Resistance to platinum-based chemotherapy is the major barrier to treating high-grade serous ovarian cancer (HGS-OvCa). To improve HGS-OvCa patient prognosis, it is critical to identify the underlying mechanisms that promote platinum resistance. The goal of the present study was to identify a lncRNA-mRNA co-expression network and key lncRNAs that predict resistance to platinum-based chemotherapy in ovarian cancer patients. By systematically analyzing the expression profiles of lncRNAs and mRNAs in HGS-OvCa samples from the Cancer Genome Atlas (TCGA), we revealed that lncRNAs play important roles in platinum resistance in HGS-OvCa patients and delineate a lncRNA-mRNA co-expression network in HGS-OvCa patients who exhibit platinum resistance. Within the platinum resistance-specific lncRNA-mRNA network, 35 lncRNAs and 270 mRNAs showed 124 significant lncRNA-mRNA co-expression relationships. Pathway analysis revealed that lncRNAs in the platinum resistance network may participate in platinum resistance by regulating metabolic pathways. Moreover, HGS-OvCa patients with low lncRNA RP5-1120P11.1 expression showed a poorer prognosis than those with high lncRNA RP5-1120P11.1 expression in TCGA dataset (P = 2.74 × 10−5, log rank test), which was also validated in the GSE63885 dataset (P = 0.0242, log rank test). Network and function analysis revealed that lncRNA RP5-1120P11.1 regulates many cancer-related signaling pathways, such as the PI3K-AKT signaling pathway (P = 1.02 × 10−5, hypergeometric test) and the Jak-STAT signaling pathway (P = 1.71 × 10−4, hypergeometric test). Particularly, lncRNA RP5-1120P11.1 expression is significantly positively correlated with ABCC10 gene expression (P = 3.89 × 10−3, Pearson correlation test). Both lncRNA RP5-1120P11.1 and ABCC10 were down-regulated in platinum-resistant HGS-OvCa patients, and RP5-1120P11.1 is located near ABCC10 on chromosome 6. Gene ABCC10 has been implicated in resistance to docetaxel treatment. The present study paves the way for investigating lncRNA functions in platinum drug resistance and identifying lncRNAs with prognostic and therapeutic potential in HGS-OvCa.
lncRNAs BRCA1 BRCA2 Prognosis Ovarian cancer
Differential expression gene
High-grade serous ovarian cancer
The cancer genome atlas
The Atlas of non-coding RNAs in cancer
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The authors appreciate the efforts of all of researchers who have contributed the data to the public databases of TCGA, TANRIC and GEO. The interpretation and reporting of these data are the sole responsibility of the authors.
Peiling Li conceived, designed, and supervised the overall study. Lei Fang and Hao Wang conducted data processing and computational analyses. Lei Fang and Peiling Li drafted the manuscript. All authors read and approved the final manuscript.
Compliance with ethical standards
Consent for publication
All authors have provided consent for the publication of this manuscript in Investigational New Drugs.
Availability of data and materials
The datasets supporting the conclusions of this article are included within this manuscript.
The authors declare that they have no competing interests.
Liu J, Matulonis UA (2014) New strategies in ovarian cancer: translating the molecular complexity of ovarian cancer into treatment advances. Clin Cancer Res 20:5150–5156CrossRefPubMedGoogle Scholar
Bowtell DD, Bohm S, Ahmed AA, Aspuria PJ, Bast RC Jr, Beral V et al (2015) Rethinking ovarian cancer ii: reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer 15:668–679CrossRefPubMedPubMedCentralGoogle Scholar
Coleman RL, Monk BJ, Sood AK, Herzog TJ (2013) Latest research and treatment of advanced-stage epithelial ovarian cancer. Nature reviews. Clin Oncol 10:211–224Google Scholar
Wouters MC, Komdeur FL, Workel HH, Klip HG, Plat A, Kooi NM et al (2016) Treatment regimen, surgical outcome, and t-cell differentiation influence prognostic benefit of tumor-infiltrating lymphocytes in high-grade serous ovarian cancer. Clin Cancer Res 22:714–724CrossRefPubMedGoogle Scholar
Slaughter K, Holman LL, Thomas EL, Gunderson CC, Lauer JK, Ding K et al (2016) Primary and acquired platinum-resistance among women with high grade serous ovarian cancer. Gynecol Oncol 142:225–230CrossRefPubMedGoogle Scholar
Miller DS, Blessing JA, Krasner CN, Mannel RS, Hanjani P, Pearl ML et al (2009) Phase ii evaluation of pemetrexed in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: a study of the gynecologic oncology group. J Clin Oncol Off J Am Soc Clin Oncol 27:2686–2691CrossRefGoogle Scholar
Helleman J, Jansen MP, Span PN, van Staveren IL, Massuger LF, Meijer-van Gelder ME et al (2006) Molecular profiling of platinum resistant ovarian cancer. Int J Cancer 118:1963–1971CrossRefPubMedGoogle Scholar
Peng F, Wang R, Zhang Y, Zhao Z, Zhou W, Chang Z et al (2017) Differential expression analysis at the individual level reveals a lncrna prognostic signature for lung adenocarcinoma. Mol Cancer 16:98CrossRefPubMedPubMedCentralGoogle Scholar
Chaudhary R, Gryder B, Woods WS, Subramanian M, Jones MF, Li XL, et al. (2017) Prosurvival long noncoding rna pincr regulates a subset of p53 targets in human colorectal cancer cells by binding to matrin 3. elife 6:e23244Google Scholar
Li T, Xie J, Shen C, Cheng D, Shi Y, Wu Z et al (2015) Amplification of long noncoding rna zfas1 promotes metastasis in hepatocellular carcinoma. Cancer Res 75:3181–3191CrossRefPubMedGoogle Scholar
Li H, Liu C, Lu Z, Chen L, Wang J, Li Y et al (2017) Upregulation of the long non-coding rna spry4-it1 indicates a poor prognosis and promotes tumorigenesis in ovarian cancer. Biomed Pharmacother 88:529–534CrossRefPubMedGoogle Scholar
Heery R, Finn SP, Cuffe S, Gray SG (2017) Long non-coding rnas: key regulators of epithelial-mesenchymal transition, tumour drug resistance and cancer stem cells. Cancers 9:e38Google Scholar
Zhang CL, Zhu KP, Ma XL (2017) Antisense lncrna foxc2-as1 promotes doxorubicin resistance in osteosarcoma by increasing the expression of foxc2. Cancer Lett 396:66–75CrossRefPubMedGoogle Scholar
Zhang HY, Liang F, Zhang JW, Wang F, Wang L, Kang XG (2017) Effects of long noncoding rna-ror on tamoxifen resistance of breast cancer cells by regulating microrna-205. Cancer Chemother Pharmacol 79:327–337CrossRefPubMedGoogle Scholar
Liu R, Zeng Y, Zhou CF, Wang Y, Li X, Liu ZQ et al (2017) Long noncoding rna expression signature to predict platinum-based chemotherapeutic sensitivity of ovarian cancer patients. Sci Rep 7:18CrossRefPubMedPubMedCentralGoogle Scholar
Guo X, Gao L, Liao Q, Xiao H, Ma X, Yang X et al (2013) Long non-coding rnas function annotation: a global prediction method based on bi-colored networks. Nucleic Acids Res e35:41Google Scholar
Jiang Q, Ma R, Wang J, Wu X, Jin S, Peng J et al (2015) Lncrna2function: a comprehensive resource for functional investigation of human lncrnas based on rna-seq data. BMC Genomics 16(Suppl 3):S2CrossRefPubMedPubMedCentralGoogle Scholar
Zhang Z, Zhang J, Fan C, Tang Y, Deng L (2017) Katzlgo: large-scale prediction of lncrna functions by using the katz measure based on multiple networks. IEEE/ACM Trans Comput Biol Bioinform 99:1Google Scholar
Cancer Genome Atlas Research Network (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474:609–615CrossRefGoogle Scholar
Li J, Han L, Roebuck P, Diao L, Liu L, Yuan Y et al (2015) Tanric: an interactive open platform to explore the function of lncrnas in cancer. Cancer Res 75:3728–3737CrossRefPubMedPubMedCentralGoogle Scholar
Zaidi SZ, Motabi IH, Al-Shanqeeti A (2016) Cd56 and runx1 isoforms in aml prognosis and their therapeutic potential. Hematol Oncol Stem Cell Ther 9:129–130CrossRefPubMedGoogle Scholar
Shiohama T, Fujii K, Hino M, Shimizu K, Ohashi H, Kambe M et al (2016) Coexistence of neuroblastoma and ganglioneuroma in a girl with a hemizygous deletion of chromosome 11q14.1-23.3. Am J Med Genet A 170A:492–497CrossRefPubMedGoogle Scholar
Domanitskaya N, Wangari-Talbot J, Jacobs J, Peiffer E, Mahdaviyeh Y, Paulose C et al (2014) Abcc10 status affects mammary tumour growth, metastasis, and docetaxel treatment response. Br J Cancer 111:696–707CrossRefPubMedPubMedCentralGoogle Scholar
Kathawala RJ, Sodani K, Chen K, Patel A, Abuznait AH, Anreddy N et al (2014) Masitinib antagonizes atp-binding cassette subfamily c member 10-mediated paclitaxel resistance: a preclinical study. Mol Cancer Ther 13:714–723CrossRefPubMedPubMedCentralGoogle Scholar
Martini P, Paracchini L, Caratti G, Mello-Grand M, Fruscio R, Beltrame L et al (2017) Lncrnas as novel indicators of patients' prognosis in stage i epithelial ovarian cancer: a retrospective and multicentric study. Clin Cancer Res 23:2356–2366CrossRefPubMedGoogle Scholar
Qiu H, Wang X, Guo R, Liu Q, Wang Y, Yuan Z et al (2017) Hotair rs920778 polymorphism is associated with ovarian cancer susceptibility and poor prognosis in a chinese population. Future Oncol 13:347–355CrossRefPubMedGoogle Scholar
Ren C, Li X, Wang T, Wang G, Zhao C, Liang T et al (2015) Functions and mechanisms of long noncoding rnas in ovarian cancer. Int J Gynecol Cancer 25:566–569CrossRefPubMedGoogle Scholar
Zhang H, Patel A, Wang YJ, Zhang YK, Kathawala RJ, Qiu LH et al (2017) The btk inhibitor ibrutinib (pci-32765) overcomes paclitaxel resistance in abcb1- and abcc10-overexpressing cells and tumors. Mol Cancer Ther 16:1021–1030CrossRefPubMedGoogle Scholar
Xie T, Geng J, Wang Y, Wang L, Huang M, Chen J et al (2017) Foxm1 evokes 5-fluorouracil resistance in colorectal cancer depending on abcc10. Oncotarget 8:8574–8589PubMedGoogle Scholar
Gu Y, Zhang M, Peng F, Fang L, Zhang Y, Liang H et al (2015) The brca1/2-directed mirna signature predicts a good prognosis in ovarian cancer patients with wild-type brca1/2. Oncotarget 6:2397–2406PubMedGoogle Scholar