Dickkopf-1 and Amphiregulin as Novel Biomarkers and Potential Therapeutic Targets in Hepatocellular Carcinoma
Abstract
Background: Hepatocellular carcinoma (HCC) is a highly fatal tumor which represents a major health problem worldwide. Due to asymptomatic nature of HCC, most patients present with the progressive stage of the disease, so, unfortunately, there are no effective therapies. Existing techniques for HCC surveillance and diagnosis lack the required accuracy. Therefore, searching for new diagnostic and/or therapeutic tools could improve patient survival. This study aimed to estimate the diagnostic role of Dickkopf-1 (DKK1) and amphiregulin (AREG) and to find out their correlation with different clinicopathological parameters in HCC patients.
Materials and Methods: Serum levels of DKK1 and AREG in 55 HCC patients, 20 cirrhotic patients, and 15 healthy subjects as control group were measured using the ELISA technique.
Results: Both of DKK1 and AREG showed a significant increase in the HCC group compared to cirrhotic and healthy groups. DKK1 at a cutoff point of 8.92 ng/ml showed that the area under the curve (AUC) was 0.826 with 87.3% sensitivity and 82.9% specificity. DKK1 showed a significant correlation with tumor size, liver dysfunction, and poor performance status in HCC patients. AREG at a cutoff point of 8.74 pg/ml showed a sensitivity of 74.5% but low specificity (47.1%). AREG showed a significant correlation with portal vein thrombosis and tumor metastasis in HCC patients.
Conclusion: Serum DKK1 could be a diagnostic biomarker for HCC. Both of DKK1 and AREG may play significant roles in tumor progression and may offer promising therapeutic targets in HCC patients.
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4. Wong RJ, Ahmed A, Gish RG, et al. Elevated alpha-fetoprotein: differential diagnosis - hepatocellular carcinoma and other disorders. Clin Liver Dis. 2015; 19(2):309-23.
5. Farinati F, Marino D, De Giorgio M, et al. Diagnostic and prognostic role of alpha-fetoprotein in hepatocellular carcinoma: both or neither?Am J Gastroenterol. 2006; 101(3): 524-32.
6. Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018; 67(1):358-380.
7. Karin Komposch , Maria Sibilia. EGFR signaling in liver diseases. Int J Mol Sci. 2016; 17(1): 30.
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10. Semënov MV, Tamai K, Brott BK, et al. Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr Biol. 2001; 11(12): 951-61.
11. Yamamoto H, Sakane H, Yamamoto H, et al. Wnt3a and Dkk1 regulate distinct internalization pathways of LRP6 to tune the activation of β-catenin signaling. Dev Cell. 2008; 15(1): 37-48.
12. Niida A, Hiroko T, Kasai M, et al. DKK1, a negative regulator of Wnt signaling, is a target of the β-catenin/TCF pathway. Oncogene. 2004; 23(52): 8520-6.
13. Sarwat Fatima, Nikki P Lee, John M Luk. Dickkopfs and Wnt/β-catenin signalling in liver cancer. World J Clin Oncol. 2011; 2(8): 311–325.
14. Bhavanasi D, Speer KF, Klein PS. CKAP4 is identified as a receptor for Dickkopf in cancer cells. J Clin Invest. 2016; 126(7):2419-21.
15. Berasain C, Castillo J, Perugorría MJ, et al. Amphiregulin: a new growth factor in hepatocarcinogenesis. Cancer Lett. 2007; 254(1): 30-41.
16. Yotsumoto F, Fukami T, Yagi H, et al. Amphiregulin regulates the activation of ERK and Akt through epidermal growth factor receptor and HER3 signals involved in the progression of pancreatic cancer. Cancer Sci. 2010; 101(11): 2351-60.
17. Berasain C, García-Trevijano ER, Castillo J, et al. Novel role for amphiregulin in protection from liver injury. J Biol Chem. 2005; 280(19):19012-20.
18. Berasain C, García-Trevijano ER, Castillo J, et al. Amphiregulin: an early trigger of liver regeneration in mice. Gastroenterology. 2005; 128(2):424-32.
19. Liu Q, Rehman H, Krishnasamy Y, et al. Amphiregulin Stimulates Liver Regeneration after Small‐for‐Size Mouse Liver Transplantation. Am J Transplant. 2012; 12(8): 2052–2061.
20. Castillo J, Erroba E, Perugorría MJ, et al. Amphiregulin contributes to the transformed phenotype of human hepatocellular carcinoma cells. Cancer Res. 2006; 66(12):6129-38.
21. Thomas MB, Zhu AX. Hepatocellular carcinoma: the need for progress. J Clin Oncol. 2005; 23(13):2892-9.
22. Kudo M, Han KH, Kokudo N, et al. Liver cancer working group report. Jpn J Clin Oncol. 2010; 40 Suppl 1:i19-27.
23. 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.
24. 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.
25. Yang H, Chen GD, Fang F, et al. Dickkopf-1: as a diagnostic and prognostic serum marker for early hepatocellular carcinoma. Int J Biol Markers. 2013; 28(3):286-97.
26. Erdal H, Gül Utku Ö, Karatay E, et al. Combination of DKK1 and AFP improves diagnostic accuracy of hepatocellular carcinoma compared with either marker alone. Turk J Gastroenterol. 2016; 27(4):375-81.
27. Tung E K, 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.
28. Mohamed FZ, Barakat LA, Radwan NH, et al. Comparative study between DKK1 and AFP for diagnosis of hepatocellular carcinoma among Egyptian patients. Eur J Pharm Med Res. 2016; 3(9): 20-27.
29. Kikuchi A, Fumoto K, Kimura H. The Dickkopf1‐cytoskeleton‐associated protein 4 axis creates a novel signalling pathway and may represent a molecular target for cancer therapy. Br J Pharmacol. 2017; 174(24):4651-4665.
30. Glaw JT, Skalak TC, Peirce SM. Inhibition of canonical Wnt signaling increases microvascular hemorrhaging and venular remodeling in adult rats. Microcirculation. 2010; 17(5):348-57.
31. Choi SH, Kim H, Lee HG, et al. Dickkopf-1 induces angiogenesis via VEGF receptor 2 regulation independent of the Wnt signaling pathway. Oncotarget. 2017; 8(35): 58974–58984.
32. Yao L, Zhang D, Zhao X, et al. Dickkopf‐1‐promoted vasculogenic mimicry in non‐small cell lung cancer is associated with EMT and development of a cancer stem‐like cell phenotype. J Cell Mol Med. 2016; 20(9):1673-85.
33. Behnke M, Reimers M, Fisher R. The Expression of Embryonic Liver Development Genes in Hepatitis C Induced Cirrhosis and Hepatocellular Carcinoma. Cancers (Basel). 2012; 4(3):945-68.
34. Bonacini M, Hadi G, Govindarajan S, et al. Utility of a discriminant score for diagnosing advanced fibrosis or cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol. 1997; 92(8):1302-4.
35. Sheth SG, Flamm SL, Gordon FD, et al. AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol. 1998; 93(1):44-8.
36. Botros M, Sikaris KA. The de ritis ratio: the test of time. Clin Biochem Rev. 2013; 34(3): 117–130.
37. KamimotoY, Horiuchi S, Tanase S, et al. Plasma clearance of intravenously injected aspartate aminotransferase isozymes: evidence for preferential uptake by sinusoidal liver cells. Hepatology. 1985; 5(3):367-75.
38. Urtasun R, Latasa MU, Demartis MI, et al. Connective tissue growth factor autocriny in human hepatocellular carcinoma: Oncogenic role and regulation by epidermal growth factor receptor/yes‐associated protein–mediated activation. Hepatology. 2011; 54(6): 2149-58.
39. Perugorria MJ, Latasa MU, Nicou A, et al. The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis. Hepatology. 2008; 48(4):1251-61.
40. Qi Y, Operario DJ , Oberholzer CM, et al. Human basophils express amphiregulin in response to T cell–derived IL-3. J Allergy Clin Immunol. 2010; 126(6):1260-6.e4.
41. Salimi M, Barlow JL, Saunders SP, et al. A role for IL-25 and IL-33–driven type-2 innate lymphoid cells in atopic dermatitis. J Exp Med. 2013; 210(13):2939-50.
42. Adib-Conquy M, Pedron T, Petit-Bertron A-F, et al. Neutrophils in cystic fibrosis display a distinct gene expression pattern. Mol Med. 2008; 14(1-2): 36–44.
43. Zaiss, DM, Yang L, Shah PR, et al. Amphiregulin, a TH2 cytokine enhancing resistance to nematodes. Science. 2006; 314(5806): 1746.
44. Burzyn D, Kuswanto W, Kolodin D, et al. A special population of regulatory T cells potentiates muscle repair. Cell. 2013; 155(6): 1282-95.
45. Jamieson AM, Pasman L, Yu S, et al. Role of tissue protection in lethal respiratory viral-bacterial coinfection. Science. 2013; 340(6137): 1230-4.
46. Liu K, Lin D, Ouyang Y, et al. Amphiregulin impairs apoptosis-stimulating protein 2 of p53 overexpression–induced apoptosis in hepatoma cells. Tumor Biol. 2017; 39(3): 1010428317695026.
47. Han SX, Bai E, Jin GH, et al. Expression and clinical significance of YAP, TAZ, and AREG in hepatocellular carcinoma. J Immunol Res. 2014; 2014:261365.
48. Zhang J, Ji JY, Yu M, et al. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol. 2009; 11(12):1444-50.
49. Chang CJ, Yin PH, Yang DM, et al. Mitochondrial dysfunction-induced amphiregulin upregulation mediates chemo-resistance and cell migration in HepG2 cells. Cell Mol Life Sci. 2009; 66(10):1755-65.
50. Liu JF, Tsao YT, Hou CH. Amphiregulin enhances intercellular adhesion molecule-1 expression and promotes tumor metastasis in human osteosarcoma. Oncotarget. 2015; 6(38): 40880-95.
51. Willmarth NE, Ethier SP. Autocrine and juxtacrine effects of amphiregulin on the proliferative, invasive, and migratory properties of normal and neoplastic human mammary epithelial cells. J Biol Chem. 2006; 281(49): 37728-37.
52. Higginbotham JN, Demory Beckler M, Gephart JD, et al. Amphiregulin exosomes increase cancer cell invasion. Curr Biol. 2011; 21(9):779-86.
53. Azmi AS, Bao B, Sarkar FH. Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev. 2013; 32(3-4): 623-642.
54. Santangelo L, Battistelli C, Montaldo C, et al. Functional roles and therapeutic applications of exosomes in hepatocellular carcinoma. Biomed Res Int. 2017; 2017:2931813.
55. Chai H, Brown RE. Field effect in cancer–an update. Ann Clin Lab Sci. 2009; 39(4):331-7.
56. Hendrix A, Westbroek W, Bracke M, et al. An ex (o) citing machinery for invasive tumor growth. Cancer Res. 2010; 70(23): 9533-7.
57. Taverna S, Pucci M, Giallombardo M, et al. Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway. Sci Rep. 2017; 7(1):3170.
58. Tanaka H, Nishioka Y, Yokoyama Y, et al. Nuclear envelope-localized EGF family protein amphiregulin activates breast cancer cell migration in an EGF-like domain independent manner. Biochem Biophys Res Commun. 2012; 420(4):721-6.
2. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008; 100(10):698-711.
3. Gustavo Ferrín, Patricia Aguilar-Melero, Manuel Rodríguez-Perálvarez, et al. Biomarkers for hepatocellular carcinoma: diagnostic and therapeutic utility. Hepat Med. 2015; 7: 1–10.
4. Wong RJ, Ahmed A, Gish RG, et al. Elevated alpha-fetoprotein: differential diagnosis - hepatocellular carcinoma and other disorders. Clin Liver Dis. 2015; 19(2):309-23.
5. Farinati F, Marino D, De Giorgio M, et al. Diagnostic and prognostic role of alpha-fetoprotein in hepatocellular carcinoma: both or neither?Am J Gastroenterol. 2006; 101(3): 524-32.
6. Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018; 67(1):358-380.
7. Karin Komposch , Maria Sibilia. EGFR signaling in liver diseases. Int J Mol Sci. 2016; 17(1): 30.
8. Vilchez V, Turcios L, Marti F, et al. Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment. World J Gastroenterol. 2016; 22(2):823-32.
9. Acebron SP, Niehrs C. β-Catenin-independent roles of Wnt/LRP6 signaling. Trends Cell Biol. 2016; 26(12): 956-967.
10. Semënov MV, Tamai K, Brott BK, et al. Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr Biol. 2001; 11(12): 951-61.
11. Yamamoto H, Sakane H, Yamamoto H, et al. Wnt3a and Dkk1 regulate distinct internalization pathways of LRP6 to tune the activation of β-catenin signaling. Dev Cell. 2008; 15(1): 37-48.
12. Niida A, Hiroko T, Kasai M, et al. DKK1, a negative regulator of Wnt signaling, is a target of the β-catenin/TCF pathway. Oncogene. 2004; 23(52): 8520-6.
13. Sarwat Fatima, Nikki P Lee, John M Luk. Dickkopfs and Wnt/β-catenin signalling in liver cancer. World J Clin Oncol. 2011; 2(8): 311–325.
14. Bhavanasi D, Speer KF, Klein PS. CKAP4 is identified as a receptor for Dickkopf in cancer cells. J Clin Invest. 2016; 126(7):2419-21.
15. Berasain C, Castillo J, Perugorría MJ, et al. Amphiregulin: a new growth factor in hepatocarcinogenesis. Cancer Lett. 2007; 254(1): 30-41.
16. Yotsumoto F, Fukami T, Yagi H, et al. Amphiregulin regulates the activation of ERK and Akt through epidermal growth factor receptor and HER3 signals involved in the progression of pancreatic cancer. Cancer Sci. 2010; 101(11): 2351-60.
17. Berasain C, García-Trevijano ER, Castillo J, et al. Novel role for amphiregulin in protection from liver injury. J Biol Chem. 2005; 280(19):19012-20.
18. Berasain C, García-Trevijano ER, Castillo J, et al. Amphiregulin: an early trigger of liver regeneration in mice. Gastroenterology. 2005; 128(2):424-32.
19. Liu Q, Rehman H, Krishnasamy Y, et al. Amphiregulin Stimulates Liver Regeneration after Small‐for‐Size Mouse Liver Transplantation. Am J Transplant. 2012; 12(8): 2052–2061.
20. Castillo J, Erroba E, Perugorría MJ, et al. Amphiregulin contributes to the transformed phenotype of human hepatocellular carcinoma cells. Cancer Res. 2006; 66(12):6129-38.
21. Thomas MB, Zhu AX. Hepatocellular carcinoma: the need for progress. J Clin Oncol. 2005; 23(13):2892-9.
22. Kudo M, Han KH, Kokudo N, et al. Liver cancer working group report. Jpn J Clin Oncol. 2010; 40 Suppl 1:i19-27.
23. 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.
24. 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.
25. Yang H, Chen GD, Fang F, et al. Dickkopf-1: as a diagnostic and prognostic serum marker for early hepatocellular carcinoma. Int J Biol Markers. 2013; 28(3):286-97.
26. Erdal H, Gül Utku Ö, Karatay E, et al. Combination of DKK1 and AFP improves diagnostic accuracy of hepatocellular carcinoma compared with either marker alone. Turk J Gastroenterol. 2016; 27(4):375-81.
27. Tung E K, 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.
28. Mohamed FZ, Barakat LA, Radwan NH, et al. Comparative study between DKK1 and AFP for diagnosis of hepatocellular carcinoma among Egyptian patients. Eur J Pharm Med Res. 2016; 3(9): 20-27.
29. Kikuchi A, Fumoto K, Kimura H. The Dickkopf1‐cytoskeleton‐associated protein 4 axis creates a novel signalling pathway and may represent a molecular target for cancer therapy. Br J Pharmacol. 2017; 174(24):4651-4665.
30. Glaw JT, Skalak TC, Peirce SM. Inhibition of canonical Wnt signaling increases microvascular hemorrhaging and venular remodeling in adult rats. Microcirculation. 2010; 17(5):348-57.
31. Choi SH, Kim H, Lee HG, et al. Dickkopf-1 induces angiogenesis via VEGF receptor 2 regulation independent of the Wnt signaling pathway. Oncotarget. 2017; 8(35): 58974–58984.
32. Yao L, Zhang D, Zhao X, et al. Dickkopf‐1‐promoted vasculogenic mimicry in non‐small cell lung cancer is associated with EMT and development of a cancer stem‐like cell phenotype. J Cell Mol Med. 2016; 20(9):1673-85.
33. Behnke M, Reimers M, Fisher R. The Expression of Embryonic Liver Development Genes in Hepatitis C Induced Cirrhosis and Hepatocellular Carcinoma. Cancers (Basel). 2012; 4(3):945-68.
34. Bonacini M, Hadi G, Govindarajan S, et al. Utility of a discriminant score for diagnosing advanced fibrosis or cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol. 1997; 92(8):1302-4.
35. Sheth SG, Flamm SL, Gordon FD, et al. AST/ALT ratio predicts cirrhosis in patients with chronic hepatitis C virus infection. Am J Gastroenterol. 1998; 93(1):44-8.
36. Botros M, Sikaris KA. The de ritis ratio: the test of time. Clin Biochem Rev. 2013; 34(3): 117–130.
37. KamimotoY, Horiuchi S, Tanase S, et al. Plasma clearance of intravenously injected aspartate aminotransferase isozymes: evidence for preferential uptake by sinusoidal liver cells. Hepatology. 1985; 5(3):367-75.
38. Urtasun R, Latasa MU, Demartis MI, et al. Connective tissue growth factor autocriny in human hepatocellular carcinoma: Oncogenic role and regulation by epidermal growth factor receptor/yes‐associated protein–mediated activation. Hepatology. 2011; 54(6): 2149-58.
39. Perugorria MJ, Latasa MU, Nicou A, et al. The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis. Hepatology. 2008; 48(4):1251-61.
40. Qi Y, Operario DJ , Oberholzer CM, et al. Human basophils express amphiregulin in response to T cell–derived IL-3. J Allergy Clin Immunol. 2010; 126(6):1260-6.e4.
41. Salimi M, Barlow JL, Saunders SP, et al. A role for IL-25 and IL-33–driven type-2 innate lymphoid cells in atopic dermatitis. J Exp Med. 2013; 210(13):2939-50.
42. Adib-Conquy M, Pedron T, Petit-Bertron A-F, et al. Neutrophils in cystic fibrosis display a distinct gene expression pattern. Mol Med. 2008; 14(1-2): 36–44.
43. Zaiss, DM, Yang L, Shah PR, et al. Amphiregulin, a TH2 cytokine enhancing resistance to nematodes. Science. 2006; 314(5806): 1746.
44. Burzyn D, Kuswanto W, Kolodin D, et al. A special population of regulatory T cells potentiates muscle repair. Cell. 2013; 155(6): 1282-95.
45. Jamieson AM, Pasman L, Yu S, et al. Role of tissue protection in lethal respiratory viral-bacterial coinfection. Science. 2013; 340(6137): 1230-4.
46. Liu K, Lin D, Ouyang Y, et al. Amphiregulin impairs apoptosis-stimulating protein 2 of p53 overexpression–induced apoptosis in hepatoma cells. Tumor Biol. 2017; 39(3): 1010428317695026.
47. Han SX, Bai E, Jin GH, et al. Expression and clinical significance of YAP, TAZ, and AREG in hepatocellular carcinoma. J Immunol Res. 2014; 2014:261365.
48. Zhang J, Ji JY, Yu M, et al. YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nat Cell Biol. 2009; 11(12):1444-50.
49. Chang CJ, Yin PH, Yang DM, et al. Mitochondrial dysfunction-induced amphiregulin upregulation mediates chemo-resistance and cell migration in HepG2 cells. Cell Mol Life Sci. 2009; 66(10):1755-65.
50. Liu JF, Tsao YT, Hou CH. Amphiregulin enhances intercellular adhesion molecule-1 expression and promotes tumor metastasis in human osteosarcoma. Oncotarget. 2015; 6(38): 40880-95.
51. Willmarth NE, Ethier SP. Autocrine and juxtacrine effects of amphiregulin on the proliferative, invasive, and migratory properties of normal and neoplastic human mammary epithelial cells. J Biol Chem. 2006; 281(49): 37728-37.
52. Higginbotham JN, Demory Beckler M, Gephart JD, et al. Amphiregulin exosomes increase cancer cell invasion. Curr Biol. 2011; 21(9):779-86.
53. Azmi AS, Bao B, Sarkar FH. Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev. 2013; 32(3-4): 623-642.
54. Santangelo L, Battistelli C, Montaldo C, et al. Functional roles and therapeutic applications of exosomes in hepatocellular carcinoma. Biomed Res Int. 2017; 2017:2931813.
55. Chai H, Brown RE. Field effect in cancer–an update. Ann Clin Lab Sci. 2009; 39(4):331-7.
56. Hendrix A, Westbroek W, Bracke M, et al. An ex (o) citing machinery for invasive tumor growth. Cancer Res. 2010; 70(23): 9533-7.
57. Taverna S, Pucci M, Giallombardo M, et al. Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation through the activation of EGFR pathway. Sci Rep. 2017; 7(1):3170.
58. Tanaka H, Nishioka Y, Yokoyama Y, et al. Nuclear envelope-localized EGF family protein amphiregulin activates breast cancer cell migration in an EGF-like domain independent manner. Biochem Biophys Res Commun. 2012; 420(4):721-6.
| Files | ||
| Issue | Vol 13, No 3 (2019) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijhoscr.v13i3.1275 | |
| Keywords | ||
| HCC, Dickkopf-1, Amphiregulin | ||
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How to Cite
1.
Awad A, Ebrahim M, Eissa L, El-Shishtawy M. Dickkopf-1 and Amphiregulin as Novel Biomarkers and Potential Therapeutic Targets in Hepatocellular Carcinoma. Int J Hematol Oncol Stem Cell Res. 2019;13(3):153-163.
