Integrative Evaluation of the Clinical Significance Underlying Protein Arginine Methyltransferases in Hepatocellular Carcinoma
Abstract
:Simple Summary
Abstract
1. Introduction
2. Methods
2.1. Data Collection and Preprocessing
2.2. Gene Ontology (GO) Enrichment Analysis
2.3. Trajectory Analysis and Gene Expression Assessment
2.4. Clinical Specimens for Prognostic Relevance Evaluation via Immunofluorescent Staining
2.5. Data Analysis, Visualization, and Statistics
- Data preprocessing: dplyr, stringr, reshape2, naniar, and skimr.
- Boxplot and survival curve: ggplot2, ggpubr, pROC, multipleROC, survival, survminer, egg, gridExtra, and grid.
3. Results
3.1. Expression Patterns of PRMTs in Human HCC
3.2. PRMT Expression Is Associated with Clinicopathological Characteristics in Human HCC
3.3. Prognostic Significance of PRMT Expression in Human HCC
3.4. Gender- and Ethnicity-Specific Correlations of PRMT Expression in Human HCC
3.5. Single-Cell Transcriptomic Analysis of CD8+ T Cell Suggests an Association between PRMT1 Expression and Tex
3.6. Verification of PRMT1 Expression Patterns in Human HCC and Its Potential Role in Tex
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA-Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
- Goh, L.Y.; Leow, A.H.R.; Goh, K.L. Observations on the epidemiology of gastrointestinal and liver cancers in the Asia-Pacific region. J. Digest Dis. 2014, 15, 463–468. [Google Scholar] [CrossRef]
- Shao, X.Y.; Dong, J.; Zhang, H.; Wu, Y.S.; Zheng, L. Systematic Analyses of the Role of the Reader Protein of N (6)-Methyladenosine RNA Methylation, YTH Domain Family 2, in Liver Hepatocellular Carcinoma. Front. Mol. Biosci. 2020, 7, 577460. [Google Scholar] [CrossRef] [PubMed]
- Orcutt, S.T.; Anaya, D.A. Liver Resection and Surgical Strategies for Management of Primary Liver Cancer. Cancer Control 2018, 25, 1073274817744621. [Google Scholar] [CrossRef]
- Llovet, J.M.; Burroughs, A.; Bruix, J. Hepatocellular carcinoma. Lancet 2003, 362, 1907–1917. [Google Scholar] [CrossRef]
- Song, P.; Cai, Y.; Tang, H.; Li, C.; Huang, J. The clinical management of hepatocellular carcinoma worldwide: A concise review and comparison of current guidelines from 2001 to 2017. Biosci. Trends 2017, 11, 389–398. [Google Scholar] [CrossRef] [PubMed]
- Koufaris, C.; Kirmizis, A. Identification of NAA40 as a Potential Prognostic Marker for Aggressive Liver Cancer Subtypes. Front. Oncol. 2021, 11, 691950. [Google Scholar] [CrossRef] [PubMed]
- Liu, H.T.; Jiang, M.J.; Deng, Z.J.; Li, L.; Huang, J.L.; Liu, Z.X.; Li, L.Q.; Zhong, J.H. Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Progresses and Challenges. Front. Oncol. 2021, 11, 737497. [Google Scholar] [CrossRef] [PubMed]
- Yang, Y.; Bedford, M.T. Protein arginine methyltransferases and cancer. Nat. Rev. Cancer 2013, 13, 37–50. [Google Scholar] [CrossRef]
- Pyun, J.H.; Kim, H.J.; Jeong, M.H.; Ahn, B.Y.; Vuong, T.A.; Lee, D.I.; Choi, S.; Koo, S.H.; Cho, H.; Kang, J.S. Cardiac specific PRMT1 ablation causes heart failure through CaMKII dysregulation. Nat. Commun. 2018, 9, 5107. [Google Scholar] [CrossRef]
- Choi, S.; Jeong, H.J.; Kim, H.; Choi, D.; Cho, S.C.; Seong, J.K.; Koo, S.H.; Kang, J.S. Skeletal muscle-specific Prmt1 deletion causes muscle atrophy via deregulation of the PRMT6-FOXO3 axis. Autophagy 2019, 15, 1069–1081. [Google Scholar] [CrossRef]
- Guccione, E.; Richard, S. The regulation, functions and clinical relevance of arginine methylation. Nat. Rev. Mol. Cell Biol. 2019, 20, 642–657. [Google Scholar] [CrossRef]
- Lee, Y.H.; Stallcup, M.R. Minireview: Protein arginine methylation of nonhistone proteins in transcriptional regulation. Mol. Endocrinol. 2009, 23, 425–433. [Google Scholar] [CrossRef] [PubMed]
- Litt, M.; Qiu, Y.; Huang, S. Histone arginine methylations: Their roles in chromatin dynamics and transcriptional regulation. Biosci. Rep. 2009, 29, 131–141. [Google Scholar] [CrossRef]
- Krzystek-Korpacka, M.; Szczesniak-Siega, B.; Szczuka, I.; Fortuna, P.; Zawadzki, M.; Kubiak, A.; Mierzchala-Pasierb, M.; Fleszar, M.G.; Lewandowski, L.; Serek, P.; et al. L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs. Cancers 2020, 12, 2594. [Google Scholar] [CrossRef] [PubMed]
- Sauter, C.; Simonet, J.; Guidez, F.; Dumetier, B.; Pernon, B.; Callanan, M.; Bastie, J.N.; Aucagne, R.; Delva, L. Protein Arginine Methyltransferases as Therapeutic Targets in Hematological Malignancies. Cancers 2022, 14, 5443. [Google Scholar] [CrossRef] [PubMed]
- Suresh, S.; Huard, S.; Brisson, A.; Nemati, F.; Dakroub, R.; Poulard, C.; Ye, M.; Martel, E.; Reyes, C.; Silvestre, D.C.; et al. PRMT1 Regulates EGFR and Wnt Signaling Pathways and Is a Promising Target for Combinatorial Treatment of Breast Cancer. Cancers 2022, 14, 306. [Google Scholar] [CrossRef] [PubMed]
- Szemes, M.; Melegh, Z.; Bellamy, J.; Park, J.H.; Chen, B.; Greenhough, A.; Catchpoole, D.; Malik, K. Transcriptomic Analyses of MYCN-Regulated Genes in Anaplastic Wilms’ Tumour Cell Lines Reveals Oncogenic Pathways and Potential Therapeutic Vulnerabilities. Cancers 2021, 13, 656. [Google Scholar] [CrossRef]
- Dong, F.; Li, Q.; Yang, C.; Huo, D.; Wang, X.; Ai, C.; Kong, Y.; Sun, X.; Wang, W.; Zhou, Y.; et al. PRMT2 links histone H3R8 asymmetric dimethylation to oncogenic activation and tumorigenesis of glioblastoma. Nat. Commun. 2018, 9, 4552. [Google Scholar] [CrossRef]
- Li, Z.; Chen, C.; Yong, H.; Jiang, L.; Wang, P.; Meng, S.; Chu, S.; Li, Z.; Guo, Q.; Zheng, J.; et al. PRMT2 promotes RCC tumorigenesis and metastasis via enhancing WNT5A transcriptional expression. Cell Death Dis. 2023, 14, 322. [Google Scholar] [CrossRef]
- Zhang, X.; Wang, K.; Feng, X.; Wang, J.; Chu, Y.; Jia, C.; He, Q.; Chen, C. PRMT3 promotes tumorigenesis by methylating and stabilizing HIF1alpha in colorectal cancer. Cell Death Dis. 2021, 12, 1066. [Google Scholar] [CrossRef]
- Hwang, J.W.; Cho, Y.; Bae, G.U.; Kim, S.N.; Kim, Y.K. Protein arginine methyltransferases: Promising targets for cancer therapy. Exp. Mol. Med. 2021, 53, 788–808. [Google Scholar] [CrossRef] [PubMed]
- Jiang, H.; Zhu, Y.; Zhou, Z.; Xu, J.; Jin, S.; Xu, K.; Zhang, H.; Sun, Q.; Wang, J.; Xu, J. PRMT5 promotes cell proliferation by inhibiting BTG2 expression via the ERK signaling pathway in hepatocellular carcinoma. Cancer Med. 2018, 7, 869–882. [Google Scholar] [CrossRef] [PubMed]
- Mei, S.; Ge, S.; Wang, J.; Li, H.; Jing, X.; Liang, K.; Zhang, X.; Xue, C.; Zhang, C.; Zhang, T. PRMT5 promotes progression of endometrioid adenocarcinoma via ERalpha and cell cycle signaling pathways. J. Pathol. Clin. Res. 2021, 7, 154–164. [Google Scholar] [CrossRef]
- Chen, Z.; Gan, J.; Wei, Z.; Zhang, M.; Du, Y.; Xu, C.; Zhao, H. The Emerging Role of PRMT6 in Cancer. Front. Oncol. 2022, 12, 841381. [Google Scholar] [CrossRef] [PubMed]
- Avasarala, S.; Wu, P.Y.; Khan, S.Q.; Yanlin, S.; Van Scoyk, M.; Bao, J.; Di Lorenzo, A.; David, O.; Bedford, M.T.; Gupta, V.; et al. PRMT6 Promotes Lung Tumor Progression via the Alternate Activation of Tumor-Associated Macrophages. Mol. Cancer Res. 2020, 18, 166–178. [Google Scholar] [CrossRef]
- Liu, F.; Wan, L.; Zou, H.; Pan, Z.; Zhou, W.; Lu, X. PRMT7 promotes the growth of renal cell carcinoma through modulating the beta-catenin/C-MYC axis. Int. J. Biochem. Cell Biol. 2020, 120, 105686. [Google Scholar] [CrossRef]
- Hernandez, S.J.; Dolivo, D.M.; Dominko, T. PRMT8 demonstrates variant-specific expression in cancer cells and correlates with patient survival in breast, ovarian and gastric cancer. Oncol. Lett. 2017, 13, 1983–1989. [Google Scholar] [CrossRef] [PubMed]
- Zhang, X.P.; Jiang, Y.B.; Zhong, C.Q.; Ma, N.; Zhang, E.B.; Zhang, F.; Li, J.J.; Deng, Y.Z.; Wang, K.; Xie, D.; et al. PRMT1 Promoted HCC Growth and Metastasis In Vitro and In Vivo via Activating the STAT3 Signalling Pathway. Cell Physiol. Biochem. 2018, 47, 1643–1654. [Google Scholar] [CrossRef]
- Hu, G.; Yan, C.; Xie, P.; Cao, Y.; Shao, J.; Ge, J. PRMT2 accelerates tumorigenesis of hepatocellular carcinoma by activating Bcl2 via histone H3R8 methylation. Exp. Cell Res. 2020, 394, 112152. [Google Scholar] [CrossRef] [PubMed]
- Zhong, X.Y.; Yuan, X.M.; Xu, Y.Y.; Yin, M.; Yan, W.W.; Zou, S.W.; Wei, L.M.; Lu, H.J.; Wang, Y.P.; Lei, Q.Y. CARM1 Methylates GAPDH to Regulate Glucose Metabolism and Is Suppressed in Liver Cancer. Cell Rep. 2018, 24, 3207–3223. [Google Scholar] [CrossRef]
- Qin, Q.F.; Li, X.J.; Li, Y.S.; Zhang, W.K.; Tian, G.H.; Shang, H.C.; Tang, H.B. AMPK-ERK/CARM1 Signaling Pathways Affect Autophagy of Hepatic Cells in Samples of Liver Cancer Patients. Front. Oncol. 2019, 9, 1247. [Google Scholar] [CrossRef]
- Jiang, H.; Zhou, Z.; Jin, S.; Xu, K.; Zhang, H.; Xu, J.; Sun, Q.; Wang, J.; Xu, J. PRMT9 promotes hepatocellular carcinoma invasion and metastasis via activating PI3K/Akt/GSK-3beta/Snail signaling. Cancer Sci. 2018, 109, 1414–1427. [Google Scholar] [CrossRef]
- Donisi, C.; Puzzoni, M.; Ziranu, P.; Lai, E.; Mariani, S.; Saba, G.; Impera, V.; Dubois, M.; Persano, M.; Migliari, M.; et al. Immune Checkpoint Inhibitors in the Treatment of HCC. Front. Oncol. 2020, 10, 601240. [Google Scholar] [CrossRef] [PubMed]
- Xia, Y.; Gao, B.; Zhang, X. Targeting mitochondrial quality control of T cells: Regulating the immune response in HCC. Front. Oncol. 2022, 12, 993437. [Google Scholar] [CrossRef]
- Sung, B.Y.; Lin, Y.H.; Kong, Q.; Shah, P.D.; Glick Bieler, J.; Palmer, S.; Weinhold, K.J.; Chang, H.R.; Huang, H.; Avery, R.K.; et al. Wnt activation promotes memory T cell polyfunctionality via epigenetic regulator PRMT1. J. Clin. Investig. 2022, 132, e140508. [Google Scholar] [CrossRef] [PubMed]
- Parry, R.V.; Ward, S.G. Protein arginine methylation: A new handle on T lymphocytes? Trends Immunol. 2010, 31, 164–169. [Google Scholar] [CrossRef]
- Roessler, S.; Jia, H.L.; Budhu, A.; Forgues, M.; Ye, Q.H.; Lee, J.S.; Thorgeirsson, S.S.; Sun, Z.; Tang, Z.Y.; Qin, L.X.; et al. A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients. Cancer Res. 2010, 70, 10202–10212. [Google Scholar] [CrossRef]
- Lamb, J.R.; Zhang, C.; Xie, T.; Wang, K.; Zhang, B.; Hao, K.; Chudin, E.; Fraser, H.B.; Millstein, J.; Ferguson, M.; et al. Predictive genes in adjacent normal tissue are preferentially altered by sCNV during tumorigenesis in liver cancer and may rate limiting. PLoS ONE 2011, 6, e20090. [Google Scholar] [CrossRef] [PubMed]
- Lim, H.Y.; Sohn, I.; Deng, S.; Lee, J.; Jung, S.H.; Mao, M.; Xu, J.; Wang, K.; Shi, S.; Joh, J.W.; et al. Prediction of disease-free survival in hepatocellular carcinoma by gene expression profiling. Ann. Surg. Oncol. 2013, 20, 3747–3753. [Google Scholar] [CrossRef] [PubMed]
- Zheng, C.; Zheng, L.; Yoo, J.K.; Guo, H.; Zhang, Y.; Guo, X.; Kang, B.; Hu, R.; Huang, J.Y.; Zhang, Q.; et al. Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing. Cell 2017, 169, 1342–1356.e16. [Google Scholar] [CrossRef]
- Moon, K.R.; van Dijk, D.; Wang, Z.; Gigante, S.; Burkhardt, D.B.; Chen, W.S.; Yim, K.; Elzen, A.V.D.; Hirn, M.J.; Coifman, R.R.; et al. Visualizing structure and transitions in high-dimensional biological data. Nat. Biotechnol. 2019, 37, 1482–1492. [Google Scholar] [CrossRef]
- Pak, K.; Oh, S.O.; Goh, T.S.; Heo, H.J.; Han, M.E.; Jeong, D.C.; Lee, C.S.; Sun, H.; Kang, J.; Choi, S.; et al. A User-Friendly, Web-Based Integrative Tool (ESurv) for Survival Analysis: Development and Validation Study. J. Med. Internet Res. 2020, 22, e16084. [Google Scholar] [CrossRef] [PubMed]
- Mo, Z.; Yu, L.; Cao, Z.; Hu, H.; Luo, S.; Zhang, S. Identification of a Hypoxia-Associated Signature for Lung Adenocarcinoma. Front. Genet. 2020, 11, 647. [Google Scholar] [CrossRef] [PubMed]
- Zhao, J.; O’Neil, M.; Schonfeld, M.; Komatz, A.; Weinman, S.A.; Tikhanovich, I. Hepatocellular Protein Arginine Methyltransferase 1 Suppresses Alcohol-Induced Hepatocellular Carcinoma Formation by Inhibition of Inducible Nitric Oxide Synthase. Hepatol. Commun. 2020, 4, 790–808. [Google Scholar] [CrossRef] [PubMed]
- Schonfeld, M.; Villar, M.T.; Artigues, A.; Weinman, S.A.; Tikhanovich, I. Arginine Methylation of Integrin Alpha-4 Prevents Fibrosis Development in Alcohol-Associated Liver Disease. Cell Mol. Gastroenterol. Hepatol. 2023, 15, 39–59. [Google Scholar] [CrossRef]
- Blum, H.E. Treatment of hepatocellular carcinoma. Best. Pract. Res. Clin. Gastroenterol. 2005, 19, 129–145. [Google Scholar] [CrossRef]
- Raza, A.; Sood, G.K. Hepatocellular carcinoma review: Current treatment, and evidence-based medicine. World J. Gastroenterol. 2014, 20, 4115–4127. [Google Scholar] [CrossRef]
- Herrmann, F.; Pably, P.; Eckerich, C.; Bedford, M.T.; Fackelmayer, F.O. Human protein arginine methyltransferases in vivo—distinct properties of eight canonical members of the PRMT family. J. Cell Sci. 2009, 122, 667–677. [Google Scholar] [CrossRef]
- Goulet, I.; Gauvin, G.; Boisvenue, S.; Cote, J. Alternative splicing yields protein arginine methyltransferase 1 isoforms with distinct activity, substrate specificity, and subcellular localization. J. Biol. Chem. 2007, 282, 33009–33021. [Google Scholar] [CrossRef]
- Zhong, J.; Cao, R.X.; Zu, X.Y.; Hong, T.; Yang, J.; Liu, L.; Xiao, X.H.; Ding, W.J.; Zhao, Q.; Liu, J.H.; et al. Identification and characterization of novel spliced variants of PRMT2 in breast carcinoma. FEBS J. 2012, 279, 316–335. [Google Scholar] [CrossRef] [PubMed]
- Miranda, T.B.; Miranda, M.; Frankel, A.; Clarke, S. PRMT7 is a member of the protein arginine methyltransferase family with a distinct substrate specificity. J. Biol. Chem. 2004, 279, 22902–22907. [Google Scholar] [CrossRef] [PubMed]
- Che, N.; Ng, K.Y.; Wong, T.L.; Tong, M.; Kau, P.W.; Chan, L.H.; Lee, T.K.; Huen, M.S.; Yun, J.P.; Ma, S. PRMT6 deficiency induces autophagy in hostile microenvironments of hepatocellular carcinoma tumors by regulating BAG5-associated HSC70 stability. Cancer Lett. 2021, 501, 247–262. [Google Scholar] [CrossRef] [PubMed]
- Yun, C.W.; Lee, S.H. The Roles of Autophagy in Cancer. Int. J. Mol. Sci. 2018, 19, 3466. [Google Scholar] [CrossRef]
- Li, Y.; Xu, A.; Jia, S.; Huang, J. Recent advances in the molecular mechanism of sex disparity in hepatocellular carcinoma. Oncol. Lett. 2019, 17, 4222–4228. [Google Scholar] [CrossRef]
- Ko, K.P.; Shin, A.; Cho, S.; Park, S.K.; Yoo, K.Y. Environmental contributions to gastrointestinal and liver cancer in the Asia-Pacific region. J. Gastroen Hepatol. 2018, 33, 111–120. [Google Scholar] [CrossRef]
- Ryu, J.W.; Kim, S.K.; Son, M.Y.; Jeon, S.J.; Oh, J.H.; Lim, J.H.; Cho, S.; Jung, C.R.; Hamamoto, R.; Kim, D.S.; et al. Novel prognostic marker PRMT1 regulates cell growth via downregulation of CDKN1A in HCC. Oncotarget 2017, 8, 115444–115455. [Google Scholar] [CrossRef] [PubMed]
- Schonfeld, M.; Zhao, J.; Komatz, A.; Weinman, S.A.; Tikhanovich, I. The polymorphism rs975484 in the protein arginine methyltransferase 1 gene modulates expression of immune checkpoint genes in hepatocellular carcinoma. J. Biol. Chem. 2020, 295, 7126–7137. [Google Scholar] [CrossRef]
- Foerster, F.; Hess, M.; Gerhold-Ay, A.; Marquardt, J.U.; Becker, D.; Galle, P.R.; Schuppan, D.; Binder, H.; Bockamp, E. The immune contexture of hepatocellular carcinoma predicts clinical outcome. Sci. Rep. 2018, 8, 5351. [Google Scholar] [CrossRef]
- Wherry, E.J.; Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 2015, 15, 486–499. [Google Scholar] [CrossRef]
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Jiang, Y.; Wei, S.; Koo, J.-M.; Kim, H.-J.; Park, W.; Zhang, Y.; Guo, H.; Ha, K.-T.; Oh, C.-M.; Kang, J.-S.; et al. Integrative Evaluation of the Clinical Significance Underlying Protein Arginine Methyltransferases in Hepatocellular Carcinoma. Cancers 2023, 15, 4183. https://doi.org/10.3390/cancers15164183
Jiang Y, Wei S, Koo J-M, Kim H-J, Park W, Zhang Y, Guo H, Ha K-T, Oh C-M, Kang J-S, et al. Integrative Evaluation of the Clinical Significance Underlying Protein Arginine Methyltransferases in Hepatocellular Carcinoma. Cancers. 2023; 15(16):4183. https://doi.org/10.3390/cancers15164183
Chicago/Turabian StyleJiang, Yikun, Shibo Wei, Jin-Mo Koo, Hea-Ju Kim, Wonyoung Park, Yan Zhang, He Guo, Ki-Tae Ha, Chang-Myung Oh, Jong-Sun Kang, and et al. 2023. "Integrative Evaluation of the Clinical Significance Underlying Protein Arginine Methyltransferases in Hepatocellular Carcinoma" Cancers 15, no. 16: 4183. https://doi.org/10.3390/cancers15164183