- Volume 15 Issue 19
DOI QR Code
Crosstalk between EGFR and p53 in Hepatocellular Carcinoma
- Cioca, Andreea (Department of Pathology "Iuliu Hatieganu") ;
- Cimpean, Anca (Angiogenesis Research Center, "Victor Babes" University of Medicine and Pharmacy) ;
- Ceausu, Raluca (Angiogenesis Research Center, "Victor Babes" University of Medicine and Pharmacy) ;
- Fit, Ana-Maria (Department of Pathology "Iuliu Hatieganu") ;
- Zaharie, Teodor (Department of Pathology, Regional Institute of Gastroenterology and Hepatology) ;
- Al-Hajjar, Nadim (Department of Surgical, Regional Institute of Gastroenterology and Hepatology) ;
- Puia, Vlad (Department of Surgical, Regional Institute of Gastroenterology and Hepatology) ;
- Raica, Marius (Angiogenesis Research Center, "Victor Babes" University of Medicine and Pharmacy)
- Published : 2014.10.23
Background: Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide, with a high mortality. Most patients present with late stage disease, when the treatment options are limited to systemic chemotherapy. The purpose of our study was to evaluate the significance of p53 and EGFR expression in HCC, and to determine whether these two markers correlate with conventional parameters of prognosis. Materials and Methods: Our study included a total of 45 patients, diagnosed histopathologically with HCC. Clinicopathological data including sex, age, tumor necrosis, tumor size, histologic grading, tumor stage, the presence of cirrhosis and chronic hepatitis, were recorded from the Institute database. Three independent microscopic fields were selected for each sample and all the tumor cells within each microscopic field were counted, and then the positive percent of p53 cells were calculated. Three staining patterns were recognized: diffuse, heterogenous and focal. The intensity of EGFR staining was scored on a scale of 0-3+: 0 no staining; 1+ when a weak membrane staining was observed; 2+ when membrane staining is more intense than in 1+, but less than 3+, and 3+ when intense dark brown staining delineated the membrane. To determine the relationship between EGFR expression and p53, we performed double staining in the same HCC specimens. Results: By immunohistochemical staining, p53 protein was detected in tumor cell nuclei in 20 HCCs (44%). We found a significant correlation between the intensity of p53 expression and the histological grade (p=0.008). EGFR expression was detected in 17 (38%) cases, linked to histological grade (p=0.039). Moreover, the intensity of p53 expression was significantly correlated with EGFR intensity (p=0.014). Conclusions: Our results suggest that overexpression of p53 and EGFR plays an important role in hepatocarcinogenesis and contributes to more advanced disease. These markers are not only valuable predictors of prognosis in HCC, but they are also rational targets for new anti-tumor strategies.
Epidermal growth factor receptor;p53;hepatocellular carcinoma;immunohistochemistry
- Abusail MS, Dirweesh AMA, Salih RAA, Gadelkarim AH (2013). Expression of EGFR and p53 in head and neck tumors among Sudanese patients. Asian Pac J Cancer Prev, 14, 6415-8. https://doi.org/10.7314/APJCP.2013.14.11.6415
- Altimari A, Fiorentino M, Gabusi E, et al (2003). Investigation of ErbB1 and ErbB2 expression for therapeutic targeting in primary liver tumours. Dig Liver Dis, 35, 332-8. https://doi.org/10.1016/S1590-8658(03)00077-X
- Andreas P, Michael M, Joachim D (2011). Liver cancer: Targeted future options. World J Hepatol, 3, 38-44. https://doi.org/10.4254/wjh.v3.i2.38
- Bassullu N, Turkmen I, Dayangac M, et al (2012). The predictive and prognostic significance of c-erb-B2,EGFR, PTEN, mTOR, PI3K, p27, and ERCC1 Expression in Hepatocellular Carcinoma. Hepat Mon, 12, 7492.
- Berasain C, Latasa M.U, Urtasun R, et al (2011). A. Epidermal growth factor receptor (EGFR) crosstalks in liver cancer. Cancers, 3, 2444-61. https://doi.org/10.3390/cancers3022444
- Cervello M, McCubrey JA, Cusimano A, et al (2012). Targeted therapy for hepatocellular carcinoma: novel agents on the horizon. Oncotarget, 3, 236-60.
- Bonner JA, Harari PM, Giralt J, et al (2010). Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol, 11, 21-8. https://doi.org/10.1016/S1470-2045(09)70311-0
- Braicu C, Burz C, Berinde Neagoe I, et al (2009). Hepatocellular carcinoma: Tumorigenesis and prediction markers; Gastroenterol Res, 2, 191-9.
- Caruso ML, Valentini AM (1999). Overexpression of p53 in a large series of patients with hepatocellular carcinoma: a clinicopathological correlation. Anticancer Res, 19, 3853-6.
- Daveau M, Scotte M, Francois A, et al (2003). Hepatocyte growth factor, transforming growth factor alpha, and their receptors as combined markers of prognosis in hepatocellular carcinoma. Mol Carcinog, 36, 130-41. https://doi.org/10.1002/mc.10103
- Edmondson HA, Steiner PE (1954). Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer, 7, 462-503. https://doi.org/10.1002/1097-0142(195405)7:3<462::AID-CNCR2820070308>3.0.CO;2-E
- Fan FT, Shen CS, Tao L, et al (2014). PKM2 regulates HCC epithelial-mesenchymal transition and migration upon egfr activation. Asian Pac J Cancer Prev, 15, 1961-70. https://doi.org/10.7314/APJCP.2014.15.5.1961
- Gao J, Xie L, Yang WS, et al (2012). Risk factors of hepatocellular carcinoma - current status and perspectives. Asian Pac J Cancer Prev, 13, 743-52. https://doi.org/10.7314/APJCP.2012.13.3.743
- Hassan MM, Hwang LY, Hatten CJ, et al (2002). Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology, 36, 1206-13. https://doi.org/10.1053/jhep.2002.36780
- Heesue K, Lim HY (2011). Novel EGFR-TK inhibitor EKB- 569 inhibits hepatocellular carcinoma cell proliferation by AKT and MAPK pathways. J Korean Med Sci, 26, 1563-8. https://doi.org/10.3346/jkms.2011.26.12.1563
- Ito Y, Takeda T, Sakon M, et al (2001). Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer, 84, 1377-83. https://doi.org/10.1054/bjoc.2000.1580
- Hsia CC, Nakashima Y, Thorgeirsson SS, et al (2000). Correlation of immunohistochemical staining and mutations of p53 in human hepatocellular carcinoma. Oncol Rep, 7, 353-6.
- Hua J, Huamao W, Zhonghua T, et al (2011). Growth suppression of human hepatocellular carcinoma xenografts by a monoclonal antibody CH12 directed to epidermal growth factor receptor variant III. J. Biol. Chem, 286, 5913-20. https://doi.org/10.1074/jbc.M110.192252
- Huang S, Benavente S, Armstrong EA, et al (2011). p53 Modulates acquired resistance to EGFR inhibitors and radiation. Cancer Res, 71, 7071-9. https://doi.org/10.1158/0008-5472.CAN-11-0128
- Jain S, Singhal S, Lee P, Xu R. (2010). Molecular genetics of hepatocellular neoplasia. Am J Transl Res, 2, 105-18.
- Lee SN, Park CK, Sung CO, et al (2002). Correlation of mutation and immunohistochemistry of p53 in hepatocellular carcinomas in korean people. J Korean Med Sci, 17, 801-5. https://doi.org/10.3346/jkms.2002.17.6.801
- Liu J, Ma Q, Zhang M, et al (2012). Alterations of TP53 are associated with a poor outcome for patients with hepatocellular carcinoma: evidence from a systematic review and meta-analysis. Eur J Cancer, 48, 2328-38. https://doi.org/10.1016/j.ejca.2012.03.001
- Nakopoulou L, Stefanaki K, Filaktopoulos D, Giannopoulou I (1994). C-erb-B-2 oncoprotein and epidermal growth factor receptor in human hepatocellular carcinoma: an immunohistochemical study. Histol Histopathol, 9, 677-82.
- Oden-Gangloff A, Di Fiore F, Bibeau F, Lamy A, et al (2009). TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy. Br J Cancer, 100, 1330-5 https://doi.org/10.1038/sj.bjc.6605008
- Vlasoff DM, Baschinsky DY, De Young BR, et al (2002). C-erb B2 (Her2/neu) is neither overexpressed nor amplified in hepatic neoplasms. Appl Immunohistochem Mol Morphol, 10, 237-41.
- Qin LX, Tang ZY, Ma ZC, et al (2001). P53 immunohistochemical scoring: an independent prognostic marker for patients after hepatocellular carcinoma resection. World J Gastroenterol, 8, 459-63.
- Rampone B, Schiavone B, Martino A, Viviano C, Confuorto G (2009). Current management strategy of hepatocellular carcinoma. World J Gastroenterol, 15, 3210-6. https://doi.org/10.3748/wjg.15.3210
- Sung CO, Yoo BC, Koh KC, Cho JW, Park CK (2005). Prognostic significance of p53 overexpression after hepatic resection of hepatocellular carcinoma. Korean J Gastroenterol, 45, 425-30.
- Wei Z, Doria C, Liu Y (2013). Targeted therapies in the treatment of advanced hepatocellular carcinoma. Clin Med Insights Oncol, 7, 87-102.
- Xu CT, Zheng F, Dai X (2012). Association between TP53 Arg72Pro polymorphism and hepatocellular carcinoma risk: a meta-analysis. Asian Pac J Cancer Prev, 13, 4305-9. https://doi.org/10.7314/APJCP.2012.13.9.4305
- Xu J, Liu C, Zhou L, et al (2012). Distinctions between clinicopathological factors and prognosis of alphafetoprotein negative and positive hepatocellular carcinoma patients. Asian Pac J Cancer Prev, 13, 559-62. https://doi.org/10.7314/APJCP.2012.13.2.559
- Yamaguchi K, Carr BI, Nalesnik MA (1995). Concomitant and isolated expression of TGF-alpha and EGF-R in human hepatoma cells supports the hypothesis of autocrine, paracrine, and endocrine growth of human hepatoma. J Surg Oncol, 58, 240-5. https://doi.org/10.1002/jso.2930580409
- Zender L, Kubicka S (2008). Molecular pathogenesis and targeted therapy of hepatocellular carcinoma. Onkologie, 31, 550-5.
- Zhou L, Liu C, Meng FD, et al (2013). Long-term prognosis in hepatocellular carcinoma patients after hepatectomy. Asian Pac J Cancer Prev, 13, 483-6. https://doi.org/10.7314/APJCP.2012.13.2.483
- Zhou L, Liu J, Luo F (2006). Serum tumor markers for detection of hepatocellular carcinoma. World J Gastroenterol, 12, 1175-81.
- B3GNT2, a Polylactosamine Synthase, Regulates Glycosylation of EGFR in H7721 Human Hepatocellular Carcinoma Cells vol.15, pp.24, 2015, https://doi.org/10.7314/APJCP.2014.15.24.10875