Serum Midkine and Osteopontin Levels as Diagnostic Biomarkers of Hepatocellular Carcinoma
Keywords:
Hepatocellular Carcinoma, Midkine (MDK), Osteopontin (OPN)Abstract
Introduction: Hepatocellular Carcinoma (HCC) is a primary tumor of the liver; it is one of the most common cancers worldwide. Osteopontin (OPN) is a phosphorylated glycoprotein which is implicated in enhancing invasive and metastatic progression of many tumors. Midkine (MDK) is a 13-kDa small heparin-binding growth factor which plays a significant role in carcinogenesis related activities. The aim of this study was to assess the efficacy of serum Midkine and Osteopontin levels as diagnostic biomarkers of Hepatocellular Carcinoma.
Methods: This study was carried out from January 2014 to January 2016 in Internal Medicine, Clinical Oncology and Tropical Medicine Departments of Tanta University Hospital (Egypt). One hundred forty subjects were enrolled in our study, they were divided into four groups: Group I included 35 patients presented with HCV without cirrhosis; Group II included 35 patients presented with HCV with liver cirrhosis; Group III included 35 patients presented with HCC on top of cirrhosis; and Group IV included 35 apparently healthy subjects as a control group. The studied groups were age and sex matched. Routine and specific (OPN and MDK) laboratory investigations were performed in all included subjects.
Results: The main finding of the present work was that the mean serum levels of OPN and MDK were significantly elevated in HCC patients either by comparing HCC patients vs. HCV patients without cirrhosis, HCC patients vs. HCV patients with cirrhosis or HCC patients vs. healthy subjects. Interestingly, by performing a ROC analysis, serum MDK levels had better sensitivity and specificity than OPN and AFP levels in the diagnosis of HCC (98.4 %, 97.1% and 97%) and (96.2%, 95.3% and 95%) for MDK, OPN and AFP respectively.
Conclusion: Serum MDK and OPN levels are comparable to AFP levels and could be used as potential diagnostic biomarkers of HCC in HCV patients with liver cirrhosis and in the prediction of liver cirrhosis in HCV patients without cirrhosis.
References
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005; 55(2): 74- 108. doi: 10.3322/canjclin.55.2.74. PMID: 15761078.
Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet.
; 31(4): 339-46. doi: 10.1038/ng0802-339. PMID: 12149612.
Sanyal AJ, Yoon SK, Lencioni R. The etiology of hepatocellular carcinoma and consequences for
treatment. Oncologist. 2010; 15 Suppl 4: 14-22. doi: 10.1634/theoncologist.2010-S4-14. PMID: 21115577.
Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev
Cancer. 2006; 6(9): 674-87. doi: 10.1038/nrc1934. PMID: 16929323.
Trinchet JC, Alperovitch A, Bedossa P, Degos F, Hainaut P, Beers BV. Epidemiology, prevention,
screening and diagnosis of hepatocellular carcinoma. Bull Cancer. 2009; 96(1): 35-43. doi:
1684/bdc.2009.0791. PMID: 19211358.
Farinati F, Marino D, De Giorgio M, Baldan A, Cantarini M, Cursaro C, et al. Diagnostic and prognostic
role of alpha-fetoprotein in hepatocellular carcinoma: both or neither? Am J Gastroenterol. 2006; 101(3):
-32. doi: 10.1111/j.1572-0241.2006.00443.x. PMID: 16542289.
Mao Y, Yang H, Xu H, Lu X, Sang X, Du S, et al. Golgi protein 73 (GOLPH2) is a valuable serum marker
for hepatocellular carcinoma. Gut. 2010; 59(12): 1687-93. doi: 10.1136/gut.2010.214916. PMID: 20876776.
Ashizawa N, Graf K, Do YS, Nunohiro T, Giachelli CM, Meehan WP, et al. Osteopontin is produced by rat
cardiac fibroblasts and mediates A(II)-induced DNA synthesis and collagen gel contraction. J Clin Invest.
; 98(10): 2218-27. doi: 10.1172/JCI119031. PMID: 8941637, PMCID: PMC507670.
Anborgh PH, Mutrie JC, Tuck AB, Chambers AF. Pre- and post-translational regulation of osteopontin in
cancer. J Cell Commun Signal. 2011; 5(2): 111-22. doi: 10.1007/s12079-011-0130-6. PMID: 21516514,
Standal T, Borset M, Sundan A. Role of osteopontin in adhesion, migration, cell survival and bone
remodeling. Exp Oncol. 2004; 26(3): 179-84. PMID: 15494684.
Nabih MI, Aref WM, Fathy MM. Significance of plasmaosteopontin in diagnosis of hepatitis C virusrelated hepatocellular carcinoma. Arab J Gastroenterol. 2014; 15(3-4): 103-7. doi:
1016/j.ajg.2014.08.002. PMID: 25249230.
Wan HG, Xu H, Gu YM, Wang H, XuW, Zu MH. Comparison osteopontin vs AFP for the diagnosis of
HCC: a meta-analysis. Clin Res Hepatol Gastroenterol. 2014; 38(6): 706-14. doi:
1016/j.clinre.2014.06.008. PMID: 25034355.
Lee HJ, Yeon JE, Suh SJ, Lee SJ, Yoon EL, Kang K, et al. Clinical utility of plasmaglypican-3 and
osteopontin as biomarkers ofhepatocellular carcinoma. Gut Liver. 2014; 8(2): 177-85. doi:
5009/gnl.2014.8.2.177. PMID: 24672660, PMCID: PMC3964269.
Ibusuki M, Fujimori H, Yamamoto Y, Ota K, Ueda M, Shinriki S, et al. Midkine in plasma as a novel
breast cancer marker. Cancer Sci. 2009; 100(9): 1735-9. doi: 10.1111/j.1349-7006.2009.01233.x. PMID: 19538527.
Kato M, Shinozawa T, Kato Sh, Awaya A, Terada T. Increased midkine expression in hepatocellular
carcinoma. Archives of Pathology and Laboratory Medicine. 2002; 124(6): 848-85. PMID: 10835519.
Muramatsu T. Midkine and pleiotrophin: two related proteins involved in development, survival,
inflammation and tumorigenesis. J Biochem. 2002; 132(3): 359-71. doi:
1093/oxfordjournals.jbchem.a003231. PMID: 12204104.
Dawson BD, Trapp RG. Reading the medical literature: Basic & Clinical Biostatistics. Lange Medical
Book/ McGraw-Hill. Medical Publication Division, New York. 3rd ed. Ch. 7-9, PP 161-218, Ch. 8, PP 217- 23, Ch. 1, PP 275-281 and Ch. 13, PP 305-314.
El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.
Gastroenterology. 2007; 132(7): 2557-76. doi: 10.1053/j.gastro.2007.04.061. PMID: 17570226.
Shaker MK, Abdella HM, Khalifa MO, El Dorry AK. Epidemiological characteristics of hepatocellular
carcinoma in Egypt: a retrospective analysis of 1313 cases. Liver Int. 2013; 33(10): 1601-6. doi:
1111/liv.12209. PMID: 23714212.
Colli A, Fraquelli M, Conte D. Alpha-fetoprotein and hepatocellular carcinoma. Am J Gastroenterol. 2006;
(8): 1939; author reply 1940-1. doi: 10.1111/j.1572-0241.2006.00684_3.x. PMID: 16928257.
Shaheen KY, Abdel-Mageed AI, Safwat E, AlBreedy AM. The value of serum midkine level in diagnosis
of hepatocellular carcinoma. Int J Hepatol. 2015; 2015: 146389. doi: 10.1155/2015/146389. PMID:
, PMCID: PMC4337261.
Fouad SA, Mohamed NA, Fawzy MW, Moustafa DA. Plasma Osteopontin Level in Chronic Liver Disease
and Hepatocellular Carcinoma. Hepat Mon. 2015; 15(9): e30753. doi: 10.5812/hepatmon.30753. PMID:
, PMCID: PMC4612688.
Kim J, Ki SS, Lee SD, Han CJ, Kim YC, Park SH, et al. Elevated plasma osteopontin levels in patients
with hepatocellular carcinoma. Am J Gastroenterol. 2006; 101(9): 2051-9. doi: 10.1111/j.1572- 0241.2006.00679.x. PMID: 16848813.
Nabih MI, Aref WM, Fathy MM. Significance of plasma osteopontin in diagnosis of hepatitis C virusrelated hepatocellular carcinoma. Arab J Gastroenterol. 2014; 15(3-4): 103-7. doi:
1016/j.ajg.2014.08.002. PMID: 25249230.
Zhu WW, Guo JJ, Guo L, Jia HL, Zhu M, Zhang JB, et al. Evaluation of midkine as a diagnostic serum
biomarker in hepatocellular carcinoma. Clin Cancer Res. 2013; 19(14): 3944-54. doi: 10.1158/1078- 0432.CCR-12-3363. PMID: 23719264.
Vongsuvanh R, van der 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. doi: 10.1371/journal.pone.0155800. PMID: 27219517, PMCID: PMC4878793.2
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