Novel prognostic implications of YTH domain family 2 in resected hepatocellular carcinoma

Nakagawa,Nobuhiko; Sonohara,Fuminori; Tanaka,Katsuhito; Sunagawa,Yuki; Inokawa,Yoshikuni; Takami,Hideki; Hayashi,Masamichi; Yamada,Suguru; Kanda,Mitsuro; Tanaka,Chie; Nakayama,Goro; Koike,Masahiko; Kodera,Yasuhiro

doi:10.3892/ol.2021.12799

Novel prognostic implications of YTH domain family 2 in resected hepatocellular carcinoma

Authors:
- Nobuhiko Nakagawa
- Fuminori Sonohara
- Katsuhito Tanaka
- Yuki Sunagawa
- Yoshikuni Inokawa
- Hideki Takami
- Masamichi Hayashi
- Suguru Yamada
- Mitsuro Kanda
- Chie Tanaka
- Goro Nakayama
- Masahiko Koike
- Yasuhiro Kodera
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Affiliations: Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466‑8550, Japan
Published online on: May 19, 2021 https://doi.org/10.3892/ol.2021.12799
Article Number: 538
Copyright: © Nakagawa et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

N6‑methyladenosine (m⁶A), the most abundant internal RNA modification, serves a critical role in cancer development. However, the clinical implications of m⁶A in hepatocellular carcinoma (HCC) remain unclear. The present study sought to reveal the potential roles of m⁶A readers, which recognize m⁶A, in HCC. A total of 177 HCC and paired non‑cancerous liver tissues from patients who underwent hepatectomy were analysed using quantitative PCR for the expression of m⁶A readers: YT521‑B homology domain family 1 (YTHDF1) and YT521‑B homology domain family 2 (YTHDF2). The expression levels of both YTHDF1 and YTHDF2 were not significantly different between tumour and non‑cancerous tissues (P=0.93 and P=0.7, respectively). Analysis of the association between clinical features and m⁶A reader expression revealed that YTHDF1 expression was associated with formation of capsule (P=0.02), whereas low YTHDF2 expression was associated with septal formation (P=0.02). Furthermore, high YTHDF1 expression and high YTHDF2 expression were significantly associated with shorter recurrence‑free survival (RFS) [YTHDF1: Mean survival time (MST), 34.0 vs. 19.0 months, P=0.014; YTHDF2: MST, 30.1 vs. 12.9 months, P=0.0032], whereas YTHDF1 and YTHDF2 expression was not significantly associated with overall survival (OS) (YTHDF1: MST, 99.4 vs. 70.2 months, P=0.74; YTHDF2: MST, 98.4 vs. 64.1 months, P=0.28). According to multivariate analysis, serosal invasion [hazard ratio (HR), 2.39; 95% CI 1.30‑4.42; P=0.005), portal vein or hepatic vein invasion (HR, 2.82; 95% CI 1.26‑6.28; P=0.01) and YTHDF2 expression in HCC tissues (HR, 1.85; 95% CI 1.09‑3.15; P=0.02) were identified as significant independent prognostic factors for RFS. α‑fetoprotein (HR, 1.79; 95% CI 1.10‑2.92; P=0.02), serosal invasion (HR, 1.99; 95% CI 1.17‑3.34; P=0.01) and portal vein or hepatic vein invasion (HR, 3.02; 95% CI 1.38‑6.61; P=0.006) were identified as significant independent prognostic factors for OS. In conclusion, the present study revealed that high YTHDF2 expression, an m6A reader, in HCC tissues was associated with cancer recurrence.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2020. CA Cancer J Clin. 70:7–30. 2020. View Article : Google Scholar : PubMed/NCBI
2	Tabrizian P, Jibara G, Shrager B, Schwartz M and Roayaie S: Recurrence of hepatocellular cancer after resection: Patterns, treatments, and prognosis. Ann Surg. 261:947–955. 2015. View Article : Google Scholar : PubMed/NCBI
3	Roundtree IA, Evans ME, Pan T and He C: Dynamic RNA modifications in gene expression regulation. Cell. 169:1187–1200. 2017. View Article : Google Scholar : PubMed/NCBI
4	Adams JM and Cory S: Modified nucleosides and bizarre 5′-termini in mouse myeloma mRNA. Nature. 255:28–33. 1975. View Article : Google Scholar : PubMed/NCBI
5	Camper SA, Albers RJ, Coward JK and Rottman FM: Effect of undermethylation on mRNA cytoplasmic appearance and half-life. Mol Cell Biol. 4:538–543. 1984. View Article : Google Scholar : PubMed/NCBI
6	Finkel D and Groner Y: Methylations of adenosine residues (m6A) in pre-mRNA are important for formation of late simian virus 40 mRNAs. Virology. 131:409–425. 1983. View Article : Google Scholar : PubMed/NCBI
7	Gilbert WV, Bell TA and Schaening C: Messenger RNA modifications: Form, distribution, and function. Science. 352:1408–1412. 2016. View Article : Google Scholar : PubMed/NCBI
8	Ma S, Chen C, Ji X, Liu J, Zhou Q, Wang G, Yuan W, Kan Q and Sun Z: The interplay between m6A RNA methylation and noncoding RNA in cancer. J Hematol Oncol. 12:1212019. View Article : Google Scholar : PubMed/NCBI
9	Allis CD and Jenuwein T: The molecular hallmarks of epigenetic control. Nat Rev Genet. 17:487–500. 2016. View Article : Google Scholar : PubMed/NCBI
10	Du H, Zhao Y, He J, Zhang Y, Xi H, Liu M, Ma J and Wu L: YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nat Commun. 7:126262016. View Article : Google Scholar : PubMed/NCBI
11	Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, Weng X, Chen K, Shi H and He C: N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 161:1388–1399. 2015. View Article : Google Scholar : PubMed/NCBI
12	Chen J, Sun Y, Xu X, Wang D, He J, Zhou H, Lu Y, Zeng J, Du F, Gong A and Xu M: YTH domain family 2 orchestrates epithelial-mesenchymal transition/proliferation dichotomy in pancreatic cancer cells. Cell Cycle. 16:2259–2271. 2017. View Article : Google Scholar : PubMed/NCBI
13	Nishizawa Y, Konno M, Asai A, Koseki J, Kawamoto K, Miyoshi N, Takahashi H, Nishida N, Haraguchi N, Sakai D, et al: Oncogene c-Myc promotes epitranscriptome m⁶A reader YTHDF1 expression in colorectal cancer. Oncotarget. 9:7476–7486. 2018. View Article : Google Scholar : PubMed/NCBI
14	Shi Y, Fan S, Wu M, Zuo Z, Li X, Jiang L, Shen Q, Xu P, Zeng L, Zhou Y, et al: YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression. Nat Commun. 10:48922019. View Article : Google Scholar : PubMed/NCBI
15	Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, et al: N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 505:117–120. 2014. View Article : Google Scholar : PubMed/NCBI
16	Li J, Xie H, Ying Y, Chen H, Yan H, He L, Xu M, Xu X, Liang Z, Liu B, et al: YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer. Mol Cancer. 19:1522020. View Article : Google Scholar : PubMed/NCBI
17	Bai Y, Yang C, Wu R, Huang L, Song S, Li W, Yan P, Lin C, Li D and Zhang Y: YTHDF1 regulates tumorigenicity and cancer stem cell-like activity in human colorectal carcinoma. Front Oncol. 9:3322019. View Article : Google Scholar : PubMed/NCBI
18	Han J, Wang JZ, Yang X, Yu H, Zhou R, Lu HC, Yuan WB, Lu JC, Zhou ZJ, Lu Q, et al: METTL3 promote tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in m6A-dependent manner. Mol Cancer. 18:1102019. View Article : Google Scholar : PubMed/NCBI
19	Lin S, Choe J, Du P, Triboulet R and Gregory RI: The m(6)A Methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell. 62:335–345. 2016. View Article : Google Scholar : PubMed/NCBI
20	Miao W, Chen J, Jia L, Ma J and Song D: The m6A methyltransferase METTL3 promotes osteosarcoma progression by regulating the m6A level of LEF1. Biochem Biophys Res Commun. 516:719–725. 2019. View Article : Google Scholar : PubMed/NCBI
21	Wang Q, Chen C, Ding Q, Zhao Y, Wang Z, Chen J, Jiang Z, Zhang Y, Xu G, Zhang J, et al: METTL3-mediated m⁶A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance. Gut. 69:1193–1205. 2020. View Article : Google Scholar : PubMed/NCBI
22	Xia T, Wu X, Cao M, Zhang P, Shi G, Zhang J, Lu Z, Wu P, Cai B, Miao Y and Jiang K: The RNA m6A methyltransferase METTL3 promotes pancreatic cancer cell proliferation and invasion. Pathol Res Pract. 215:1526662019. View Article : Google Scholar : PubMed/NCBI
23	Li J, Han Y, Zhang H, Qian Z, Jia W, Gao Y, Zheng H and Li B: The m6A demethylase FTO promotes the growth of lung cancer cells by regulating the m6A level of USP7 mRNA. Biochem Biophys Res Commun. 512:479–485. 2019. View Article : Google Scholar : PubMed/NCBI
24	Niu Y, Lin Z, Wan A, Chen H, Liang H, Sun L, Wang Y, Li X, Xiong XF, Wei B, et al: RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3. Mol Cancer. 18:462019. View Article : Google Scholar : PubMed/NCBI
25	Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, Chen Y, Sulman EP, Xie K, Bögler O, et al: m⁶A Demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 31:591–606.e6. 2017. View Article : Google Scholar : PubMed/NCBI
26	Zhao X, Chen Y, Mao Q, Jiang X, Jiang W, Chen J, Xu W, Zhong L and Sun X: Overexpression of YTHDF1 is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Biomark. 21:859–868. 2018. View Article : Google Scholar : PubMed/NCBI
27	Qu N, Qin S, Zhang X, Bo X, Liu Z, Tan C, Wen G and Jiang H: Multiple m⁶A RNA methylation modulators promote the malignant progression of hepatocellular carcinoma and affect its clinical prognosis. BMC Cancer. 20:1652020. View Article : Google Scholar : PubMed/NCBI
28	Zhang C, Huang S, Zhuang H, Ruan S, Zhou Z, Huang K, Ji F, Ma Z, Hou B and He X: YTHDF2 promotes the liver cancer stem cell phenotype and cancer metastasis by regulating OCT4 expression via m6A RNA methylation. Oncogene. 39:4507–4518. 2020. View Article : Google Scholar : PubMed/NCBI
29	Zhong L, Liao D, Zhang M, Zeng C, Li X, Zhang R, Ma H and Kang T: YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma. Cancer Lett. 442:252–261. 2019. View Article : Google Scholar : PubMed/NCBI