Long non‑coding RNA CASC2 inhibits progression and predicts favorable prognosis in epithelial ovarian cancer

Xue,Zhuowei; Zhu,Xiaolu; Teng,Yincheng

doi:10.3892/mmr.2018.9550

Long non‑coding RNA CASC2 inhibits progression and predicts favorable prognosis in epithelial ovarian cancer

Authors:
- Zhuowei Xue
- Xiaolu Zhu
- Yincheng Teng
View Affiliations

Affiliations: Department of Obstetrics and Gynaecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
Published online on: October 10, 2018 https://doi.org/10.3892/mmr.2018.9550
Pages: 5173-5181

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

Epithelial ovarian cancer (EOC) is one of the leading causes of cancer‑associated mortality in women. At present, the overall 5‑year survival rate of patients with EOC remains poor despite advancements in diagnosis and treatment. Long non‑coding RNAs (lncRNAs) have attracted increasing attention in recent years for their extensive roles in tumorigenesis and cancer development. The lncRNA cancer susceptibility candidate 2 (CASC2) was originally identified as a downregulated gene in endometrial cancer, and subsequent studies revealed that CASC2 was able to act as a tumor suppressor gene in various types of cancer. The present study is the first, to the best of the authors' knowledge, to identify the clinical significance and potential role of CASC2 in EOC. The results demonstrated that CASC2 was downregulated in EOC cell lines and tissues. Analysis of association between clinicopathological features and CASC2 expression levels suggested that low CASC2 expression is associated with the serous histological subtype (P<0.001), lymph node metastasis (P=0.038), poor histological grade (P<0.001) and large tumor size (P=0.001) in EOC. Furthermore, low CASC2 expression predicted poor overall survival (P<0.001) and progression‑free survival (P<0.001). Functional assays, including Cell Counting kit‑8 assays, colony formation assays, and Transwell and Matrigel assays, confirmed that silencing of CASC2 promoted the proliferation, migration and invasion of EOC cells; whereas, ectopic overexpression of CASC2 suppressed the proliferation, migration and invasion of EOC cells. In addition, in the analysis of the risk factors for poor prognosis, low CASC2 expression was identified as an independent risk factor for reduced overall survival [hazard ratio (HR)=0.417; 95% confidence interval (CI)=0.251‑0.693; P=0.001] and progression‑free survival (HR=0.426; 95% CI=0.260‑0.699; P=0.001) in patients with EOC. In conclusion, CASC2 is downregulated in EOC, and it may suppress EOC progression and is an independent risk factor for poor prognosis. CASC2 may be a promising prognostic marker and therapeutic target in EOC.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
2	Goff BA, Mandel L, Muntz HG and Melancon CH: Ovarian carcinoma diagnosis. Cancer. 89:2068–2075. 2000. View Article : Google Scholar : PubMed/NCBI
3	Bookman MA, Brady MF, McGuire WP, Harper PG, Alberts DS, Friedlander M, Colombo N, Fowler JM, Argenta PA, De Geest K, et al: Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: A Phase III Trial of the Gynecologic Cancer Intergroup. J Clin Oncol. 27:1419–1425. 2009. View Article : Google Scholar : PubMed/NCBI
4	Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Morales Rivea D, Thomas K, Presser A, Bernstein BE, van Oudenaarden A, et al: Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci USA. 106:11667–11672. 2009. View Article : Google Scholar : PubMed/NCBI
5	Ulitsky I and Bartel DP: lincRNAs: Genomics, evolution, and mechanisms. Cell. 154:26–46. 2013. View Article : Google Scholar : PubMed/NCBI
6	Baldinu P, Cossu A, Manca A, Satta MP, Sini MC, Rozzo C, Dessole S, Cherchi P, Gianfrancesco F, Pintus A, et al: Identification of a novel candidate gene, CASC2, in a region of common allelic loss at chromosome 10q26 in human endometrial cancer. Hum Mutat. 23:318–326. 2004. View Article : Google Scholar : PubMed/NCBI
7	Baldinu P, Cossu A, Manca A, Satta MP, Sini MC, Palomba G, Dessole S, Cherchi P, Mara L, Tanda F and Palmieri G: CASC2a gene is down-regulated in endometrial cancer. Anticancer Res. 27:235–243. 2007.PubMed/NCBI
8	He X, Liu Z, Su J, Yang J, Yin D, Han L, De W and Guo R: Low expression of long noncoding RNA CASC2 indicates a poor prognosis and regulates cell proliferation in non-small cell lung cancer. Tumour Biol. 37:9503–9510. 2016. View Article : Google Scholar : PubMed/NCBI
9	Gan Y, Han N, He X, Yu J, Zhang M, Zhou Y, Liang H, Deng J, Zheng Y, Ge W, et al: Long non-coding RNA CASC2 regulates cell biological behaviour through the MAPK signalling pathway in hepatocellular carcinoma. Tumor Biol. 39:10104283177062292017. View Article : Google Scholar
10	Wang R, Li Y, Zhu G, Tian B, Zeng W, Yang Y and Li Z: Long noncoding RNA CASC2 predicts the prognosis of glioma patients and functions as a suppressor for gliomas by suppressing Wnt/β-catenin signaling pathway. Neuropsychiatr Dis Treat. 13:1805–1813. 2017. View Article : Google Scholar : PubMed/NCBI
11	Zhou J, Huang H, Tong S and Huo R: Overexpression of long non-coding RNA cancer susceptibility 2 inhibits cell invasion and angiogenesis in gastric cancer. Mol Med Rep. 16:5235–5240. 2017. View Article : Google Scholar : PubMed/NCBI
12	Cao Y, Xu R, Xu X, Zhou Y, Cui L and He X: Downregulation of lncRNA CASC2 by microRNA-21 increases the proliferation and migration of renal cell carcinoma cells. Mol Med Rep. 14:1019–1025. 2016. View Article : Google Scholar : PubMed/NCBI
13	Yu Y, Liang S, Zhou Y, Li S, Li Y and Liao W: HNF1A/CASC2 regulates pancreatic cancer cell proliferation through PTEN/Akt signaling. J Cell Biochem. 2017.(Epub ahead of print). View Article : Google Scholar
14	Yang X, Wang J, Li WP, Jin ZJ and Liu XJ: Desmocollin 3 mediates follicle stimulating hormone-induced ovarian epithelial cancer cell proliferation by activating the EGFR/Akt signaling pathway. Int J Clin Exp Patho. 8:6716–6723. 2015.
15	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
16	Prat J: Staging classification for cancer of the ovary, fallopian tube, and peritoneum. International journal of gynaecology and obstetrics: The official organ of the International Federation of Gynaecology and Obstetrics. 124:1–5. 2014. View Article : Google Scholar : PubMed/NCBI
17	Bhan A, Soleimani M and Mandal SS: Long Noncoding RNA and Cancer: A New Paradigm. Cancer Res. 77:3965–3981. 2017. View Article : Google Scholar : PubMed/NCBI
18	Jarroux J, Morillon A and Pinskaya M: History, discovery, and classification of lncRNAs. Adv Exp Med Biol. 1008:1–46. 2017. View Article : Google Scholar : PubMed/NCBI
19	Shen L, Liu W, Cui J, Li J and Li C: Analysis of long non-coding RNA expression profiles in ovarian cancer. Oncol Lett. 14:1526–1530. 2017. View Article : Google Scholar : PubMed/NCBI
20	Zhou M, Sun Y, Sun Y, Xu W, Zhang Z, Zhao H, Zhong Z and Sun J: Comprehensive analysis of lncRNA expression profiles reveals a novel lncRNA signature to discriminate nonequivalent outcomes in patients with ovarian cancer. Oncotarget. 7:32433–32448. 2016.PubMed/NCBI
21	Wang LL, Sun KX, Wu DD, Xiu YL, Chen X, Chen S, Zong ZH, Sang XB, Liu Y and Zhao Y: DLEU1 contributes to ovarian carcinoma tumourigenesis and development by interacting with miR-490-3p and altering CDK1 expression. J Cell Mol Med. 21:3055–3065. 2017. View Article : Google Scholar : PubMed/NCBI
22	Medrzycki M, Zhang Y, Zhang W, Cao K, Pan C, Lailler N, McDonald JF, Bouhassira EE and Fan Y: Histone h1.3 suppresses h19 noncoding RNA expression and cell growth of ovarian cancer cells. Cancer Res. 74:6463–6473. 2014. View Article : Google Scholar : PubMed/NCBI
23	Dong L and Hui L: HOTAIR promotes proliferation, migration, and invasion of ovarian cancer SKOV3 cells through regulating PIK3R3. Med Sci Monit. 22:325–331. 2016. View Article : Google Scholar : PubMed/NCBI
24	Teschendorff AE, Lee SH, Jones A, Fiegl H, Kalwa M, Wagner W, Chindera K, Evans I, Dubeau L, Orjalo A, et al: HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer. Genome Med. 7:1082015. View Article : Google Scholar : PubMed/NCBI
25	Zhang Z, Cheng J, Wu Y, Qiu J, Sun Y and Tong X: LncRNA HOTAIR controls the expression of Rab22a by sponging miR-373 in ovarian cancer. Mol Med Rep. 14:2465–2472. 2016. View Article : Google Scholar : PubMed/NCBI
26	Ozes AR, Miller DF, Ozes ON, Fang F, Liu Y, Matei D, Huang T and Nephew KP: NF-κB-HOTAIR axis links DNA damage response, chemoresistance and cellular senescence in ovarian cancer. Oncogene. 35:5350–5361. 2016. View Article : Google Scholar : PubMed/NCBI
27	Chai Y, Liu J, Zhang Z and Liu L: HuR-regulated lncRNA NEAT1 stability in tumorigenesis and progression of ovarian cancer. Cancer Med. 5:1588–1598. 2016. View Article : Google Scholar : PubMed/NCBI
28	An J, Lv W and Zhang Y: LncRNA NEAT1 contributes to paclitaxel resistance of ovarian cancer cells by regulating ZEB1 expression via miR-194. Onco Targets Ther. 10:5377–5390. 2017. View Article : Google Scholar : PubMed/NCBI
29	Zhou Y, Xu X, Lv H, Wen Q, Li J, Tan L, Li J and Sheng X: The long noncoding RNA MALAT-1 is highly expressed in ovarian cancer and induces cell growth and migration. PLoS One. 11:e01552502016. View Article : Google Scholar : PubMed/NCBI
30	Mitra R, Chen X, Greenawalt EJ, Maulik U, Jiang W, Zhao Z and Eischen CM: Decoding critical long non-coding RNA in ovarian cancer epithelial-to-mesenchymal transition. Nat Commun. 8:16042017. View Article : Google Scholar : PubMed/NCBI
31	Ren C, Li X, Wang T, Wang G, Zhao C, Liang T, Zhu Y, Li M, Yang C, Zhao Y and Zhang GM: Functions and mechanisms of long noncoding RNAs in ovarian cancer. Int J Gynecol Cancer. 25:566–569. 2015. View Article : Google Scholar : PubMed/NCBI
32	Cheng Z, Guo J, Chen L, Luo N, Yang W and Qu X: A long noncoding RNA AB073614 promotes tumorigenesis and predicts poor prognosis in ovarian cancer. Oncotarget. 6:25381–25389. 2015. View Article : Google Scholar : PubMed/NCBI
33	Huang S, Qing C, Huang Z and Zhu Y: The long non-coding RNA CCAT2 is up-regulated in ovarian cancer and associated with poor prognosis. Diagn Pathol. 11:492016. View Article : Google Scholar : PubMed/NCBI
34	Yan C, Jiang Y, Wan Y, Zhang L, Liu J, Zhou S and Cheng W: Long noncoding RNA NBAT-1 suppresses tumorigenesis and predicts favorable prognosis in ovarian cancer. Onco Targets Ther. 10:1993–2002. 2017. View Article : Google Scholar : PubMed/NCBI
35	Palmieri G, Paliogiannis P, Sini MC, Manca A, Palomba G, Doneddu V, Tanda F, Pascale MR and Cossu A: Long non-coding RNA CASC2 in human cancer. Crit Rev Oncol Hematol. 111:31–38. 2017. View Article : Google Scholar : PubMed/NCBI
36	Ba Z, Gu L, Hao S, Wang X, Cheng Z and Nie G: Downregulation of lncRNA CASC2 facilitates osteosarcoma growth and invasion through miR-181a. Cell Prolif. 51:2018. View Article : Google Scholar : PubMed/NCBI
37	Zeng F, Le YG, Fan JC and Xin L: LncRNA CASC2 inhibited the viability and induced the apoptosis of hepatocellular carcinoma cells through regulating miR-24-3p. J Cell Biochem. 119:6391–6397. 2018. View Article : Google Scholar : PubMed/NCBI
38	Liao Y, Shen L, Zhao H, Liu Q, Fu J, Guo Y, Peng R and Cheng L: LncRNA CASC2 interacts with miR-181a to modulate glioma growth and resistance to TMZ through PTEN pathway. J Cell Biochem. 118:1889–1899. 2017. View Article : Google Scholar : PubMed/NCBI
39	Jiang C, Shen F, Du J, Fang X, Li X, Su J, Wang X, Huang X and Liu Z: Upregulation of CASC2 sensitized glioma to temozolomide cytotoxicity through autophagy inhibition by sponging miR-193a-5p and regulating mTOR expression. Biomed Pharmacother. 97:844–850. 2018. View Article : Google Scholar : PubMed/NCBI
40	Liu C, Sun Y, She X, Tu C, Cheng X, Wang L, Yu Z, Li P, Liu Q, Yang H, et al: CASC2c as an unfavorable prognosis factor interacts with miR-101 to mediate astrocytoma tumorigenesis. Cell Death Dis. 8:e26392017. View Article : Google Scholar : PubMed/NCBI
41	Zhang W, He W, Gao J, Wang Y, Zang W, Dong Z and Zhao G: Retraction notice to the long noncoding RNA CASC2 inhibits tumorigenesis through modulating the expression of PTEN by targeting miR-18a-5p in esophageal carcinoma. Exp Cell Res. 361:30–38. 2017. View Article : Google Scholar : PubMed/NCBI
42	Wang Y, Liu Z, Yao B, Li Q, Wang L, Wang C, Dou C, Xu M, Liu Q and Tu K: Long non-coding RNA CASC2 suppresses epithelial-mesenchymal transition of hepatocellular carcinoma cells through CASC2/miR-367/FBXW7 axis. Mol Cancer. 16:1232017. View Article : Google Scholar : PubMed/NCBI
43	Wang P, Liu YH, Yao YL, Li Z, Li ZQ, Ma J and Xue YX: Long non-coding RNA CASC2 suppresses malignancy in human gliomas by miR-21. Cell Signal. 27:275–282. 2015. View Article : Google Scholar : PubMed/NCBI
44	Feng Y, Zou W, Hu C, Li G, Zhou S, He Y, Ma F, Deng C and Sun L: Modulation of CASC2/miR-21/PTEN pathway sensitizes cervical cancer to cisplatin. Arch Biochem Biophys. 623–624:20–30. 2017. View Article : Google Scholar
45	Pei Z, Du X, Song Y, Fan L, Li F, Gao Y, Wu R, Chen Y, Li W, Zhou H, et al: Down-regulation of lncRNA CASC2 promotes cell proliferation and metastasis of bladder cancer by activation of the Wnt/beta-catenin signaling pathway. Oncotarget. 8:18145–18153. 2017. View Article : Google Scholar : PubMed/NCBI
46	Xiong X, Zhu H and Chen X: Low expression of long noncoding RNA CASC2 indicates a poor prognosis and promotes tumorigenesis in thyroid carcinoma. Biomed Pharmacother. 93:391–397. 2017. View Article : Google Scholar : PubMed/NCBI