Protein arginine methyltransferase 5 is associated with malignant phenotype and peritoneal metastasis in gastric cancer

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

doi:10.3892/ijo.2016.3584

Protein arginine methyltransferase 5 is associated with malignant phenotype and peritoneal metastasis in gastric cancer

Authors:
- Mitsuro Kanda
- Dai Shimizu
- Tsutomu Fujii
- Haruyoshi Tanaka
- Masahiro Shibata
- Naoki Iwata
- Masamichi Hayashi
- Daisuke Kobayashi
- Chie Tanaka
- Suguru Yamada
- Goro Nakayama
- Hiroyuki Sugimoto
- Masahiko Koike
- Michitaka Fujiwara
- 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: June 17, 2016 https://doi.org/10.3892/ijo.2016.3584
Pages: 1195-1202

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Abstract

Identification of novel gastric cancer (GC)-related molecules is necessary to improve management of patients with GC in both diagnostic and therapeutic aspects. The aim of the present study was to determine whether protein arginine methyltransferase 5 (PRMT5) acts as an oncogene in the progression of GC and whether it serves as a novel diagnostic marker and therapeutic target. We conducted global expression profiling of GC cell lines and RNA interference experiments to evaluate the effect of PRMT5 expression on the phenotype of GC cells. We analysed tissues of 179 patients with GC to assess the association of PRMT5 mRNA levels with clinicopathological factors. Differential expression of PRMT5 mRNA by GC cell lines correlated positively with the levels of GEMIN2, STAT3 and TGFB3. PRMT5 knockdown reduced the proliferation, invasion and migration of a GC cell line. PRMT5 mRNA levels were significantly higher in GC tissues than the corresponding adjacent normal tissues and were independent of tumour depth, differentiation and lymph node metastasis. High PRMT5 expression was an independent risk factor of positive peritoneal lavage cytology (odds ratio 3.90, P=0.003) and decreased survival. PRMT5 enhances the malignant phenotype of GC cell lines and its expression in gastric tissues may serve as a biomarker for patient stratification and a potential target of therapy.

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1	Hartgrink HH, Jansen EP, van Grieken NC and van de Velde CJ: Gastric cancer. Lancet. 374:477–490. 2009. View Article : Google Scholar : PubMed/NCBI
2	Kanda M, Kobayashi D, Tanaka C, Iwata N, Yamada S, Fujii T, Nakayama G, Sugimoto H, Koike M, Nomoto S, et al: Adverse prognostic impact of perioperative allogeneic transfusion on patients with stage II/III gastric cancer. Gastric Cancer. 19:255–263. 2016. View Article : Google Scholar
3	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
4	Leung WK, Wu MS, Kakugawa Y, Kim JJ, Yeoh KG, Goh KL, Wu KC, Wu DC, Sollano J, Kachintorn U, et al; Asia Pacific Working Group on Gastric Cancer. Screening for gastric cancer in Asia: Current evidence and practice. Lancet Oncol. 9:279–287. 2008. View Article : Google Scholar : PubMed/NCBI
5	Kanda M, Mizuno A, Fujii T, Shimoyama Y, Yamada S, Tanaka C, Kobayashi D, Koike M, Iwata N, Niwa Y, et al: Tumor infiltrative pattern predicts sites of recurrence after curative gastrectomy for stages 2 and 3 gastric cancer. Ann Surg Oncol. 23:1934–1940. 2016. View Article : Google Scholar : PubMed/NCBI
6	Paoletti X, Oba K, Burzykowski T, Michiels S, Ohashi Y, Pignon JP, Rougier P, Sakamoto J, Sargent D, Sasako M, et al; GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) Group. Benefit of adjuvant chemotherapy for resectable gastric cancer: A meta-analysis. JAMA. 303:1729–1737. 2010. View Article : Google Scholar : PubMed/NCBI
7	McLean MH and El-Omar EM: Genetics of gastric cancer. Nat Rev Gastroenterol Hepatol. 11:664–674. 2014. View Article : Google Scholar : PubMed/NCBI
8	Kanda M, Nomoto S, Oya H, Takami H, Shimizu D, Hibino S, Hashimoto R, Kobayashi D, Tanaka C, Yamada S, et al: The expression of melanoma-associated antigen D2 both in surgically resected and serum samples serves as clinically relevant biomarker of gastric cancer progression. Ann Surg Oncol. 23(Suppl 2): S214–S221. 2016. View Article : Google Scholar
9	Jang BG and Kim WH: Molecular pathology of gastric carcinoma. Pathobiology. 78:302–310. 2011. View Article : Google Scholar : PubMed/NCBI
10	Resende C, Thiel A, Machado JC and Ristimäki A: Gastric cancer: Basic aspects. Helicobacter. 16(Suppl 1): 38–44. 2011. View Article : Google Scholar : PubMed/NCBI
11	Kanda M, Shimizu D, Tanaka H, Shibata M, Iwata N, Hayashi M, Kobayashi D, Tanaka C, Yamada S, Fujii T, et al: Metastatic pathway-specific transcriptome analysis identifies MFSD4 as a putative tumor suppressor and biomarker for hepatic metastasis in patients with gastric cancer. Oncotarget. 7:13667–13679. 2016.PubMed/NCBI
12	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
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	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
15	Aggarwal P, Vaites LP, Kim JK, Mellert H, Gurung B, Nakagawa H, Herlyn M, Hua X, Rustgi AK, McMahon SB, et al: Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyl-transferase. Cancer Cell. 18:329–340. 2010. View Article : Google Scholar : PubMed/NCBI
16	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 pluri-potency. Genes Dev. 24:2772–2777. 2010. View Article : Google Scholar : PubMed/NCBI
17	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
18	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
19	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
20	Stopa N, Krebs JE and Shechter D: The PRMT5 arginine methyl-transferase: Many roles in development, cancer and beyond. Cell Mol Life Sci. 72:2041–2059. 2015. View Article : Google Scholar : PubMed/NCBI
21	Kanda M, Shimizu D, Nomoto S, Takami H, Hibino S, Oya H, Hashimoto R, Suenaga M, Inokawa Y, Kobayashi D, et al: Prognostic impact of expression and methylation status of DENN/MADD domain-containing protein 2D in gastric cancer. Gastric Cancer. 18:288–296. 2015. View Article : Google Scholar
22	Kanda M, Kodera Y and Sakamoto J: Updated evidence on adjuvant treatments for gastric cancer. Expert Rev Gastroenterol Hepatol. 9:1549–1560. 2015. View Article : Google Scholar : PubMed/NCBI
23	Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, et al; ACTS-GC Group. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 357:1810–1820. 2007. View Article : Google Scholar : PubMed/NCBI
24	Kanda M, Murotani K, Kobayashi D, Tanaka C, Yamada S, Fujii T, Nakayama G, Sugimoto H, Koike M, Fujiwara M, et al: Postoperative adjuvant chemotherapy with S-1 alters recurrence patterns and prognostic factors among patients with stage II/III gastric cancer: A propensity score matching analysis. Surgery. 158:1573–1580. 2015. View Article : Google Scholar : PubMed/NCBI
25	Kanda M, Oya H, Nomoto S, Takami H, Shimizu D, Hashimoto R, Sueoka S, Kobayashi D, Tanaka C, Yamada S, et al: Diversity of clinical implication of B-cell translocation gene 1 expression by histopathologic and anatomic subtypes of gastric cancer. Dig Dis Sci. 60:1256–1264. 2015. View Article : Google Scholar
26	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
27	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
28	Gervasi M, Bianchi-Smiraglia A, Cummings M, Zheng Q, Wang D, Liu S and Bakin AV: JunB contributes to Id2 repression and the epithelial-mesenchymal transition in response to transforming growth factor-β. J Cell Biol. 196:589–603. 2012. View Article : Google Scholar : PubMed/NCBI
29	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
30	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
31	Hu M, Xia M, Chen X, Lin Z, Xu Y, Ma Y and Su L: MicroRNA-141 regulates Smad interacting protein 1 (SIP1) and inhibits migration and invasion of colorectal cancer cells. Dig Dis Sci. 55:2365–2372. 2010. View Article : Google Scholar
32	Okugawa Y, Inoue Y, Tanaka K, Kawamura M, Saigusa S, Toiyama Y, Ohi M, Uchida K, Mohri Y and Kusunoki M: Smad interacting protein 1 (SIP1) is associated with peritoneal carcinomatosis in intestinal type gastric cancer. Clin Exp Metastasis. 30:417–429. 2013. View Article : Google Scholar
33	Karihtala P, Auvinen P, Kauppila S, Haapasaari KM, Jukkola-Vuorinen A and Soini Y: Vimentin, zeb1 and Sip1 are up-regulated in triple-negative and basal-like breast cancers: Association with an aggressive tumour phenotype. Breast Cancer Res Treat. 138:81–90. 2013. View Article : Google Scholar : PubMed/NCBI
34	Thakur R, Trivedi R, Rastogi N, Singh M and Mishra DP: Inhibition of STAT3, FAK and Src mediated signaling reduces cancer stem cell load, tumorigenic potential and metastasis in breast cancer. Sci Rep. 5:101942015. View Article : Google Scholar : PubMed/NCBI
35	Wang T, Yuan J, Zhang J, Tian R, Ji W, Zhou Y, Yang Y, Song W, Zhang F and Niu R: Anxa2 binds to STAT3 and promotes epithelial to mesenchymal transition in breast cancer cells. Oncotarget. 6:30975–30992. 2015.PubMed/NCBI
36	Kim BR, Oh SC, Lee DH, Kim JL, Lee SY, Kang MH, Lee SI, Kang S, Joung SY and Min BW: BMP-2 induces motility and invasiveness by promoting colon cancer stemness through STAT3 activation. Tumour Biol. 36:9475–9486. 2015. View Article : Google Scholar : PubMed/NCBI
37	Taylor MA, Davuluri G, Parvani JG, Schiemann BJ, Wendt MK, Plow EF, Schiemann WP and Sossey-Alaoui K: Upregulated WAVE3 expression is essential for TGF-β-mediated EMT and metastasis of triple-negative breast cancer cells. Breast Cancer Res Treat. 142:341–353. 2013. View Article : Google Scholar : PubMed/NCBI
38	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
39	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
40	Yoo CH, Noh SH, Shin DW, Choi SH and Min JS: Recurrence following curative resection for gastric carcinoma. Br J Surg. 87:236–242. 2000. View Article : Google Scholar : PubMed/NCBI
41	Shen L, Shan YS, Hu HM, Price TJ, Sirohi B, Yeh KH, Yang YH, Sano T, Yang HK, Zhang X, et al: Management of gastric cancer in Asia: Resource-stratified guidelines. Lancet Oncol. 14:e535–e547. 2013. View Article : Google Scholar : PubMed/NCBI
42	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