex regulates human embryonic stem cell differentiation. J Cell Biol, 218, 2564.
4.
BillM., PapaioannouD., KarunasiriM., KohlschmidtJ., PepeF., WalkerC.J., et al. (2019). Expression and functional relevance of long non-coding RNAs in acute myeloid leukemia stem cells. Leukemia, 33, 2169–2182.
5.
ChangJ.G., ChenC.C., WuY.Y., CheT.F., HuangY.S., YehK.T., et al. (2016). Uncovering synthetic lethal interactions for therapeutic targets and predictive markers in lung adenocarcinoma. Oncotarget, 7, 73664–73680.
6.
CheethamS.W., GruhlF., MattickJ.S., and DingerM.E. (2013). Long noncoding RNAs and the genetics of cancer. Br J Cancer, 108, 2419–2425.
7.
ChenW., ZhengR., BaadeP.D., ZhangS., ZengH., BrayF., et al. (2016). Cancer statistics in China, 2015. CA Cancer J Clin, 66, 115–132.
8.
ChengZ., GuoJ., ChenL., LuoN., YangW., and QuX. (2015). A long noncoding RNA AB073614 promotes tumorigenesis and predicts poor prognosis in ovarian cancer. Oncotarget, 6, 25381–25389.
9.
DongP., XiongY., YueJ., XuD., IhiraK., KonnoY., et al. (2019a). Long noncoding RNA NEAT1 drives aggressive endometrial cancer progression via miR-361-regulated networks involving STAT3 and tumor microenvironment-related genes. J Exp Clin Cancer Res, 38, 295.
10.
DongS., WangR., WangH., DingQ., ZhouX., WangJ., et al. (2019b). HOXD-AS1 promotes the epithelial to mesenchymal transition of ovarian cancer cells by regulating miR-186-5p and PIK3R3. J Exp Clin Cancer Res, 38, 110.
11.
FangL., WangH., and LiP. (2018). Systematic analysis reveals a lncRNA-mRNA co-expression network associated with platinum resistance in high-grade serous ovarian cancer. Invest New Drugs, 36, 187–194.
12.
FaticaA., and BozzoniI. (2014). Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet, 15, 7–21.
13.
FeigenbergT., ClarkeB., VirtanenC., PlotkinA., LetarteM., RosenB., et al. (2014). Molecular profiling and clinical outcome of high-grade serous ovarian cancer presenting with low- versus high-volume ascites. Biomed Res Int, 2014, 367103.
14.
GoemanJ.J. (2010). L1 penalized estimation in the Cox proportional hazards model. Biom J, 52, 70–84.
15.
GordonM.A., BabbsB., CochraneD.R., BitlerB.G., and RicherJ.K. (2019). The long non-coding RNA MALAT1 promotes ovarian cancer progression by regulating RBFOX2-mediated alternative splicing. Mol Carcinog, 58, 196–205.
16.
GuoY.Z., SunH.H., WangX.T., and WangM.T. (2018). Transcriptomic analysis reveals key lncRNAs associated with ribosomal biogenesis and epidermis differentiation in head and neck squamous cell carcinoma. J Zhejiang Univ Sci B, 19, 674–688.
17.
HeagertyP.J., LumleyT., and PepeM.S. (2000). Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics, 56, 337–344.
18.
HellstromI., RaycraftJ., Hayden-LedbetterM., LedbetterJ.A., SchummerM., McIntoshM., et al. (2003). The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res, 63, 3695–3700.
HuangS., QingC., HuangZ., and ZhuY. (2016). The long non-coding RNA CCAT2 is up-regulated in ovarian cancer and associated with poor prognosis. Diagn Pathol, 11, 49.
21.
JacobsI., OramD., FairbanksJ., TurnerJ., FrostC., and GrudzinskasJ.G. (1990). A risk of malignancy index incorporating CA 125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer. Br J Obstet Gynaecol, 97, 922–929.
22.
JiangX., JiangX., and YangZ. (2018). NRAGE confers poor prognosis and promotes proliferation, invasion, and chemoresistance in gastric cancer. Gene, 668, 114–120.
23.
JunT., ZhengF.S., RenK.M., ZhangH.Y., ZhaoJ.G., and ZhaoJ.Z. (2018). Long non-coding RNA UCA1 regulates the proliferation, migration and invasion of human lung cancer cells by modulating the expression of microRNA-143. Eur Rev Med Pharmacol Sci, 22, 8343–8352.
24.
LiG.Y., WangW., SunJ.Y., XinB., ZhangX., WangT., et al. (2018). Long non-coding RNAs AC026904.1 and UCA1: a “one-two punch” for TGF-beta-induced SNAI2 activation and epithelial-mesenchymal transition in breast cancer. Theranostics, 8, 2846–2861.
25.
LiJ., HanL., RoebuckP., DiaoL., LiuL., YuanY., et al. (2015). TANRIC: an interactive open platform to explore the function of lncRNAs in cancer. Cancer Res, 75, 3728–3737.
26.
LiJ., HaoY., MaoW., XueX., XuP., LiuL., et al. (2019). LincK contributes to breast tumorigenesis by promoting proliferation and epithelial-to-mesenchymal transition. J Hematol Oncol, 12, 19.
27.
LiaoM., LiaoW., XuN., LiB., LiuF., ZhangS., et al. (2019). LncRNA EPB41L4A-AS1 regulates glycolysis and glutaminolysis by mediating nucleolar translocation of HDAC2. EBioMedicine, 41, 200–213.
28.
LiuB., PanS., XiaoY., LiuQ., XuJ., and JiaL. (2018). LINC01296/miR-26a/GALNT3 axis contributes to colorectal cancer progression by regulating O-glycosylated MUC1 via PI3K/AKT pathway. J Exp Clin Cancer Res, 37, 316.
29.
LiuR., ZengY., ZhouC.F., WangY., LiX., LiuZ.Q., et al. (2017a). Long noncoding RNA expression signature to predict platinum-based chemotherapeutic sensitivity of ovarian cancer patients. Sci Rep, 7, 18.
30.
LiuR.T., CaoJ.L., YanC.Q., WangY., AnC.J., LvH.T. (2017b). Effects of LncRNA-HOST2 on cell proliferation, migration, invasion and apoptosis of human hepatocellular carcinoma cell line SMMC-7721. Biosci Rep, 37, BSR20160532.
31.
LouY., JiangH., CuiZ., WangL., WangX., and TianT. (2017). Linc-ROR induces epithelial-to-mesenchymal transition in ovarian cancer by increasing Wnt/beta-catenin signaling. Oncotarget, 8, 69983–69994.
32.
MaM., XuH., LiuG., WuJ., LiC., WangX., et al. (2019). Metabolism-induced tumor activator 1 (MITA1), an energy stress-inducible long noncoding RNA, promotes hepatocellular carcinoma metastasis. Hepatology, 70, 215–230.
33.
MengX., Jin-ChengG., JueZ., Quan-FuM., BinY., and Xu-FengW. (2017). Protein-coding genes, long non-coding RNAs combined with microRNAs as a novel clinical multi-dimension transcriptome signature to predict prognosis in ovarian cancer. Oncotarget, 8, 72847–72859.
34.
MercerT.R., DingerM.E., and MattickJ.S. (2009). Long non-coding RNAs: insights into functions. Nat Rev Genet, 10, 155–159.
35.
MittalK., ChoiD.H., KlimovS., PawarS., KaurR., MitraA.K., et al. (2016). A centrosome clustering protein, KIFC1, predicts aggressive disease course in serous ovarian adenocarcinomas. J Ovarian Res, 9, 17.
36.
MooreR.G., McMeekinD.S., BrownA.K., DiSilvestroP., MillerM.C., AllardW.J., et al. (2009). A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol, 112, 40–46.
37.
ParkS.H., SongJ.Y., KimY.K., HeoJ.H., KangH., KimG., et al. (2014). Fascin1 expression in high-grade serous ovarian carcinoma is a prognostic marker and knockdown of fascin1 suppresses the proliferation of ovarian cancer cells. Int J Oncol, 44, 637–646.
38.
RinnJ.L., and ChangH.Y. (2012). Genome regulation by long noncoding RNAs. Annu Rev Biochem, 81, 145–166.
39.
ShannonP., MarkielA., OzierO., BaligaN.S., WangJ.T., RamageD., et al. (2003). Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res, 13, 2498–2504.
40.
ShenX., ZhongJ., YuP., ZhaoQ., and HuangT. (2019). YY1-regulated LINC00152 promotes triple negative breast cancer progression by affecting on stability of PTEN protein. Biochem Biophys Res Commun, 509, 448–454.
41.
SiegelR.L., MillerK.D., and JemalA. (2016). Cancer statistics, 2016. CA Cancer J Clin, 66, 7–30.
42.
SongJ., ZhangW., WangS., LiuK., SongF., and RanL. (2018). A panel of 7 prognosis-related long non-coding RNAs to improve platinum-based chemoresistance prediction in ovarian cancer. Int J Oncol, 53, 866–876.
43.
SpizzoR., AlmeidaM.I., ColombattiA., and CalinG.A. (2012). Long non-coding RNAs and cancer: a new frontier of translational research?. Oncogene, 31, 4577–4587.
44.
SubramanianA., TamayoP., MoothaV.K., MukherjeeS., EbertB.L., GilletteM.A., et al. (2005). Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A, 102, 15545–15550.
45.
TakahashiM., SugiuraT., AbeM., IshiiK., and ShirasunaK. (2007). Regulation of c-Met signaling by the tetraspanin KAI-1/CD82 affects cancer cell migration. Int J Cancer, 121, 1919–1929.
46.
WangA., JinC., LiH., QinQ., and LiL. (2018a). LncRNA ADAMTS9-AS2 regulates ovarian cancer progression by targeting miR-182-5p/FOXF2 signaling pathway. Int J Biol Macromol, 120, 1705–1713.
47.
WangJ., XuW., HeY., XiaQ., and LiuS. (2018b). LncRNA MEG3 impacts proliferation, invasion, and migration of ovarian cancer cells through regulating PTEN. Inflamm Res, 67, 927–936.
48.
WangJ., YeC., LiuJ., and HuY. (2018c). UCA1 confers paclitaxel resistance to ovarian cancer through miR-129/ABCB1 axis. Biochem Biophys Res Commun, 501, 1034–1040.
49.
WangX., YuH., SunW., KongJ., ZhangL., TangJ., et al. (2018d). The long non-coding RNA CYTOR drives colorectal cancer progression by interacting with NCL and Sam68. Mol Cancer, 17, 110.
50.
WuD.I., WangT., RenC., LiuL., KongD., JinX., et al. (2016). Downregulation of BC200 in ovarian cancer contributes to cancer cell proliferation and chemoresistance to carboplatin. Oncol Lett, 11, 1189–1194.
51.
WuD.M., ZhengZ.H., ZhangY.B., FanS.H., ZhangZ.F., WangY.J., et al. (2019a). Down-regulated lncRNA DLX6-AS1 inhibits tumorigenesis through STAT3 signaling pathway by suppressing CADM1 promoter methylation in liver cancer stem cells. J Exp Clin Cancer Res, 38, 237.
52.
WuJ., DuM., ZhangQ., ZhangW., FanY., YinL., et al. (2018b). Long noncoding RNA UCA1 promotes the proliferation, invasion, and migration of nasopharyngeal carcinoma cells via modulation of miR-145. Onco Targets Ther, 11, 7483–7492.
53.
WuX.B., FengX., ChangQ.M., ZhangC.W., WangZ.F., LiuJ., et al. (2019b). Cross-talk among AFAP1-AS1, ACVR1 and microRNA-384 regulates the stemness of pancreatic cancer cells and tumorigenicity in nude mice. J Exp Clin Cancer Res, 38, 107.
54.
WuY., WangP.S., WangB.G., XuL., FangW.X., CheX.F., et al. (2018a). Genomewide identification of a novel six-LncRNA signature to improve prognosis prediction in resectable hepatocellular carcinoma. Cancer Med, 7, 6219–6233.
55.
XiongH.G., LiH., XiaoY., YangQ.C., YangL.L., ChenL., et al. (2019). Long noncoding RNA MYOSLID promotes invasion and metastasis by modulating the partial epithelial-mesenchymal transition program in head and neck squamous cell carcinoma. J Exp Clin Cancer Res, 38, 278.
56.
YongW., YuD., JunZ., YachenD., WeiweiW., MidieX., et al. (2018). Long noncoding RNA NEAT1, regulated by LIN28B, promotes cell proliferation and migration through sponging miR-506 in high-grade serous ovarian cancer. Cell Death Dis, 9, 861.
57.
ZhangJ., and LiW. (2018). Long noncoding RNA CYTOR sponges miR-195 to modulate proliferation, migration, invasion and radiosensitivity in nonsmall cell lung cancer cells. Biosci Rep, 38, BSR20181599.
58.
ZhangM., ZhengY., SunY., LiS., ChenL., JinX., et al. (2019a). Knockdown of NEAT1 induces tolerogenic phenotype in dendritic cells by inhibiting activation of NLRP3 inflammasome. Theranostics, 9, 3425–3442.
59.
ZhangP., CaoL., ZhouR., YangX., and WuM. (2019b). The lncRNA Neat1 promotes activation of inflammasomes in macrophages. Nat Commun, 10, 1495.
60.
ZhangS., DongX., JiT., ChenG., and ShanL. (2017). Long non-coding RNA UCA1 promotes cell progression by acting as a competing endogenous RNA of ATF2 in prostate cancer. Am J Transl Res, 9, 366–375.
61.
ZhengA., SongX., ZhangL., ZhaoL., MaoX., WeiM., et al. (2019a). Long non-coding RNA LUCAT1/miR-5582-3p/TCF7L2 axis regulates breast cancer stemness via Wnt/beta-catenin pathway. J Exp Clin Cancer Res, 38, 305.
62.
ZhengY.L., LiL., JiaY.X., ZhangB.Z., LiJ.C., ZhuY.H., et al. (2019b). LINC01554-mediated glucose metabolism reprogramming suppresses tumorigenicity in hepatocellular carcinoma via downregulating PKM2 expression and inhibiting Akt/mTOR signaling pathway. Theranostics, 9, 796–810.
63.
ZhengZ.G., XuH., SuoS.S., XuX.L., NiM.W., GuL.H., et al. (2016). The essential role of H19 contributing to cisplatin resistance by regulating glutathione metabolism in high-grade serous ovarian cancer. Sci Rep, 6, 26093.
64.
ZhouM., SunY., SunY., XuW., ZhangZ., ZhaoH., et al. (2016a). Comprehensive analysis of lncRNA expression profiles reveals a novel lncRNA signature to discriminate nonequivalent outcomes in patients with ovarian cancer. Oncotarget, 7, 32433–32448.
65.
ZhouM., WangX., ShiH., ChengL., WangZ., ZhaoH., et al. (2016b). Characterization of long non-coding RNA-associated ceRNA network to reveal potential prognostic lncRNA biomarkers in human ovarian cancer. Oncotarget, 7, 12598–12611.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
