Abstract
Background
Hypomethylation of long interspersed nuclear element-1 (LINE-1) is closely related to certain cancers and concerns with aggressive tumor behavior. Previously, we reported LINE-1 open reading frame-1 (ORF1) protein level was significantly up-regulated in ovarian cancers compared with normal ovary. Hypomethylation of local LINE-1 sequence has been reported to reactivate MET proto-oncogene in colon cancers and hepatocellular carcinoma. However, the relationship between LINE-1 and c-MET expressions in ovarian cancer is not yet studied.
Method
Here, we analyzed the expression patterns of LINE-1 ORF1 and c-Met protein in ovarian cancer tissue microarrays containing 208 surgical specimens including normal ovary and malignant ovarian cancers.
Results
The expressions of both LINE-1 ORF1 and c-Met protein were significantly increased in ovarian cancers and peaked in early stage of tumor. Other clinical data including age and tumor types were not significantly related with both proteins. Co-relationship between LINE-1 ORF1 and c-Met protein was significant (p = 0.03) but several patients show different expression patterns.
Conclusions
These results propose that LINE-1 ORF1 significantly activates c-Met but not in all cases, suggesting other factors may be involved simultaneously.
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References
Appleman LJ (2011) MET signaling pathway: a rational target for cancer therapy. J Clin Oncol 29:4837–4838
Bae JM, Shin SH, Kwon HJ, Park SY, Kook MC, Kim YW, Cho NY, Kim N, Kim TY, Kim D et al (2012) ALU and LINE-1 hypomethylations in multistep gastric carcinogenesis and their prognostic implications. Int J Cancer 131:1323–1331
Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915–925
Bu R, Uddin S, Bavi P, Hussain AR, Al-Dayel F, Ghourab S, Ahmed M, Al-Kuraya KS (2011) HGF/c-Met pathway has a prominent role in mediating antiapoptotic signals through AKT in epithelial ovarian carcinoma. Lab Invest 91:124–137
Di Renzo MF, Olivero M, Katsaros D, Crepaldi T, Gaglia P, Zola P, Sismondi P, Comoglio PM (1994) Overexpression of the Met/HGF receptor in ovarian cancer. Int J Cancer 58:658–662
Dobbin ZC, Landen CN (2013) The importance of the PI3 K/AKT/MTOR pathway in the progression of ovarian cancer. Int J Mol Sci 14:8213–8227
Gherardi E, Birchmeier W, Birchmeier C, Vande Woude G (2012) Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12:89–103
Hur K, Cejas P, Feliu J, Moreno-Rubio J, Burgos E, Boland CR, Goel A (2014) Hypomethylation of long interspersed nuclear element-1 (LINE-1) leads to activation of proto-oncogenes in human colorectal cancer metastasis. Gut 63:635–646
Igarashi S, Suzuki H, Niinuma T, Shimizu H, Nojima M, Iwaki H, Nobuoka T, Nishida T, Miyazaki Y, Takamaru H et al (2010) A novel correlation between LINE-1 hypomethylation and the malignancy of gastrointestinal stromal tumors. Clin Cancer Res 16:5114–5123
Iwagami S, Baba Y, Watanabe M, Shigaki H, Miyake K, Ishimoto T, Iwatsuki M, Sakamaki K, Ohashi Y, Baba H (2013) LINE-1 hypomethylation is associated with a poor prognosis among patients with curatively resected esophageal squamous cell carcinoma. Ann Surg 257:449–455
Koon EC, Ma PC, Salgia R, Welch WR, Christensen JG, Berkowitz RS, Mok SC (2008) Effect of a c-Met-specific, ATP-competitive small-molecule inhibitor SU11274 on human ovarian carcinoma cell growth, motility, and invasion. Int J Gynecol Cancer 18:976–984
Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921
Miglio U, Berrino E, Panero M, Ferrero G, Coscujuela Tarrero L, Miano V, Dell’Aglio C, Sarotto I, Annaratone L, Marchio C et al (2018) The expression of LINE1-MET chimeric transcript identifies a subgroup of aggressive breast cancers. Int J Cancer 143:2838–2848
Pattamadilok J, Huapai N, Rattanatanyong P, Vasurattana A, Triratanachat S, Tresukosol D, Mutirangura A (2008) LINE-1 hypomethylation level as a potential prognostic factor for epithelial ovarian cancer. Int J Gynecol Cancer 18:711–717
Rodic N, Sharma R, Sharma R, Zampella J, Dai L, Taylor MS, Hruban RH, Iacobuzio-Donahue CA, Maitra A, Torbenson MS et al (2014) Long interspersed element-1 protein expression is a hallmark of many human cancers. Am J Pathol 184:1280–1286
Roman-Gomez J, Jimenez-Velasco A, Agirre X, Cervantes F, Sanchez J, Garate L, Barrios M, Castillejo JA, Navarro G, Colomer D et al (2005) Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense/antisense transcription and marks the progression of chronic myeloid leukemia. Oncogene 24:7213–7223
Sawada K, Radjabi AR, Shinomiya N, Kistner E, Kenny H, Becker AR, Turkyilmaz MA, Salgia R, Yamada SD, Vande Woude GF et al (2007) c-Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion. Cancer Res 67:1670–1679
Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61:212–236
Takai D, Yagi Y, Habib N, Sugimura T, Ushijima T (2000) Hypomethylation of LINE1 retrotransposon in human hepatocellular carcinomas, but not in surrounding liver cirrhosis. Jpn J Clin Oncol 30:306–309
Widschwendter M, Jiang G, Woods C, Muller HM, Fiegl H, Goebel G, Marth C, Muller-Holzner E, Zeimet AG, Laird PW et al (2004) DNA hypomethylation and ovarian cancer biology. Cancer Res 64:4472–4480
Wolff EM, Byun HM, Han HF, Sharma S, Nichols PW, Siegmund KD, Yang AS, Jones PA, Liang G (2010) Hypomethylation of a LINE-1 promoter activates an alternate transcript of the MET oncogene in bladders with cancer. PLoS Genet 6:e1000917
Yamamoto E, Toyota M, Suzuki H, Kondo Y, Sanomura T, Murayama Y, Ohe-Toyota M, Maruyama R, Nojima M, Ashida M et al (2008) LINE-1 hypomethylation is associated with increased CpG island methylation in Helicobacter pylori-related enlarged-fold gastritis. Cancer Epidemiol Biomark Prev 17:2555–2564
Yamashita Y, Akatsuka S, Shinjo K, Yatabe Y, Kobayashi H, Seko H, Kajiyama H, Kikkawa F, Takahashi T, Toyokuni S (2013) Met is the most frequently amplified gene in endometriosis-associated ovarian clear cell adenocarcinoma and correlates with worsened prognosis. PLoS One 8:e57724
Yoshida T, Yamashita S, Takamura-Enya T, Niwa T, Ando T, Enomoto S, Maekita T, Nakazawa K, Tatematsu M, Ichinose M et al (2011) Alu and Satalpha hypomethylation in Helicobacter pylori-infected gastric mucosae. Int J Cancer 128:33–39
Yun KY, Ko EJ, Kim HY, Lee JY, Eo WK, Ock MS, Kim HS, Kim KH, Cha HJ (2017) Long interspersed element-1 open reading frame 1 protein expression profiles in ovarian cancers. Genes Genom 39:1157–1162
Zhu C, Utsunomiya T, Ikemoto T, Yamada S, Morine Y, Imura S, Arakawa Y, Takasu C, Ishikawa D, Imoto I et al (2014) Hypomethylation of long interspersed nuclear element-1 (LINE-1) is associated with poor prognosis via activation of c-MET in hepatocellular carcinoma. Ann Surg Oncol 21(Suppl 4):S729–S735
Zillhardt M, Christensen JG, Lengyel E (2010) An orally available small-molecule inhibitor of c-Met, PF-2341066, reduces tumor burden and metastasis in a preclinical model of ovarian cancer metastasis. Neoplasia 12:1–10
Zillhardt M, Park SM, Romero IL, Sawada K, Montag A, Krausz T, Yamada SD, Peter ME, Lengyel E (2011) Foretinib (GSK1363089), an orally available multikinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer metastasis. Clin Cancer Res 17:4042–4051
Acknowledgements
This study was supported by Busan Cancer Center Research Grant (2018), Pusan National University Hospital.
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Author Eun-Ji Ko, author Young Lim Oh, author Heung Yeol Kim, author Wan Kyu Eo, author Hongbae Kim, author Mee Sun Ock, author Heui-Soo Kim, author Ki Hyung Kim, and author Hee-Jae Cha declare that they have no conflict of interest.
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Ko, EJ., Oh, Y.L., Kim, H.Y. et al. Correlation of long interspersed element-1 open reading frame 1 and c-Met proto-oncogene protein expression in ovarian cancer. Genes Genom 41, 1293–1299 (2019). https://doi.org/10.1007/s13258-019-00858-y
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DOI: https://doi.org/10.1007/s13258-019-00858-y