High LIN28A and PLK4 co‑expression is associated with poor prognosis in epithelial ovarian cancer

He,Yao; Wang,Hui; Yan,Meina; Yang,Xinxin; Shen,Rong; Ni,Xiaoge; Chen,Xiaokun; Yang,Peifang; Chen,Miao; Lu,Xiaodong; Shao,Genbao; Zhou,Xiaoming; Shao,Qixiang

doi:10.3892/mmr.2018.9562

High LIN28A and PLK4 co‑expression is associated with poor prognosis in epithelial ovarian cancer

Authors:
- Yao He
- Hui Wang
- Meina Yan
- Xinxin Yang
- Rong Shen
- Xiaoge Ni
- Xiaokun Chen
- Peifang Yang
- Miao Chen
- Xiaodong Lu
- Genbao Shao
- Xiaoming Zhou
- Qixiang Shao
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Affiliations: Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China, Department of Gynecology and Obstetrics, Affiliated People's Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China, Department of Gynecology and Obstetrics, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
Published online on: October 16, 2018 https://doi.org/10.3892/mmr.2018.9562
Pages: 5327-5336
Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. LIN28 homolog A (LIN28A) is a RNA‑binding protein, which serves a fundamental role in cell development and pluripotency. Polo‑like kinase 4 (PLK4) is a member of the polo‑like kinase family, which primarily takes part in the mitotic regulation. Overexpression of LIN28A has been demonstrated in ovarian cancer; however, the expression of PLK4 and the correlation between the expression of LIN28A and PLK4 in EOC has not been discussed. In the present study, the mRNA and protein levels of LIN28A and PLK4 were evaluated by reverse transcription‑quantitative polymerase chain reaction and immunohistochemistry in ovarian tissues of patients. Results demonstrated significantly increased expression in EOC compared with benign epithelial ovarian tumors. High expression of LIN28A and PLK4 was detected at the advanced pathological stage. Furthermore, PLK4 expression was positively correlated with LIN28A (r=0.555; P=0.039). The median survival analysis of patients with EOC with LIN28A and PLK4 double positive expression was 14 months, compared with 30 months in single positive and 60 months in double negative patients by Kaplan‑Meier analysis (P<0.05). The expressions of LIN28A and PLK4 was elevated in different EOC cell lines compared to with a normal ovarian cell line. The 293T cells transfected with LIN28A plus a PLK4 plasmid were the fastest‑growing group. These results suggest that co‑expression of LIN28A and PLK4 may be associated with poor prognosis of EOC and could serve as promising prognostic biomarkers and therapeutic targets in EOC. LIN28A and PLK4 may be used along with traditional morphological and clinical characteristics for predicting prognosis.

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1	Matz M, Coleman MP, Sant M, Chirlaque MD, Visser O, Gore M and Allemani C: the CONCORD Working Group: The histology of ovarian cancer: Worldwide distribution and implications for international survival comparisons (CONCORD-2). Gynecol Oncol. 144:405–413. 2017. View Article : Google Scholar : PubMed/NCBI
2	Kurman RJ and Shih Ie M: Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer-shifting the paradigm. Hum Pathol. 42:918–931. 2011. View Article : Google Scholar : PubMed/NCBI
3	The trouble with ovarian cancer. Lancet. 374:13022009. View Article : Google Scholar
4	Kurman RJ and Shih Ie M: The dualistic model of ovarian carcinogenesis: Revisited, revised, and expanded. Am J Pathol. 186:733–747. 2016. View Article : Google Scholar : PubMed/NCBI
5	Chien J, Kuang R, Landen C and Shridhar V: Platinum-sensitive recurrence in ovarian cancer: The role of tumor microenvironment. Front Oncol. 3:2512013. View Article : Google Scholar : PubMed/NCBI
6	Burgos-Ojeda D, Rueda BR and Buckanovich RJ: Ovarian cancer stem cell markers: Prognostic and therapeutic implications. Cancer Lett. 322:1–7. 2012. View Article : Google Scholar : PubMed/NCBI
7	Carmel-Gross I, Bollag N, Armon L and Urbach A: LIN28: A stem cell factor with a key role in pediatric tumor formation. Stem Cells Dev. 25:367–377. 2016. View Article : Google Scholar : PubMed/NCBI
8	Heo I, Joo C, Cho J, Ha M, Han J and Kim VN: Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. Mol Cell. 32:276–284. 2008. View Article : Google Scholar : PubMed/NCBI
9	Zhou J, Ng SB and Chng WJ: LIN28/LIN28B: An emerging oncogenic driver in cancer stem cells. Int J Biochem Cell Biol. 45:973–978. 2013. View Article : Google Scholar : PubMed/NCBI
10	Shyh-Chang N and Daley GQ: Lin28: Primal regulator of growth and metabolism in stem cells. Cell Stem Cell. 12:395–406. 2013. View Article : Google Scholar : PubMed/NCBI
11	Feng C, Neumeister V, Ma W, Xu J, Lu L, Bordeaux J, Maihle NJ, Rimm DL and Huang Y: Lin28 regulates HER2 and promotes malignancy through multiple mechanisms. Cell Cycle. 11:2486–2494. 2012. View Article : Google Scholar : PubMed/NCBI
12	Ma W, Ma J, Xu J, Qiao C, Branscum A, Cardenas A, Baron AT, Schwartz P, Maihle NJ and Huang Y: Lin28 regulates BMP4 and functions with Oct4 to affect ovarian tumor microenvironment. Cell Cycle. 12:88–97. 2013. View Article : Google Scholar : PubMed/NCBI
13	Li N, Zhong X, Lin X, Guo J, Zou L, Tanyi JL, Shao Z, Liang S, Wang LP, Hwang WT, et al: Lin-28 homologue A (LIN28A) promotes cell cycle progression via regulation of cyclin-dependent kinase 2 (CDK2), cyclin D1 (CCND1), and cell division cycle 25 homolog A (CDC25A) expression in cancer. J Biol Chem. 287:17386–17397. 2012. View Article : Google Scholar : PubMed/NCBI
14	de Cárcer G, Manning G and Malumbres M: From Plk1 to Plk5: Functional evolution of polo-like kinases. Cell Cycle. 10:2255–2262. 2011. View Article : Google Scholar : PubMed/NCBI
15	Takai N, Hamanaka R, Yoshimatsu J and Miyakawa I: Polo-like kinases (Plks) and cancer. Oncogene. 24:287–291. 2005. View Article : Google Scholar : PubMed/NCBI
16	Weiss L and Efferth T: Polo-like kinase 1 as target for cancer therapy. Exp Hematol Oncol. 1:382012. View Article : Google Scholar : PubMed/NCBI
17	Lohse I, Mason J, Cao PM, Pintilie M, Bray M and Hedley DW: Activity of the novel polo-like kinase 4 inhibitor CFI-400945 in pancreatic cancer patient-derived xenografts. Oncotarget. 8:3064–3071. 2017. View Article : Google Scholar : PubMed/NCBI
18	Denu RA, Zasadil LM, Kanugh C, Laffin J, Weaver BA and Burkard ME: Centrosome amplification induces high grade features and is prognostic of worse outcomes in breast cancer. BMC Cancer. 16:472016. View Article : Google Scholar : PubMed/NCBI
19	Li Z, Dai K, Wang C, Song Y, Gu F, Liu F and Fu L: Expression of polo-like kinase 4(PLK4) in breast cancer and its response to taxane-based neoadjuvant chemotherapy. J Cancer. 7:1125–1132. 2016. View Article : Google Scholar : PubMed/NCBI
20	Bonni S, Ganuelas ML, Petrinac S and Hudson JW: Human Plk4 phosphorylates Cdc25C. Cell Cycle. 7:545–547. 2008. View Article : Google Scholar : PubMed/NCBI
21	Mutch DG and Prat J: 2014 FIGO staging for ovarian, fallopian, tube and peritoneal cancer. Gynecol Oncol. 133:401–404. 2014. View Article : Google Scholar : PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
23	Helland Å, Anglesio MS, George J, Cowin PA, Johnstone CN, House CM, Sheppard KE, Etemadmoghadam D, Melnyk N, Rustgi AK, et al: Deregulation of MYCN, LIN28B and LET7 in a molecular subtype of aggressive high-grade serous ovarian cancers. PLoS One. 6:e180642011. View Article : Google Scholar : PubMed/NCBI
24	Wang T, Wang G, Hao D, Liu X, Wang D, Ning N and Li X: Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors and its effects on the hallmarks of cancer. Mol Cancer. 14:1252015. View Article : Google Scholar : PubMed/NCBI
25	Enriquez VA, Cleys ER, Da Silveira JC, Spillman MA, Winger QA and Bouma GJ: High LIN28A expressing ovarian cancer cells secrete exosomes that induce invasion and migration in HEK293 cells. Biomed Res Int. 2015:7013902015. View Article : Google Scholar : PubMed/NCBI
26	Tu HC, Schwitalla S, Qian Z, LaPier GS, Yermalovich A, Ku YC, Chen SC, Viswanathan SR, Zhu H, Nishihara R, et al: LIN28 cooperates with WNT signaling to drive invasive intestinal and colorectal adenocarcinoma in mice and humans. Genes Dev. 29:1074–1086. 2015. View Article : Google Scholar : PubMed/NCBI
27	Spence T, Perotti C, Sin-Chan P, Picard D, Wu W, Singh A, Anderson C, Blough MD, Cairncross JG, Lafay-Cousin L, et al: A novel C19MC amplified cell line links Lin28/let-7 to mTOR signaling in embryonal tumor with multilayered rosettes. Neuro Oncol. 16:62–71. 2014. View Article : Google Scholar : PubMed/NCBI
28	Rubens JA, Wang SZ, Price A, Weingart MF, Allen SJ, Orr BA, Eberhart CG and Raabe EH: The TORC1/2 inhibitor TAK228 sensitizes atypical teratoid rhabdoid tumors to cisplatin-induced cytotoxicity. Neuro Oncol. 19:1361–1371. 2017. View Article : Google Scholar : PubMed/NCBI
29	Zeng Y, Yao B, Shin J, Lin L, Kim N, Song Q, Liu S, Su Y, Guo JU, Huang L, et al: Lin28A binds active promoters and recruits Tet1 to regulate gene expression. Mol Cell. 61:153–160. 2016. View Article : Google Scholar : PubMed/NCBI
30	Sillibourne JE and Bornens M: Polo-like kinase 4: The odd one out of the family. Cell Div. 5:252010. View Article : Google Scholar : PubMed/NCBI
31	Shinmura K, Kurabe N, Goto M, Yamada H, Natsume H, Konno H and Sugimura H: PLK4 overexpression and its effect on centrosome regulation and chromosome stability in human gastric cancer. Mol Biol Rep. 41:6635–6644. 2014. View Article : Google Scholar : PubMed/NCBI
32	Ling H, Hanashiro K, Luong TH, Benavides L and Fukasawa K: Functional relationship among PLK2, PLK4 and ROCK2 to induce centrosome amplification. Cell Cycle. 14:544–553. 2015. View Article : Google Scholar : PubMed/NCBI
33	Rosario CO, Kazazian K, Zih FS, Brashavitskaya O, Haffani Y, Xu RS, George A, Dennis JW and Swallow CJ: A novel role for Plk4 in regulating cell spreading and motility. Oncogene. 34:3441–3451. 2015. View Article : Google Scholar : PubMed/NCBI
34	Kazazian K, Go C, Wu H, Brashavitskaya O, Xu R, Dennis JW, Gingras AC and Swallow CJ: Plk4 promotes cancer invasion and metastasis through Arp2/3 complex regulation of the actin cytoskeleton. Cancer Res. 77:434–447. 2017. View Article : Google Scholar : PubMed/NCBI
35	Mason JM, Lin DC, Wei X, Che Y, Yao Y, Kiarash R, Cescon DW, Fletcher GC, Awrey DE, Bray MR, et al: Functional characterization of CFI-400945, a Polo-like kinase 4 inhibitor, as a potential anticancer agent. Cancer Cell. 26:163–176. 2014. View Article : Google Scholar : PubMed/NCBI
36	Yu B, Yu Z, Qi PP, Yu DQ and Liu HM: Discovery of orally active anticancer candidate CFI-400945 derived from biologically promising spirooxindoles: Success and challenges. Eur J Med Chem. 95:35–40. 2015. View Article : Google Scholar : PubMed/NCBI
37	Liu L, Zhang CZ, Cai M, Fu J, Chen GG and Yun J: Downregulation of polo-like kinase 4 in hepatocellular carcinoma associates with poor prognosis. PLoS One. 7:e412932012. View Article : Google Scholar : PubMed/NCBI
38	Ko MA, Rosario CO, Hudson JW, Kulkarni S, Pollett A, Dennis JW and Swallow CJ: Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis. Nat Genet. 37:883–888. 2005. View Article : Google Scholar : PubMed/NCBI
39	Ward A, Morettin A, Shum D and Hudson JW: Aberrant methylation of Polo-like kinase CpG islands in Plk4 heterozygous mice. BMC Cancer. 11:712011. View Article : Google Scholar : PubMed/NCBI
40	Boutros R, Lobjois V and Ducommun B: CDC25 phosphatases in cancer cells: Key players? Good targets? Nat Rev Cancer. 7:495–507. 2007. View Article : Google Scholar : PubMed/NCBI
41	Broggini M, Buraggi G, Brenna A, Riva L, Codegoni AM, Torri V, Lissoni AA, Mangioni C and D'Incalci M: Cell cycle-related phosphatases CDC25A and B expression correlates with survival in ovarian cancer patients. Anticancer Res. 20:4835–4840. 2000.PubMed/NCBI
42	Yang J, Bennett BD, Luo S, Inoue K, Grimm SA, Schroth GP, Bushel PR, Kinyamu HK and Archer TK: LIN28A modulates splicing and gene expression programs in breast cancer cells. Mol Cell Biol. 35:3225–3243. 2015.PubMed/NCBI
43	Ueland FR: A perspective on ovarian cancer biomarkers: Past, present and yet-to-come. Diagnostics (Basel). 7:E142017. View Article : Google Scholar : PubMed/NCBI
44	Wei SU, Li H and Zhang B: The diagnostic value of serum HE4 and CA-125 and ROMA index in ovarian cancer. Biomed Rep. 5:41–44. 2016. View Article : Google Scholar : PubMed/NCBI
45	Sölétormos G, Duffy MJ, Othman Abu Hassan S, Verheijen RH, Tholander B, Bast RC Jr, Gaarenstroom KN, Sturgeon CM, Bonfrer JM, Petersen PH, et al: Clinical use of cancer biomarkers in epithelial ovarian cancer: Updated guidelines from the european group on tumor markers. Int J Gynecol Cancer. 26:43–51. 2016. View Article : Google Scholar : PubMed/NCBI
46	Arts-De Jong M, De Bock GH, Van Asperen CJ, Mourits MJ, de Hullu JA and Kets CM: Germline BRCA1/2 mutation testing is indicated in every patient with epithelial ovarian cancer: A systematic review. Eur J Cancer. 61:137–145. 2016. View Article : Google Scholar : PubMed/NCBI
47	Pujade-Lauraine E, Selle F, Weber B, Ray-Coquard IL, Vergote I, Sufliarsky J, Del Campo JM, Lortholary A, Lesoin A, Follana P, et al: Volasertib versus chemotherapy in platinum-resistant or -refractory ovarian cancer: A randomized phase II groupe des investigateurs nationaux pour l'etude des cancers de l'ovaire study. J Clin Oncol. 34:706–713. 2016. View Article : Google Scholar : PubMed/NCBI
48	Peng S, Maihle NJ and Huang Y: Pluripotency factors Lin28 and Oct4 identify a sub-population of stem cell-like cells in ovarian cancer. Oncogene. 29:2153–2159. 2010. View Article : Google Scholar : PubMed/NCBI