The protein arginine methyltransferase 5 promotes malignant phenotype of hepatocellular carcinoma cells and is associated with adverse patient outcomes after curative hepatectomy

Shimizu,Dai; Kanda,Mitsuro; Sugimoto,Hiroyuki; Shibata,Masahiro; Tanaka,Haruyoshi; Takami,Hideki; Iwata,Naoki; Hayashi,Masamichi; Tanaka,Chie; Kobayashi,Daisuke; Yamada,Suguru; Nakayama,Goro; Koike,Masahiko; Fujiwara,Michitaka; Fujii,Tsutomu; Kodera,Yasuhiro

doi:10.3892/ijo.2017.3833

The protein arginine methyltransferase 5 promotes malignant phenotype of hepatocellular carcinoma cells and is associated with adverse patient outcomes after curative hepatectomy

Authors:
- Dai Shimizu
- Mitsuro Kanda
- Hiroyuki Sugimoto
- Masahiro Shibata
- Haruyoshi Tanaka
- Hideki Takami
- Naoki Iwata
- Masamichi Hayashi
- Chie Tanaka
- Daisuke Kobayashi
- Suguru Yamada
- Goro Nakayama
- Masahiko Koike
- Michitaka Fujiwara
- Tsutomu Fujii
- Yasuhiro Kodera
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Affiliations: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
Published online on: January 2, 2017 https://doi.org/10.3892/ijo.2017.3833
Pages: 381-386
Copyright: © Shimizu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The prognosis of advanced hepatocellular carcinoma (HCC) is dismal. Novel molecular targets for diagnosis and therapy is urgently required. This study evaluated expression and functions of the protein arginine methyltransferase 5 (PRMT5) in HCC. Using HCC cell lines, the expression levels of PRMT5 mRNA were determined using the quantitative real-time reverse-transcription polymerase chain reaction, and the effect of a small interfering PRMT5-siRNA on cell phenotype was evaluated. Further, PRMT5 expression was determined in 144 pairs of resected liver tissues to evaluate its clinical significance. Regardless of their differentiated phenotypes, nine HCC cell lines expressed different levels of PRMT5 mRNA. Inhibition of PRMT5 expression significantly decreased the proliferation, invasion, and migration of HCC cell lines. Although the level of PRMT5 mRNA was not influenced by patient's background liver status, it was significantly higher in HCC tissues than in the corresponding noncancerous tissues. High levels of PRMT5 mRNA in HCC tissues were significantly associated with advanced disease stage and adverse prognosis. In conclusion, our results indicate that PRMT5 may act as a putative oncogene in HCC and that the levels of PRMT5 mRNA represent a promising prognostic marker and a potential target of molecular therapy for HCC.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
2	Kanda M, Sugimoto H and Kodera Y: Genetic and epigenetic aspects of initiation and progression of hepatocellular carcinoma. World J Gastroenterol. 21:10584–10597. 2015. View Article : Google Scholar : PubMed/NCBI
3	Llovet JM, Burroughs A and Bruix J: Hepatocellular carcinoma. Lancet. 362:1907–1917. 2003. View Article : Google Scholar : PubMed/NCBI
4	Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, et al: Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10:25–34. 2009. View Article : Google Scholar
5	El-Serag HB: Hepatocellular carcinoma. N Engl J Med. 365:1118–1127. 2011. View Article : Google Scholar : PubMed/NCBI
6	Kanda M, Sugimoto H, Nomoto S, Oya H, Hibino S, Shimizu D, Takami H, Hashimoto R, Okamura Y, Yamada S, et al: B cell translocation gene 1 serves as a novel prognostic indicator of hepatocellular carcinoma. Int J Oncol. 46:641–648. 2015.
7	Stopa N, Krebs JE and Shechter D: The PRMT5 arginine methyltransferase: Many roles in development, cancer and beyond. Cell Mol Life Sci. 72:2041–2059. 2015. View Article : Google Scholar : PubMed/NCBI
8	Tanaka H, Hoshikawa Y, Oh-hara T, Koike S, Naito M, Noda T, Arai H, Tsuruo T and Fujita N: PRMT5, a novel TRAIL receptor-binding protein, inhibits TRAIL-induced apoptosis via nuclear factor-kappaB activation. Mol Cancer Res. 7:557–569. 2009. View Article : Google Scholar : PubMed/NCBI
9	Tee WW, Pardo M, Theunissen TW, Yu L, Choudhary JS, Hajkova P and Surani MA: Prmt5 is essential for early mouse development and acts in the cytoplasm to maintain ES cell pluripotency. Genes Dev. 24:2772–2777. 2010. View Article : Google Scholar : PubMed/NCBI
10	Nicholas C, Yang J, Peters SB, Bill MA, Baiocchi RA, Yan F, Sïf S, Tae S, Gaudio E, Wu X, et al: PRMT5 is upregulated in malignant and metastatic melanoma and regulates expression of MITF and p27(Kip1). PLoS One. 8:e747102013. View Article : Google Scholar
11	Han X, Li R, Zhang W, Yang X, Wheeler CG, Friedman GK, Province P, Ding Q, You Z, Fathallah-Shaykh HM, et al: Expression of PRMT5 correlates with malignant grade in gliomas and plays a pivotal role in tumor growth in vitro. J Neurooncol. 118:61–72. 2014. View Article : Google Scholar : PubMed/NCBI
12	Li Y, Chitnis N, Nakagawa H, Kita Y, Natsugoe S, Yang Y, Li Z, Wasik M, Klein-Szanto AJ, Rustgi AK, et al: PRMT5 is required for lymphomagenesis triggered by multiple oncogenic drivers. Cancer Discov. 5:288–303. 2015. View Article : Google Scholar : PubMed/NCBI
13	Bao X, Zhao S, Liu T, Liu Y, Liu Y and Yang X: Overexpression of PRMT5 promotes tumor cell growth and is associated with poor disease prognosis in epithelial ovarian cancer. J Histochem Cytochem. 61:206–217. 2013. View Article : Google Scholar : PubMed/NCBI
14	Ibrahim R, Matsubara D, Osman W, Morikawa T, Goto A, Morita S, Ishikawa S, Aburatani H, Takai D, Nakajima J, et al: Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial-mesenchymal transition. Hum Pathol. 45:1397–1405. 2014. View Article : Google Scholar : PubMed/NCBI
15	Zhang B, Dong S, Li Z, Lu L, Zhang S, Chen X, Cen X and Wu Y: Targeting protein arginine methyltransferase 5 inhibits human hepatocellular carcinoma growth via the downregulation of beta-catenin. J Transl Med. 13:3492015. View Article : Google Scholar : PubMed/NCBI
16	Ezaka K, Kanda M, Sugimoto H, Shimizu D, Oya H, Nomoto S, Sueoka S, Tanaka Y, Takami H, Hashimoto R, et al: Reduced expression of adherens junctions associated protein 1 predicts recurrence of hepatocellular carcinoma after curative hepatectomy. Ann Surg Oncol. 22(Suppl 3): S1499–S1507. 2015. View Article : Google Scholar : PubMed/NCBI
17	Kanda M, Nomoto S, Okamura Y, Hayashi M, Hishida M, Fujii T, Nishikawa Y, Sugimoto H, Takeda S and Nakao A: Promoter hypermethylation of fibulin 1 gene is associated with tumor progression in hepatocellular carcinoma. Mol Carcinog. 50:571–579. 2011. View Article : Google Scholar : PubMed/NCBI
18	Kanda M, Nomoto S, Oya H, Takami H, Hibino S, Hishida M, Suenaga M, Yamada S, Inokawa Y, Nishikawa Y, et al: Downregulation of DENND2D by promoter hypermethylation is associated with early recurrence of hepatocellular carcinoma. Int J Oncol. 44:44–52. 2014.
19	Sobin LH, Gospodarowicz MK and Wittekind CH: International Union Against Cancer: TNM Classification of Malignant Tumors. 7th edition. Wiley-Blackwell; New York: 2009
20	Kanda M, Nomoto S, Oya H, Hashimoto R, Takami H, Shimizu D, Sonohara F, Kobayashi D, Tanaka C, Yamada S, et al: Decreased expression of prenyl diphosphate synthase subunit 2 correlates with reduced survival of patients with gastric cancer. J Exp Clin Cancer Res. 33:882014. View Article : Google Scholar : PubMed/NCBI
21	Kanda M, Nomoto S, Oya H, Shimizu D, Takami H, Hibino S, Hashimoto R, Kobayashi D, Tanaka C, Yamada S, et al: Dihydropyrimidinase-like 3 facilitates malignant behavior of gastric cancer. J Exp Clin Cancer Res. 33:662014. View Article : Google Scholar : PubMed/NCBI
22	Kanda M, Nomoto S, Okamura Y, Nishikawa Y, Sugimoto H, Kanazumi N, Takeda S and Nakao A: Detection of metallothionein 1G as a methylated tumor suppressor gene in human hepatocellular carcinoma using a novel method of double combination array analysis. Int J Oncol. 35:477–483. 2009.PubMed/NCBI
23	Kanda M, Shimizu D, Fujii T, Sueoka S, Tanaka Y, Ezaka K, Takami H, Tanaka H, Hashimoto R, Iwata N, et al: Function and diagnostic value of Anosmin-1 in gastric cancer progression. Int J Cancer. 138:721–730. 2016. View Article : Google Scholar
24	Oya H, Kanda M, Sugimoto H, Shimizu D, Takami H, Hibino S, Hashimoto R, Okamura Y, Yamada S, Fujii T, et al: Dihydropyrimidinase-like 3 is a putative hepatocellular carcinoma tumor suppressor. J Gastroenterol. 50:590–600. 2015. View Article : Google Scholar
25	BLAST: Basic Local Alignment Search Tool. http://blast.ncbi.nlm.nih.gov/Blast.cgi. Accessed March 10, 2016.
26	Smil D, Eram MS, Li F, Kennedy S, Szewczyk MM, Brown PJ, Barsyte-Lovejoy D, Arrowsmith CH, Vedadi M and Schapira M: Discovery of a dual PRMT5-PRMT7 inhibitor. ACS Med Chem Lett. 6:408–412. 2015. View Article : Google Scholar : PubMed/NCBI
27	Yan F, Alinari L, Lustberg ME, Martin LK, Cordero-Nieves HM, Banasavadi-Siddegowda Y, Virk S, Barnholtz-Sloan J, Bell EH, Wojton J, et al: Genetic validation of the protein arginine methyltransferase PRMT5 as a candidate therapeutic target in glioblastoma. Cancer Res. 74:1752–1765. 2014. View Article : Google Scholar : PubMed/NCBI
28	Kim S, Günesdogan U, Zylicz JJ, Hackett JA, Cougot D, Bao S, Lee C, Dietmann S, Allen GE, Sengupta R, et al: PRMT5 protects genomic integrity during global DNA demethylation in primordial germ cells and preimplantation embryos. Mol Cell. 56:564–579. 2014. View Article : Google Scholar : PubMed/NCBI
29	Gao J, Zhu Y, Nilsson M and Sundfeldt K: TGF-β isoforms induce EMT independent migration of ovarian cancer cells. Cancer Cell Int. 14:722014. View Article : Google Scholar
30	Cho EC, Zheng S, Munro S, Liu G, Carr SM, Moehlenbrink J, Lu YC, Stimson L, Khan O, Konietzny R, et al: Arginine methylation controls growth regulation by E2F-1. EMBO J. 31:1785–1797. 2012. View Article : Google Scholar : PubMed/NCBI