Expression of AMP‑activated protein kinase/ten‑eleven translocation 2 and their clinical relevance in colorectal cancer

Kang,Dong Hyun; Jeong,Dong Jun; Ahn,Tae Sung; Lee,Hyun Yong; Kim,Han Jo; Bae,Sang Byung; Kim,Hyeong Joo; Lee,Moon Soo; Kwon,Hyog Young; Baek,Moo-Jun

doi:10.3892/ol.2021.12425

Expression of AMP‑activated protein kinase/ten‑eleven translocation 2 and their clinical relevance in colorectal cancer

Authors:
- Dong Hyun Kang
- Dong Jun Jeong
- Tae Sung Ahn
- Hyun Yong Lee
- Han Jo Kim
- Sang Byung Bae
- Hyeong Joo Kim
- Moon Soo Lee
- Hyog Young Kwon
- Moo-Jun Baek
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Affiliations: Division of Colon and Rectal Surgery, Department of Surgery, College of Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Chungcheongnam‑do 31151, Republic of Korea, Soonchunhyang Medical Science Research Institute, College of Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Chungcheongnam‑do 31151, Republic of Korea, Department of Oncology, College of Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Chungcheongnam‑do 31151, Republic of Korea, Division of Gastrointestinal Surgery, Department of Surgery, College of Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Chungcheongnam‑do 31151, Republic of Korea, Soonchunhyang Institute of Medi‑bio Science (SIMS), Soonchunhyang University, Cheonan, Chungcheongnam‑do 31151, Republic of Korea
Published online on: January 4, 2021 https://doi.org/10.3892/ol.2021.12425
Article Number: 164
Copyright: © Kang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Inactivation of the ten‑eleven translocation (TET) family members and catalyzation of 5‑methylcytosine (5‑mC) into 5‑hydroxymethylcytosine (5‑hmC) is associated with cancer initiation and progression. AMP‑activated protein kinase (AMPK) is an enzyme that stabilizes TET2; however, the clinical relevance of AMPK and TET2 expression levels is currently unclear. Therefore, the present study aimed to investigate the clinical implications of AMPK/TET2 expression levels in colorectal cancer (CRC). Immunohistochemistry was used to retrospectively examine the expression levels of AMPK and TET2 in paraffin‑embedded specimens obtained from 343 patients with CRC. The results demonstrated that AMPK and TET2 were highly expressed in CRC samples. No significant association was observed between the expression levels of TET2 and patient clinicopathological characteristics (age, tumor location, lymphatic, vascular and perineural invasion, Tumor‑Node‑Metastasis stages and differentiation); however, patients with low expression levels of TET2 more frequently presented with distant metastasis. By contrast, the expression levels of AMPK were significantly associated with lymph node and distant metastases. The survival analysis results revealed that high expression levels of TET2 were an independent predictor of favorable prognosis compared with low TET2 levels. However, no significant differences in overall survival were observed between patients with high and low expression levels of AMPK. These results described the clinical significance of AMPK/TET2 in CRC. The results of the multivariate analysis demonstrated that high expression levels of TET2 were a predictor of a favorable prognosis, whereas AMPK was not a significant factor for determining patient prognosis; therefore, further functional analysis of AMPK/TET2 expression in CRC is needed.

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1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Jung KW, Won YJ, Hong S, Kong HJ and Lee ES: Prediction of cancer incidence and mortality in Korea, 2020. Cancer Res Treat. 52:351–358. 2020. View Article : Google Scholar : PubMed/NCBI
3	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2020. CA Cancer J Clin. 70:7–30. 2020. View Article : Google Scholar : PubMed/NCBI
4	Ogino S and Goel A: Molecular classification and correlates in colorectal cancer. J Mol Diagn. 10:13–27. 2008. View Article : Google Scholar : PubMed/NCBI
5	Li D: Recent advances in colorectal cancer screening. Chronic Dis Transl Med. 4:139–147. 2018.PubMed/NCBI
6	Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, Fuks F, Lo Coco F, Kouzarides T, Nervi C, et al: Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science. 295:1079–1082. 2002. View Article : Google Scholar : PubMed/NCBI
7	Ko M, An J and Rao A: DNA methylation and hydroxymethylation in hematologic differentiation and transformation. Curr Opin Cell Biol. 37:91–101. 2015. View Article : Google Scholar : PubMed/NCBI
8	Jones PA: Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nat Rev Genet. 13:484–492. 2012. View Article : Google Scholar : PubMed/NCBI
9	Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L and Rao A: Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 324:930–935. 2009. View Article : Google Scholar : PubMed/NCBI
10	Jin SG, Jiang Y, Qiu R, Rauch TA, Wang Y, Schackert G, Krex D, Lu Q and Pfeifer GP: 5-Hydroxymethylcytosine is strongly depleted in human cancers but its levels do not correlate with IDH1 mutations. Cancer Res. 71:7360–7365. 2011. View Article : Google Scholar : PubMed/NCBI
11	Haffner MC, Chaux A, Meeker AK, Esopi DM, Gerber J, Pellakuru LG, Toubaji A, Argani P, Iacobuzio-Donahue C, Nelson WG, et al: Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers. Oncotarget. 2:627–637. 2011. View Article : Google Scholar : PubMed/NCBI
12	Wang W and Guan KL: AMP-activated protein kinase and cancer. Acta Physiol (Oxf). 196:55–63. 2009. View Article : Google Scholar : PubMed/NCBI
13	Hardie DG: AMP-activated/SNF1 protein kinases: Conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 8:774–785. 2007. View Article : Google Scholar : PubMed/NCBI
14	Marin TL, Gongol B, Zhang F, Martin M, Johnson DA, Xiao H, Wang Y, Subramaniam S, Chien S and Shyy JY: AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1. Sci Signal. 10:eaaf74782017. View Article : Google Scholar : PubMed/NCBI
15	Wu D, Hu D, Chen H, Shi G, Fetahu IS, Wu F, Rabidou K, Fang R, Tan L, Xu S, et al: Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature. 559:637–641. 2018. View Article : Google Scholar : PubMed/NCBI
16	Edge SB and Compton CC: The American Joint Committee on Cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 17:1471–1474. 2010. View Article : Google Scholar : PubMed/NCBI
17	Warburg O, Wind F and Negelein E: The metabolism of tumors in the body. J Gen Physiol. 8:519–530. 1927. View Article : Google Scholar : PubMed/NCBI
18	Ríos M, Foretz M, Viollet B, Prieto A, Fraga M, Costoya JA and Señarís R: AMPK activation by oncogenesis is required to maintain cancer cell proliferation in astrocytic tumors. Cancer Res. 73:2628–2638. 2013. View Article : Google Scholar : PubMed/NCBI
19	Park HU, Suy S, Danner M, Dailey V, Zhang Y, Li H, Hyduke DR, Collins BT, Gagnon G, Kallakury B, et al: AMP-activated protein kinase promotes human prostate cancer cell growth and survival. Mol Cancer Ther. 8:733–741. 2009. View Article : Google Scholar : PubMed/NCBI
20	Baba Y, Nosho K, Shima K, Meyerhardt JA, Chan AT, Engelman JA, Cantley LC, Loda M, Giovannucci E, Fuchs CS and Ogino S: Prognostic significance of AMP-activated protein kinase expression and modifying effect of MAPK3/1 in colorectal cancer. Br J Cancer. 103:1025–1033. 2010. View Article : Google Scholar : PubMed/NCBI
21	Buckendahl AC, Budczies J, Fiehn O, Darb-Esfahani S, Kind T, Noske A, Weichert W, Sehouli J, Braicu E, Dietel M and Denkert C: Prognostic impact of AMP-activated protein kinase expression in ovarian carcinoma: Correlation of protein expression and GC/TOF-MS-based metabolomics. Oncol Rep. 25:1005–1012. 2011.PubMed/NCBI
22	Tsavachidou-Fenner D, Tannir N, Tamboli P, Liu W, Petillo D, The B, Mills GB and Jonasch E: Gene and protein expression markers of response to combined antiangiogenic and epidermal growth factor targeted therapy in renal cell carcinoma. Ann Oncol. 21:1599–1606. 2010. View Article : Google Scholar : PubMed/NCBI
23	Okoshi R, Ozaki T, Yamamoto H, Ando K, Koida N, Ono S, Koda T, Kamijo T, Nakagawara A and Kizaki H: Activation of AMP-activated protein kinase induces p53-dependent apoptotic cell death in response to energetic stress. J Biol Chem. 283:3979–3987. 2008. View Article : Google Scholar : PubMed/NCBI
24	Jang T, Calaoagan JM, Kwon E, Samuelsson S, Recht L and Laderoute KR: 5′-AMP-activated protein kinase activity is elevated early during primary brain tumor development in the rat. Int J Cancer. 128:2230–2239. 2011. View Article : Google Scholar : PubMed/NCBI
25	Kola B, Boscaro M, Rutter GA, Grossman AB and Korbonits M: Expanding role of AMPK in endocrinology. Trends Endocrinol Metab. 17:205–215. 2006. View Article : Google Scholar : PubMed/NCBI
26	Mistry T, Digby JE, Desai KM and Randeva HS: Obesity and prostate cancer: A role for adipokines. Eur Urol. 52:46–53. 2007. View Article : Google Scholar : PubMed/NCBI
27	Rankin EB and Giaccia AJ: The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 15:678–685. 2008. View Article : Google Scholar : PubMed/NCBI
28	Hadad SM, Baker L, Quinlan PR, Robertson KE, Bray SE, Thomson G, Kellock D, Jordan LB, Purdie CA, Hardie DG, et al: Histological evaluation of AMPK signalling in primary breast cancer. BMC Cancer. 9:3072009. View Article : Google Scholar : PubMed/NCBI
29	Chen P, Li K, Liang Y, Li L and Zhu X: High NUAK1 expression correlates with poor prognosis and involved in NSCLC cells migration and invasion. Exp Lung Res. 39:9–17. 2013. View Article : Google Scholar : PubMed/NCBI
30	Suzuki A, Lu J, Kusakai G, Kishimoto A, Ogura T and Esumi H: ARK5 is a tumor invasion-associated factor downstream of Akt signaling. Mol Cell Biol. 24:3526–3535. 2004. View Article : Google Scholar : PubMed/NCBI
31	Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J, Xu ZD, Zhu HG, Ling ZQ, Ye D, et al: Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene. 32:663–669. 2013. View Article : Google Scholar : PubMed/NCBI
32	Zhang LY, Li PL, Wang TZ and Zhang XC: Prognostic values of 5-hmC, 5-mC and TET2 in epithelial ovarian cancer. Arch Gynecol Obstet. 292:891–897. 2015. View Article : Google Scholar : PubMed/NCBI
33	Hemerly JP, Bastos AU and Cerutti JM: Identification of several novel non-p.R132 IDH1 variants in thyroid carcinomas. Eur J Endocrinol. 163:747–755. 2010. View Article : Google Scholar : PubMed/NCBI
34	Pansuriya TC, van Eijk R, d'Adamo P, van Ruler MA, Kuijjer ML, Oosting J, Cleton-Jansen AM, van Oosterwijk JG, Verbeke SL, Meijer D, et al: Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet. 43:1256–1261. 2011. View Article : Google Scholar : PubMed/NCBI
35	Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, et al: An integrated genomic analysis of human glioblastoma multiforme. Science. 321:1807–1812. 2008. View Article : Google Scholar : PubMed/NCBI
36	Rasmussen KD and Helin K: Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 30:733–750. 2016. View Article : Google Scholar : PubMed/NCBI
37	Guo X, Wang L, Li J, Ding Z, Xiao J, Yin X, He S, Shi P, Dong L, Li G, et al: Structural insight into autoinhibition and histone H3-induced activation of DNMT3A. Nature. 517:640–644. 2015. View Article : Google Scholar : PubMed/NCBI
38	Otani J, Nankumo T, Arita K, Inamoto S, Ariyoshi M and Shirakawa M: Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain. EMBO Rep. 10:1235–1241. 2009. View Article : Google Scholar : PubMed/NCBI
39	Boulard M, Edwards JR and Bestor TH: FBXL10 protects Polycomb-bound genes from hypermethylation. Nat Genet. 47:479–485. 2015. View Article : Google Scholar : PubMed/NCBI