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Low cytoplasmic casein kinase 1 epsilon expression predicts poor prognosis in patients with hepatocellular carcinoma

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Tumor Biology

Abstract

Casein kinase 1 epsilon (CK1ε) is a member of the casein kinase 1 (CK1) family, which comprises highly conserved and ubiquitous serine/threonine protein kinases. Recent studies have demonstrated that CK1ε plays a role in human cancers; however, the role of CK1ε in hepatocellular carcinoma (HCC) remains unclear. The study used immunohistochemistry to examine CK1ε expression in 230 HCC specimens by tissue microarray (TMA) and assessed the effect of CK1ε knockdown on migration of human hepatoma cells in vitro. The immunohistochemical analyses showed that low CK1ε expression was significantly correlated with tumor differentiation (p = 0.008), T classification (p = 0.016), tumor vascular invasion (p = 0.002), and cancer stage (p = 0.010). The univariate and multivariate analyses showed that patients with low CK1ε expression had a considerably lower OS rate than that of the patients with high CK1ε expression (p = 0.041, hazard ratio = 1.4; p = 0.039, hazard ratio = 1.4). Moreover, CK1ε small interfering RNA (siRNA) treatment exerted an invasion-promoting effect in human hepatoma cells. In conclusion, our data indicated that low CK1ε expression is correlated with a low survival rate and CK1ε may play a role as a tumor suppressor in hepatocarcinogenesis.

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References

  1. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol. 2013;47(Suppl):S2–6.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Fares N, Peron JM. Epidemiology, natural history, and risk factors of hepatocellular carcinoma. La Revue du Praticien. 2013;63:216–7. 220–212.

    PubMed  Google Scholar 

  3. Guthle M, Dollinger MM. Epidemiology and risk factors of hepatocellular carcinoma. Radiologe. 2014;54:654–9.

    Article  CAS  PubMed  Google Scholar 

  4. Sherman M. Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis. 2005;25:143–54.

    Article  PubMed  Google Scholar 

  5. Zhou XD. Recurrence and metastasis of hepatocellular carcinoma: progress and prospects. Hepatobiliary Pancreat Dis Int: HBPD INT. 2002;1:35–41.

    PubMed  Google Scholar 

  6. Dhanasekaran R, Limaye A, Cabrera R. Hepatocellular carcinoma: current trends in worldwide epidemiology, risk factors, diagnosis, and therapeutics. Hepatic Med: Evid Res. 2012;4:19–37.

    Google Scholar 

  7. Kane RC, Farrell AT, Madabushi R, et al. Sorafenib for the treatment of unresectable hepatocellular carcinoma. Oncologist. 2009;14:95–100.

    Article  CAS  PubMed  Google Scholar 

  8. Cheong JK, Virshup DM. Casein kinase 1: complexity in the family. Int J Biochem Cell Biol. 2011;43:465–9.

    Article  CAS  PubMed  Google Scholar 

  9. Knippschild U, Gocht A, Wolff S, Huber N, Lohler J, Stoter M. The casein kinase 1 family: participation in multiple cellular processes in eukaryotes. Cell Signal. 2005;17:675–89.

    Article  CAS  PubMed  Google Scholar 

  10. Gross SD, Anderson RA. Casein kinase 1: spatial organization and positioning of a multifunctional protein kinase family. Cell Signal. 1998;10:699–711.

    Article  CAS  PubMed  Google Scholar 

  11. Huang Y, Li J, Wu L, et al. Association between a casein kinase 1 epsilon gene polymorphism and schizophrenia in a Chinese Han population. J Mol Neurosci: MN. 2012;47:470–4.

    Article  CAS  PubMed  Google Scholar 

  12. Flajolet M, He G, Heiman M, Lin A, Nairn AC, Greengard P. Regulation of Alzheimer’s disease amyloid-beta formation by casein kinase 1. Proc Natl Acad Sci U S A. 2007;104:4159–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ghoshal N, Smiley JF, DeMaggio AJ, et al. A new molecular link between the fibrillar and granulovacuolar lesions of Alzheimer’s disease. Am J Pathol. 1999;155:1163–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Frierson Jr HF, El-Naggar AK, Welsh JB, et al. Large scale molecular analysis identifies genes with altered expression in salivary adenoid cystic carcinoma. Am J Pathol. 2002;161:1315–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Polakis P. The many ways of Wnt in cancer. Curr Opin Genet Dev. 2007;17:45–51.

    Article  CAS  PubMed  Google Scholar 

  16. Peters JM, McKay RM, McKay JP, Graff JM. Casein kinase 1 transduces Wnt signals. Nature. 1999;401:345–50.

    Article  CAS  PubMed  Google Scholar 

  17. Brockschmidt C, Hirner H, Huber N, et al. Anti-apoptotic and growth-stimulatory functions of CK1 delta and epsilon in ductal adenocarcinoma of the pancreas are inhibited by IC261 in vitro and in vivo. Gut. 2008;57:799–806.

    Article  CAS  PubMed  Google Scholar 

  18. Foldynova-Trantirkova S, Sekyrova P, Tmejova K, et al. Breast cancer-specific mutations in ck1epsilon inhibit Wnt/beta-catenin and activate the Wnt/Rac1/JNK and NFAT pathways to decrease cell adhesion and promote cell migration. Breast Cancer Res: BCR. 2010;12:R30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Modak C, Bryant P. Casein kinase 1 epsilon positively regulates the Akt pathway in breast cancer cell lines. Biochem Biophys Res Commun. 2008;368:801–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kim SY, Dunn IF, Firestein R, et al. CK1epsilon is required for breast cancers dependent on beta-catenin activity. PLoS One. 2010;5, e8979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hsu CM, Lin SF, Lu CT, Lin PM, Yang MY. Altered expression of circadian clock genes in head and neck squamous cell carcinoma. Tumour Biol: J Int Soc Oncodev Biol Med. 2012;33:149–55.

    Article  CAS  Google Scholar 

  22. Richter J, Ullah K, Xu P, Alscher V, Blatz A, Peifer C, et al. Effects of altered expression and activity levels of CK1delta and varepsilon on tumor growth and survival of colorectal cancer patients. Int J Cancer J Int du Cancer. 2015;136:2799–810.

    Article  CAS  Google Scholar 

  23. Rodriguez N, Yang J, Hasselblatt K, et al. Casein kinase 1 epsilon interacts with mitochondrial proteins for the growth and survival of human ovarian cancer cells. EMBO Mol Med. 2012;4:952–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lin SH, Lin YM, Yeh CM, et al. Casein kinase 1 epsilon expression predicts poorer prognosis in low t-stage oral cancer patients. Int J Mol Sci. 2014;15:2876–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Teufel A, Staib F, Kanzler S, et al. Genetics of hepatocellular carcinoma. World J Gastroenterol: WJG. 2007;13:2271–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Schittek B, Sinnberg T. Biological functions of casein kinase 1 isoforms and putative roles in tumorigenesis. Mol Cancer. 2014;13:231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Relles D, SendeCK J, Chipitsyna G, Hyslop T, Yeo CJ, Arafat HA. Circadian gene expression and clinicopathologic correlates in pancreatic cancer. J Gastrointest Surg: Off J Soc Surg Aliment Tract. 2013;17:443–50.

    Article  Google Scholar 

  28. Yang WS, Stockwell BR. Inhibition of casein kinase 1-epsilon induces cancer-cell-selective, period2-dependent growth arrest. Genome Biol. 2008;9:R92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Knippschild U, Kruger M, Richter J, et al. The CK1 family: contribution to cellular stress response and its role in carcinogenesis. Front Oncol. 2014;4:96.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by a research grant from Changhua Christian Hospital, Taiwan.

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Correspondence to Kun-Tu Yeh or Shun-Fa Yang.

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Shu-Hui Lin and Chung-Min Yeh contributed equally to this work.

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Lin, SH., Yeh, CM., Hsieh, MJ. et al. Low cytoplasmic casein kinase 1 epsilon expression predicts poor prognosis in patients with hepatocellular carcinoma. Tumor Biol. 37, 3997–4005 (2016). https://doi.org/10.1007/s13277-015-4225-1

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  • DOI: https://doi.org/10.1007/s13277-015-4225-1

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