The Expression Profile and Prognostic Significance of Metallothionein Genes in Colorectal Cancer
Abstract
1. Introduction
2. Results
2.1. mRNA Expression of Six Metallothionein (MT) Genes in Various Human Cancers
2.2. mRNA Expression of Six MT Genes in Pairs of Tumor (T) and Adjacent Non-Tumor (N) CRC Tissues
2.3. mRNA Expressionof Six MT Genes in Colorectal Cancer Tissues
2.4. Prognostic Relevance of the Six Investigated MT Genes in Colorectal Cancer Tissues
2.5. A Combination Four-Gene Signature Predicts Survival in Colorectal Cancer Patients
3. Discussion
4. Materials and Methods
4.1. Tissue Samples and Ethics Statement
4.2. Quantitative Reverse-Transcription (RT)-(q)PCR
4.3. CellMiner Data Mining and Analysis
4.4. Oncomine Database Analysis
4.5. SurvExpress Database Analysis
4.6. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
- Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin. 2019, 69, 7–34. [Google Scholar] [CrossRef] [PubMed]
- Arnold, M.; Sierra, M.S.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global patterns and trends in colorectal cancer incidence and mortality. Gut 2017, 66, 683–691. [Google Scholar] [CrossRef] [PubMed]
- Linnekamp, J.F.; Wang, X.; Medema, J.P.; Vermeulen, L. Colorectal cancer heterogeneity and targeted therapy: A case for molecular disease subtypes. Cancer Res. 2015, 75, 245–249. [Google Scholar] [CrossRef] [PubMed]
- Grady, W.M.; Markowitz, S.D. The molecular pathogenesis of colorectal cancer and its potential application to colorectal cancer screening. Dig. Dis. Sci. 2015, 60, 762–772. [Google Scholar] [CrossRef] [PubMed]
- Zarkavelis, G.; Boussios, S.; Papadaki, A.; Katsanos, K.H.; Christodoulou, D.K.; Pentheroudakis, G. Current and future biomarkers in colorectal cancer. Ann. Gastroenterol. 2017, 30, 613–621. [Google Scholar] [CrossRef] [PubMed]
- Li, S.; Xuan, Y.; Gao, B.; Sun, X.; Miao, S.; Lu, T.; Wang, Y.; Jiao, W. Identification of an eight-gene prognostic signature for lung adenocarcinoma. Cancer Manag. Res. 2018, 10, 3383–3392. [Google Scholar] [CrossRef] [PubMed]
- Aran, V.; Victorino, A.P.; Thuler, L.C.; Ferreira, C.G. Colorectal Cancer: Epidemiology, Disease Mechanisms and Interventions to Reduce Onset and Mortality. Clin. Colorectal Cancer 2016, 15, 195–203. [Google Scholar] [CrossRef] [PubMed]
- Grzadkowski, M.R.; Sendorek, D.H.; P’ng, C.; Huang, V.; Boutros, P.C. A comparative study of survival models for breast cancer prognostication revisited: The benefits of multi-gene models. BMC Bioinform. 2018, 19, 400. [Google Scholar] [CrossRef]
- Su, Y.H.; Tang, W.C.; Cheng, Y.W.; Sia, P.; Huang, C.C.; Lee, Y.C.; Jiang, H.Y.; Wu, M.H.; Lai, I.L.; Lee, J.W.; et al. Targeting of multiple oncogenic signaling pathways by Hsp90 inhibitor alone or in combination with berberine for treatment of colorectal cancer. Biochim. Biophys. Acta 2015, 1853 Pt A, 2261–2272. [Google Scholar] [CrossRef]
- Takahashi, S. Positive and negative regulators of the metallothionein gene (review). Mol. Med. Rep. 2015, 12, 795–799. [Google Scholar] [CrossRef]
- Vasak, M. Advances in metallothionein structure and functions. J. Trace Elem. Med. Biol. 2005, 19, 13–17. [Google Scholar] [CrossRef] [PubMed]
- Krizkova, S.; Kepinska, M.; Emri, G.; Eckschlager, T.; Stiborova, M.; Pokorna, P.; Heger, Z.; Adam, V. An insight into the complex roles of metallothioneins in malignant diseases with emphasis on (sub)isoforms/isoforms and epigenetics phenomena. Pharmacol. Ther. 2018, 183, 90–117. [Google Scholar] [CrossRef] [PubMed]
- Gumulec, J.; Raudenska, M.; Adam, V.; Kizek, R.; Masarik, M. Metallothionein—Immunohistochemical cancer biomarker: A meta-analysis. PLoS ONE 2014, 9, e85346. [Google Scholar] [CrossRef] [PubMed]
- Thirumoorthy, N.; Shyam Sunder, A.; Manisenthil Kumar, K.; Senthil Kumar, M.; Ganesh, G.; Chatterjee, M. A review of metallothionein isoforms and their role in pathophysiology. World J. Surg. Oncol. 2011, 9, 54. [Google Scholar] [CrossRef] [PubMed]
- Reinhold, W.C.; Sunshine, M.; Liu, H.; Varma, S.; Kohn, K.W.; Morris, J.; Doroshow, J.; Pommier, Y. CellMiner: A web-based suite of genomic and pharmacologic tools to explore transcript and drug patterns in the NCI-60 cell line set. Cancer Res. 2012, 72, 3499–3511. [Google Scholar] [CrossRef] [PubMed]
- Rhodes, D.R.; Yu, J.; Shanker, K.; Deshpande, N.; Varambally, R.; Ghosh, D.; Barrette, T.; Pandey, A.; Chinnaiyan, A.M. ONCOMINE: A cancer microarray database and integrated data-mining platform. Neoplasia 2004, 6, 1–6. [Google Scholar] [CrossRef]
- Aguirre-Gamboa, R.; Gomez-Rueda, H.; Martinez-Ledesma, E.; Martinez-Torteya, A.; Chacolla-Huaringa, R.; Rodriguez-Barrientos, A.; Tamez-Pena, J.G.; Trevino, V. SurvExpress: An online biomarker validation tool and database for cancer gene expression data using survival analysis. PLoS ONE 2013, 8, e74250. [Google Scholar] [CrossRef]
- Zhao, K.; Li, Z.; Tian, H. Twenty-gene-based prognostic model predicts lung adenocarcinoma survival. Onco Targets Ther. 2018, 11, 3415–3424. [Google Scholar] [CrossRef]
- Bogaert, J.; Prenen, H. Molecular genetics of colorectal cancer. Ann. Gastroenterol. 2014, 27, 9–14. [Google Scholar]
- Sepulveda, A.R.; Hamilton, S.R.; Allegra, C.J.; Grody, W.; Cushman-Vokoun, A.M.; Funkhouser, W.K.; Kopetz, S.E.; Lieu, C.; Lindor, N.M.; Minsky, B.D.; et al. Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. Arch. Pathol. Lab. Med. 2017, 141, 625–657. [Google Scholar] [CrossRef]
- Kocarnik, J.M.; Shiovitz, S.; Phipps, A.I. Molecular phenotypes of colorectal cancer and potential clinical applications. Gastroenterol. Rep. (Oxf.) 2015, 3, 269–276. [Google Scholar] [CrossRef]
- Sanz-Pamplona, R.; Berenguer, A.; Cordero, D.; Riccadonna, S.; Sole, X.; Crous-Bou, M.; Guino, E.; Sanjuan, X.; Biondo, S.; Soriano, A.; et al. Clinical value of prognosis gene expression signatures in colorectal cancer: A systematic review. PLoS ONE 2012, 7, e48877. [Google Scholar] [CrossRef]
- Hong, S.N. Genetic and epigenetic alterations of colorectal cancer. Intest. Res. 2018, 16, 327–337. [Google Scholar] [CrossRef]
- Iwaya, T.; Yokobori, T.; Nishida, N.; Kogo, R.; Sudo, T.; Tanaka, F.; Shibata, K.; Sawada, G.; Takahashi, Y.; Ishibashi, M.; et al. Downregulation of miR-144 is associated with colorectal cancer progression via activation of mTOR signaling pathway. Carcinogenesis 2012, 33, 2391–2397. [Google Scholar] [CrossRef]
- Aibar, S.; Fontanillo, C.; Droste, C.; Roson-Burgo, B.; Campos-Laborie, F.J.; Hernandez-Rivas, J.M.; De Las Rivas, J. Analyse multiple disease subtypes and build associated gene networks using genome-wide expression profiles. BMC Genom. 2015, 16 (Suppl. 5), S3. [Google Scholar] [CrossRef]
- Aibar, S.; Abaigar, M.; Campos-Laborie, F.J.; Sanchez-Santos, J.M.; Hernandez-Rivas, J.M.; De Las Rivas, J. Identification of expression patterns in the progression of disease stages by integration of transcriptomic data. BMC Bioinform. 2016, 17 (Suppl. 15), 432. [Google Scholar] [CrossRef]
- Ambler, G.; Seaman, S.; Omar, R.Z. An evaluation of penalised survival methods for developing prognostic models with rare events. Stat. Med. 2012, 31, 1150–1161. [Google Scholar] [CrossRef]
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Hung, K.-C.; Huang, T.-C.; Cheng, C.-H.; Cheng, Y.-W.; Lin, D.-Y.; Fan, J.-J.; Lee, K.-H. The Expression Profile and Prognostic Significance of Metallothionein Genes in Colorectal Cancer. Int. J. Mol. Sci. 2019, 20, 3849. https://doi.org/10.3390/ijms20163849
Hung K-C, Huang T-C, Cheng C-H, Cheng Y-W, Lin D-Y, Fan J-J, Lee K-H. The Expression Profile and Prognostic Significance of Metallothionein Genes in Colorectal Cancer. International Journal of Molecular Sciences. 2019; 20(16):3849. https://doi.org/10.3390/ijms20163849
Chicago/Turabian StyleHung, Kuo-Chen, Tsui-Chin Huang, Chia-Hsiung Cheng, Ya-Wen Cheng, Ding-Yen Lin, Jhen-Jia Fan, and Kuen-Haur Lee. 2019. "The Expression Profile and Prognostic Significance of Metallothionein Genes in Colorectal Cancer" International Journal of Molecular Sciences 20, no. 16: 3849. https://doi.org/10.3390/ijms20163849
APA StyleHung, K.-C., Huang, T.-C., Cheng, C.-H., Cheng, Y.-W., Lin, D.-Y., Fan, J.-J., & Lee, K.-H. (2019). The Expression Profile and Prognostic Significance of Metallothionein Genes in Colorectal Cancer. International Journal of Molecular Sciences, 20(16), 3849. https://doi.org/10.3390/ijms20163849