Prognostic significance of c-Met, β-catenin and FAK in patients with hepatocellular carcinoma following surgery

Gong,Xue‑Yi; Ma,Ning; Xu,Hong‑Xu; Chen,Fan; Huang,Xiao‑Hui; Wang,Qian

doi:10.3892/ol.2018.7733

Prognostic significance of c-Met, β-catenin and FAK in patients with hepatocellular carcinoma following surgery

Authors:
- Xue‑Yi Gong
- Ning Ma
- Hong‑Xu Xu
- Fan Chen
- Xiao‑Hui Huang
- Qian Wang
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China, Department of General Surgical Laboratory, The First Affiliated Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China, Laboratory of Medicine, The First Affiliated Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China
Published online on: January 5, 2018 https://doi.org/10.3892/ol.2018.7733
Pages: 3796-3805

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to investigate the prognostic value of specific molecular markers in patients with hepatocellular carcinoma (HCC) who had received surgery. Immunohistochemical analysis was used to measure the expression of hepatocyte growth factor receptor (c‑Met), β‑catenin and focal adhesion kinase (FAK) in patients with HCC. c‑Met expression was identified to be high in patients with larger tumors, higher α‑fetoprotein (AFP) levels, higher Edmondson grades, portal vein invasion and higher tumor‑node‑metastasis (TNM) stages. FAK expression was high in patients with portal vein invasion, higher Edmondson grades and higher TNM stages. β‑catenin expression was high in patients with larger tumors, hepatitis B virus (HBV) infection, portal vein invasion, higher Edmondson grades and higher TNM stages. Following multivariate analysis, FAK (P=0.002) and β‑catenin (P=0.006) expression levels were demonstrated to be significantly associated with Edmondson grade. Additionally, the tumor size (P=0.009) and HBV infection status (P=0.002) were revealed to be associated with β‑catenin expression. Kaplan‑Meier survival curve analysis demonstrated that patients with HCC with higher FAK expression, higher β‑catenin expression, portal vein invasion, higher Edmondson grades, higher TNM stages, younger ages and higher AFP levels had significantly poorer prognoses. Cox's regression analysis revealed that the survival period was correlated with the Edmondson grade, age, AFP level, and FAK and β‑catenin expression. Univariate analysis of c‑Met, β‑catenin and FAK identified a significant correlation between FAK and β‑catenin (P=0.015). Correlation analysis revealed no significant correlation between the three molecular markers, but β‑catenin and c‑Met were markedly correlated (P=0.052). No significant correlation between FAK, c‑Met or β‑catenin expression was identified. FAK and β‑catenin expression demonstrated a correlation with a range of clinicopathological factors, and high FAK and β‑catenin expression levels were identified to be correlated with a poor survival rate of patients with HCC. Thus, patients with higher FAK and β‑catenin expression may require more aggressive therapy. The results of the present study suggest that FAK and β‑catenin expression possess more prognostic value than c‑Met expression in patients with HCC.

View Figures

View References

1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Kim KH and Choi YK: Long-term survival after resection of hepatocellular carcinoma. Korean J Hepatobiliary Pancreat Surg. 16:98–104. 2012. View Article : Google Scholar : PubMed/NCBI
3	Shang N, Arteaga M, Zaidi A, Stauffer J, Cotler SJ, Zeleznik-Le NJ, Zhang J and Qiu W: FAK is required for c-Met/β-catenin-driven hepatocarcinogenesis. Hepatology. 61:214–226. 2015. View Article : Google Scholar : PubMed/NCBI
4	Bruix J and Sherman M: Practice Guidelines Committee, American Association for the Study of Liver Diseases: Management of hepatocellular carcinoma. Hepatology. 42:1208–1236. 2005. View Article : Google Scholar : PubMed/NCBI
5	Clevers H: Wnt/beta-catenin signaling in development and disease. Cell. 127:469–480. 2006. View Article : Google Scholar : PubMed/NCBI
6	Zhao X and Guan JL: Focal adhesion kinase and its signaling pathways in cell migration and angiogenesis. Adv Drug Deliv Rev. 63:610–615. 2011. View Article : Google Scholar : PubMed/NCBI
7	Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 359:378–390. 2008. View Article : Google Scholar : PubMed/NCBI
8	Mitra SK, Hanson DA and Schlaepfer DD: Focal adhesion kinase: In command and control of cell motility. Nat Rev Mol Cell Biol. 6:56–68. 2005. View Article : Google Scholar : PubMed/NCBI
9	Schaller MD: Cellular functions of FAK kinases: Insight into molecular mechanisms and novel functions. J Cell Sci. 123:1007–1013. 2010. View Article : Google Scholar : PubMed/NCBI
10	Zhao J and Guan JL: Signal transduction by focal adhesion kinase in cancer. Cancer Metastasis Rev. 28:35–49. 2009. View Article : Google Scholar : PubMed/NCBI
11	Parsons JT: Focal adhesion kinase: The first ten years. J Cell Sci. 116:1409–1416. 2003. View Article : Google Scholar : PubMed/NCBI
12	Patil MA, Lee SA, Macias E, Lam ET, Xu C, Jones KD, Ho C, Rodriguez-Puebla M and Chen X: Role of cyclin D1 as a mediator of c-Met and beta-catenin induced hepatocarcinogenesis. Cancer Res. 69:253–261. 2009. View Article : Google Scholar : PubMed/NCBI
13	Tward AD, Jones KD, Yant S, Cheung ST, Fan ST, Chen X, Kay MA, Wang R and Bishop JM: Distinct pathways of genomic progression to benign and malignant tumors of the liver. Proc Natl Acad Sci USA. 104:pp. 14771–14776. 2007; View Article : Google Scholar : PubMed/NCBI
14	Schlaepfer DD, Hauck CR and Sieg DJ: Signaling through focal adhesion kinase. Prog Biophys Mol Biol. 71:435–478. 1999. View Article : Google Scholar : PubMed/NCBI
15	Pylayeva Y, Gillen KM, Gerald W, Beggs HE, Reichardt LF and Giancotti FG: Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling. J Clin Invest. 119:252–266. 2009.PubMed/NCBI
16	Ashton GH, Morton JP, Myant K, Phesse TJ, Ridgway RA, Marsh V, Wilkins JA, Athineos D, Muncan V, Kemp R, et al: Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling. Dev Cell. 19:259–269. 2010. View Article : Google Scholar : PubMed/NCBI
17	Lee J, Borboa AK, Chun HB, Baird A and Eliceiri BP: Conditional deletion of the focal adhesion kinase FAK alters remodeling of the blood-brain barrier in glioma. Cancer Res. 70:10131–10140. 2010. View Article : Google Scholar : PubMed/NCBI
18	Itoh S, Maeda T, Shimada M, Aishima S, Shirabe K, Tanaka S and Maehara Y: Role of expression of focal adhesion kinase in progression of hepatocellular carcinoma. Clin Cancer Res. 10:2812–2817. 2004. View Article : Google Scholar : PubMed/NCBI
19	Fujii T, Koshikawa K, Nomoto S, Okochi O, Kaneko T, Inoue S, Yatabe Y, Takeda S and Nakao A: Focal adhesion kinase is overexpressed in hepatocellular carcinoma and can be served as an independent prognostic factor. J Hepatol. 41:104–111. 2004. View Article : Google Scholar : PubMed/NCBI
20	Kaposi-Novak P, Lee JS, Gòmez-Quiroz L, Coulouarn C, Factor VM and Thorgeirsson SS: Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest. 116:1582–1595. 2006. View Article : Google Scholar : PubMed/NCBI
21	Cieply B, Zeng G, Proverbs-Singh T, Geller DA and Monga SP: Unique phenotype of hepatocellular cancers with exon-3 mutations in beta-catenin gene. Hepatology. 49:821–831. 2009. View Article : Google Scholar : PubMed/NCBI
22	Stauffer JK, Scarzello AJ, Andersen JB, De Kluyver RL, Back TC, Weiss JM, Thorgeirsson SS and Wiltrout RH: Coactivation of AKT and β-catenin in mice rapidly induces formation of lipogenic liver tumors. Cancer Res. 71:2718–2727. 2011. View Article : Google Scholar : PubMed/NCBI
23	Edmondson HA and Steiner PE: Primary carcinoma of the liver: A study of 100 cases among 48,900 necropsies. Cancer. 7:462–503. 1954. View Article : Google Scholar : PubMed/NCBI
24	Calabrese CT, Adam YG and Volk H: Geriatric colon cancer. Am J Surg. 125:181–184. 1973. View Article : Google Scholar : PubMed/NCBI
25	Ershler WB, Socinski MA and Greene CJ: Bronchogenic cancer, metastases and aging. J Am Geriatr Soc. 31:673–676. 1983. View Article : Google Scholar : PubMed/NCBI
26	Ershler WB: Why tumors grow more slowly in old people. J Natl Cancer Inst. 77:837–839. 1986.PubMed/NCBI
27	Breuhahn K, Longerich T and Schirmacher P: Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene. 25:3787–3800. 2006. View Article : Google Scholar : PubMed/NCBI
28	Farazi PA and DePinho RA: Hepatocellular carcinoma pathogenesis: From genes to environment. Nat Rev Cancer. 6:674–687. 2006. View Article : Google Scholar : PubMed/NCBI
29	Tabor E: Tumor suppressor genes, growth factor genes, and oncogenes in hepatitis B virus-associated hepatocellular carcinoma. J Med Virol. 42:357–365. 1994. View Article : Google Scholar : PubMed/NCBI
30	Rogler CE and Chisari FV: Cellular and molecular mechanisms of hepatocarcinogenesis. Semin Liver Dis. 12:265–278. 1992. View Article : Google Scholar : PubMed/NCBI
31	Sung CO, Yoo BC, Koh KC, Cho JW and Park CK: Prognostic significance of p53 overexpression after hepatic resection of hepatocellular carcinoma. Korean J Gastroenterol. 45:425–430. 2005.PubMed/NCBI
32	Pang RW and Poon RT: From molecular biology to targeted therapies for hepatocellular carcinoma: The future is now. Oncology. 72 Suppl 1:S30–S44. 2007. View Article : Google Scholar
33	Llovet JM and Bruix J: Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 48:1312–1327. 2008. View Article : Google Scholar : PubMed/NCBI
34	André E and Becker-André M: Expression of an N-terminally truncated form of human focal adhesion kinase in brain. Biochem Biophys Res Commun. 190:140–147. 1993. View Article : Google Scholar : PubMed/NCBI
35	Fausto N, Campbell JS and Riehle KJ: Liver regeneration. Hepatology. 43(2 Suppl 1): S45–S53. 2006. View Article : Google Scholar : PubMed/NCBI
36	Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, et al: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 16:68–73. 1997. View Article : Google Scholar : PubMed/NCBI
37	Schmidt L, Junker K, Weirich G, Glenn G, Choyke P, Lubensky I, Zhuang Z, Jeffers M, Vande Woude G, Neumann H, et al: Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res. 58:1719–1722. 1998.PubMed/NCBI
38	Park WS, Dong SM, Kim SY, Na EY, Shin MS, Pi JH, Kim BJ, Bae JH, Hong YK, Lee KS, et al: Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res. 59:307–310. 1999.PubMed/NCBI
39	Ma PC, Kijima T, Maulik G, et al: c-MET mutational analysis in small cell lung cancer: Novel juxtamembrane domain mutations regulating cytoskeletal functions. Cancer Res. 63:6272–6281. 2003.PubMed/NCBI
40	Ma PC, Jagdeesh S, Jagadeeswaran R, Fox EA, Christensen J, Maulik G, Naoki K, Schaefer E, Lader A, Richards W, et al: c-MET expression/activation, functions and mutations in non-small cell lung cancer. Proc Am Assoc Cancer Res. 44:pp. 18752004;
41	Lee JH, Han SU, Cho H, Jennings B, Gerrard B, Dean M, Schmidt L, Zbar B and Vande Woude GF: A novel germ line juxtamembrane Met mutation in human gastric cancer. Oncogene. 19:4947–4953. 2000. View Article : Google Scholar : PubMed/NCBI
42	Christensen JG, Burrows J and Salgia R: c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 225:1–26. 2005. View Article : Google Scholar : PubMed/NCBI
43	Chen Z, He X, Jia M, Liu Y, Qu D, Wu D, Wu P, Ni C, Zhang Z, Ye J, et al: β-catenin overexpression in the nucleus predicts progress disease and unfavourable survival in colorectal cancer: A meta-analysis. PLoS One. 8:e638542013. View Article : Google Scholar : PubMed/NCBI
44	Gough NR: Focus issue: Wnt and beta-catenin signaling in development and disease. Sci Signal. 5:eg22012.PubMed/NCBI
45	Inagawa S, Itabashi M, Adachi S, Kawamoto T, Hori M, Shimazaki J, Yoshimi F and Fukao K: Expression and prognostic roles of beta-catenin in hepatocellular carcinoma: Correlation with tumor progression and postoperative survival. Clin Cancer Res. 8:450–456. 2002.PubMed/NCBI
46	Liu L, Zhu XD, Wang WQ, Shen Y, Qin Y, Ren ZG, Sun HC and Tang ZY: Activation of beta-catenin by hypoxia in hepatocellular carcinoma contributes to enhanced metastatic potential and poor prognosis. Clin Cancer Res. 16:2740–2750. 2010. View Article : Google Scholar : PubMed/NCBI
47	Lee JM, Yang J, Newell P, Singh S, Parwani A, Friedman SL, Nejak-Bowen KN and Monga SP: β-Catenin signaling in hepatocellular cancer: Implications in inflammation, fibrosis, and proliferation. Cancer Lett. 343:90–97. 2014. View Article : Google Scholar : PubMed/NCBI
48	Jin J, Jung HY, Wang Y, Xie J, Yeom YI, Jang JJ and Lee KB: Nuclear expression of phosphorylated TRAF2- and NCK-interacting kinase in hepatocellular carcinoma is associated with poor prognosis. Path Res Pract. 210:621–627. 2014. View Article : Google Scholar : PubMed/NCBI
49	Zulehner G, Mikula M, Schneller D, van Zijl F, Huber H, Sieghart W, Grasl-Kraupp B, Waldhör T, Peck-Radosavljevic M, Beug H and Mikulits W: Nuclear beta-catenin induces an early liver progenitor phenotype in hepatocellular carcinoma and promotes tumor recurrence. Am J Pathol. 176:472–481. 2010. View Article : Google Scholar : PubMed/NCBI
50	Liver cancer study group of Japan, . The general rules for the clinical and pathological study of primary liver cancer. 3rd. Kanehara Shuppan; Tokyo: 1992
51	Sumie S, Kuromatsu R, Okuda K, Ando E, Takata A, Fukushima N, Watanabe Y, Kojiro M and Sata M: Microvascular invasion in patients with hepatocellular carcinoma and its predictable clinicopathological factors. Ann Surg Oncol. 15:1375–1382. 2008. View Article : Google Scholar : PubMed/NCBI
52	Minagawa M, Ikai I, Matsuyama Y, Yamaoka Y and Makuuchi M: Staging of hepatocellular carcinoma: Assessment of the Japanese TNM and AJCC/UICC TNM systems in a cohort of 13,772 patients in Japan. Ann Surg. 245:909–922. 2007. View Article : Google Scholar : PubMed/NCBI
53	Henderson J, Sherman M, Tavill A, Abecassis M, Chejfec G and Gramlich T: AHPBA/AJCC consensus conference on staging of hepatocellular carcinoma: Consensus statement. HPB(Oxford). 5:243–250. 2003.PubMed/NCBI
54	Leung TW, Tang AM, Zee B, Lau WY, Lai PB, Leung KL, Lau JT, Yu SC and Johnson PJ: Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: A study based on 926 patients. Cancer. 94:1760–1769. 2002. View Article : Google Scholar : PubMed/NCBI