Dickkopf-1 and β-catenin as Biomarkers for Early Diagnosis of Hepatocellular Carcinoma

Author(s): Amal A. Mohamed, Hala M. Ghanem, Maha M. Kamal, Rehab Ahmed, Naglaa K. Madkour, Dina Abdou, Soha M. Talima, Nehad Hawash, Sherief Abd-Elsalam*

Journal Name: Current Cancer Therapy Reviews

Volume 16 , Issue 2 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background & Aims: The clinical value of alpha-fetoprotein (AFP) as a marker to detect early hepatocellular carcinoma (HCC) has been questioned owing to its low sensitivity and specificity. The purpose of this work was to investigate whether serum Wnt/β-catenin and DKK1 levels in chronic hepatitis C patients could be used as early predictors for the risk of HCC development.

Methods: The study was conducted on 37 healthy controls, and 150 CHC patients were divided into three groups: CHC, liver cirrhosis (LC), and HCC patients. AFP, AFP-L3, β-catenin, and DKK-1 were assayed by ELISA.

Results: Both β-catenin and DKK1 levels significantly increased (p < 0.001) in the HCC group in comparison to LC and CHC groups. The first cut-off value for DKK-1 was 253 pg/ml with 88% sensitivity and 86% specificity. The second was 301.5 pg/ml with 82 percent sensitivity and 100% specificity. The β-catenin cut-off value was 7.35 ng/ml with 80% sensitivity and 74% specificity. A positive correlation was observed between DKK-1 and β-catenin (r=0.491), DKK-1 and tumor size (r =0.616), and β-catenin and tumor size (r =0.472).

Conclusion: DKK-1 and β-catenin may serve as predictors for the progression of CHC and LC into HCC.

Keywords: Dickkopf-1, hepatocellular carcinoma, β-catenin, specificity, sensitivity, liver cirrhosis.

[1]
Liu H, Hu J, Pan H, Luo D, Huang M, Xu W. CSN5 promotes hepatocellular carcinoma progression by SCARA5 inhibition through suppressing β-catenin ubiquitination. Dig Dis Sci 2018; 63(1): 155-65.
[http://dx.doi.org/10.1007/s10620-017-4855-9] [PMID: 29189991]
[2]
Juárez-Hernández E, Motola-Kuba D, Chávez-Tapia NC, Uribe M, Barbero Becerra V. Biomarkers in hepatocellular carcinoma: an overview. Expert Rev Gastroenterol Hepatol 2017; 11(6): 549-58.
[http://dx.doi.org/10.1080/17474124.2017.1311785] [PMID: 28347162]
[3]
El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011; 365(12): 1118-27.
[http://dx.doi.org/10.1056/NEJMra1001683] [PMID: 21992124]
[4]
Ghazy SS, Fyala AS, Sultan AS. New predictive biomarkers for preclinical hepatocellular carcinoma in Egyptian population by detection of serum miRNAs. Cancer Res 2017; 77: 13.
[5]
Abd-Elsalam S, Elwan N, Soliman H, et al. Epidemiology of liver cancer in Nile delta over a decade: A single-center study. South Asian J Cancer 2018; 7(1): 24-6.
[http://dx.doi.org/10.4103/sajc.sajc_82_17] [PMID: 29600229]
[6]
Ziada DH, El Sadany S, Soliman H, et al. Prevalence of hepatocellular carcinoma in chronic hepatitis C patients in Mid Delta, Egypt: A single center study. J Egypt Natl Canc Inst 2016; 28(4): 257-62.
[http://dx.doi.org/10.1016/j.jnci.2016.06.001] [PMID: 27378258]
[7]
Sheta E, El-Kalla F, El-Gharib M, et al. Comparison of single-session transarterial chemoembolization combined with microwave ablation or radiofrequency ablation in the treatment of hepatocellular carcinoma: a randomized-controlled study. Eur J Gastroenterol Hepatol 2016; 28(10): 1198-203.
[http://dx.doi.org/10.1097/MEG.0000000000000688] [PMID: 27362551]
[8]
Negm O, Abou Saif S, El Gharib M, Yousef M, Abd-Elsalam S. Role of low-molecular-weight heparins in prevention of thromboembolic complication after transarterial chemoembolization in hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2017; 29(3): 317-21.
[http://dx.doi.org/10.1097/MEG.0000000000000790] [PMID: 27893491]
[9]
Elwan N, Salem ML, Kobtan A, et al. High numbers of myeloid derived suppressor cells in peripheral blood and ascitic fluid of cirrhotic and HCC patients. Immunol Invest 2018; 47(2): 169-80.
[http://dx.doi.org/10.1080/08820139.2017.1407787] [PMID: 29182438]
[10]
Abdelfattah AAM, Rizk F, Hawash N, Hanafy A, El-Kalla F, Abd-Elsalam S. Randomized trial of preoperative administration of oral pregabalin for postoperative analgesia in patients scheduled for radiofrequency ablation of focal lesions in the liver. Int J Hyperthermia 2018; 34(8): 1367-71.
[http://dx.doi.org/10.1080/02656736.2018.1424946] [PMID: 29308685]
[11]
Watany M, Badawi R, Elkhalawany W, Abd-Elsalam S. Abd- Elsalam S. Study of Dickkopf-1 (DKK-1) gene expression in hepatocellular carcinoma patients. J Clin Diagn Res 2017; 11(2): OC32-4.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376795/
[PMID: 28384913]
[12]
Erdal H, Gül Utku Ö, Karatay E, Çelik B, Elbeg Ş, Doğan İ. Combination of DKK1 and AFP improves diagnostic accuracy of hepatocellular carcinoma compared with either marker alone. Turk J Gastroenterol 2016; 27(4): 375-81.
[http://dx.doi.org/10.5152/tjg.2016.15523] [PMID: 27458854]
[13]
Bosch FX, Ribes J, Díaz M, Cléries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004; 127(5): S5-S16.
[http://dx.doi.org/10.1053/j.gastro.2004.09.011] [PMID: 15508102]
[14]
Toyodo H, Kumeda T, Maeda A. Tumor markers for HCC: Simple and significant predicators of outcome in patients with HCC. Liver Cancer 2015; 4: 126-36.
[http://dx.doi.org/10.1159/000367735] [PMID: 26020034]
[15]
Wang W, Pan Q, Fuhler GM, Smits R, Peppelenbosch MP. Action and function of Wnt/β-catenin signaling in the progression from chronic hepatitis C to hepatocellular carcinoma. J Gastroenterol 2017; 52(4): 419-31.
[http://dx.doi.org/10.1007/s00535-016-1299-5] [PMID: 28035485]
[16]
Vilchez V, Turcios L, Marti F, Gedaly R. Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment. World J Gastroenterol 2016; 22(2): 823-32.
[http://dx.doi.org/10.3748/wjg.v22.i2.823] [PMID: 26811628]
[17]
Qin QF, Weng J, Xu GX, Chen CM, Jia CK. Combination of serum tumor markers dickkopf-1, DCP and AFP for the diagnosis of primary hepatocellular carcinoma. Asian Pac J Trop Med 2017; 10(4): 409-13.
[http://dx.doi.org/10.1016/j.apjtm.2017.03.016] [PMID: 28552111]
[18]
Zekri AR, Bahnassy AA, Alam El-Din HM, et al. Serum levels of β-catenin as a potential marker for genotype 4/hepatitis C-associated hepatocellular carcinoma. Oncol Rep 2011; 26(4): 825-31.https://www.ncbi.nlm.nih.gov/pubmed/21701780
[PMID: 21701780]
[19]
Reichl P, Mikulits W. Accuracy of novel diagnostic biomarkers for hepatocellular carcinoma: An update for clinicians (Review). Oncol Rep 2016; 36(2): 613-25.
[http://dx.doi.org/10.3892/or.2016.4842] [PMID: 27278244]
[20]
Zhang Z, Zhang Y, Wang Y, Xu L, Xu W. Alpha-fetoprotein-L3 and Golgi protein 73 may serve as candidate biomarkers for diagnosing alpha-fetoprotein-negative hepatocellular carcinoma. OncoTargets Ther 2015; 9: 123-9.
[PMID: 26770061]
[21]
Thompson MD, Monga SP. WNT/beta-catenin signaling in liver health and disease. Hepatology 2007; 45(5): 1298-305.
[http://dx.doi.org/10.1002/hep.21651] [PMID: 17464972]
[22]
Sun Y, Mi W, Cai J, et al. Quantitative proteomic signature of liver cancer cells: tissue transglutaminase 2 could be a novel protein candidate of human hepatocellular carcinoma. J Proteome Res 2008; 7(9): 3847-59.
[http://dx.doi.org/10.1021/pr800153s] [PMID: 18646787]
[23]
Wang B, Xunsun JY, Liu JY, et al. The effect of cell cycle and expression of cyclin B1 and cyclin C protein in hepatocellular carcinoma cell line HepG2 and SMMC-7721 after of silencing β-catenin gene. Hepatogastroenterology 2012; 59(114): 515-8.
[PMID: 22024040]
[24]
Qu B, Liu BR, Du YJ, et al. Wnt/β-catenin signaling pathway may regulate the expression of angiogenic growth factors in hepatocellular carcinoma. Oncol Lett 2014; 7(4): 1175-8.
[http://dx.doi.org/10.3892/ol.2014.1828] [PMID: 24944688]
[25]
Inagawa S, Itabashi M, Adachi S, et al. Expression and prognostic roles of beta-catenin in hepatocellular carcinoma: correlation with tumor progression and postoperative survival. Clin Cancer Res 2002; 8(2): 450-6.
[PMID: 11839663]
[26]
Yu B, Yang X, Xu Y, et al. Elevated expression of DKK1 is associated with cytoplasmic/nuclear beta-catenin accumulation and poor prognosis in hepatocellular carcinomas. J Hepatol 2009; 50(5): 948-57.
[http://dx.doi.org/10.1016/j.jhep.2008.11.020] [PMID: 19303159]
[27]
Shen Q, Fan J, Yang XR, et al. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. Lancet Oncol 2012; 13(8): 817-26.
[http://dx.doi.org/10.1016/S1470-2045(12)70233-4] [PMID: 22738799]
[28]
Vongsuvanh R, Poorten D, Iseli T, Strasser SI, McCaughan GW, George J. Midkine increases diagnostic yield in AFP negative and NASH-related hepatocellular carcinoma. PLoS ONE 2016; 11(5): e0155800
[http://dx.doi.org/10.1371/journal. pone.0155800]
[29]
Tung EK, Mak CK, Fatima S, et al. Clinicopathological and prognostic significance of serum and tissue Dickkopf-1 levels in human hepatocellular carcinoma. Liver Int 2011; 31(10): 1494-504.
[http://dx.doi.org/10.1111/j.1478-3231.2011.02597.x] [PMID: 21955977]
[30]
Kim SU, Park JH, Kim HS, et al. Serum Dickkopf-1 as a biomarker for the diagnosis of hepatocellular carcinoma. Yonsei Med J 2015; 56(5): 1296-306.
[http://dx.doi.org/10.3349/ymj.2015.56.5.1296] [PMID: 26256972]
[31]
Wong CM, Fan ST, Ng IO. beta-Catenin mutation and overexpression in hepatocellular carcinoma: clinicopathologic and prognostic significance. Cancer 2001; 92(1): 136-45.
[http://dx.doi.org/10.1002/1097-0142(20010701)92:1<136:AID-CNCR1301>3.0.CO;2-R] [PMID: 11443619]
[32]
Bolondi L, Benzi G, Santi V, et al. Relationship between alpha-fetoprotein serum levels, tumour volume and growth rate of hepatocellular carcinoma in a western population. Ital J Gastroenterol 1990; 22(4): 190-4.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1803796/
[PMID: 1720058]
[33]
Ferenci P, Fried M, Labrecque D, et al. World Gastroenterology Organization. Hepatocellular carcinoma (HCC): a global perspective. J Clin Gastroenterol 2010; 44(4): 239-45.
[http://dx.doi.org/10.1097/MCG.0b013e3181d46ef2] [PMID: 20216082]
[34]
Tsai JF, Jeng JE, Chuang LY, et al. Serum insulin-like growth factor-II as a serologic marker of small hepatocellular carcinoma. Scand J Gastroenterol 2005; 40(1): 68-75.
[http://dx.doi.org/10.1080/00365520410009311] [PMID: 15841717]
[35]
Nouso K, Kobayashi Y, Nakamura S, et al. Prognostic importance of fucosylated alpha-fetoprotein in hepatocellular carcinoma patients with low alpha-fetoprotein. J Gastroenterol Hepatol 2011; 26(7): 1195-200.
[http://dx.doi.org/10.1111/j.1440-1746.2011.06720.x] [PMID: 21410750]


open access plus

Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 2
Year: 2020
Page: [136 - 144]
Pages: 9
DOI: 10.2174/1573394715666191122094659

Article Metrics

PDF: 13
HTML: 1