|Year : 2018 | Volume
| Issue : 8 | Page : 28-35
Human epidermal growth factor receptor 2, epidermal growth factor receptor, and c-MET overexpression and survival in biliary tract cancer: A meta-analysis
Wei Zhou1, Congqing Jiang2, Nan Zhan3, Xiaoguang Lv3, Lifang Fan1, Maskey Ninu4
1 Department of Pathology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei, China
2 Department of Colorectal Surgery, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
3 Department of Pathology, Renmin Hospital, Wuhan University, Wuhan, Hubei, China
4 Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China
|Date of Web Publication||26-Mar-2018|
Department of Pathology, School of Basic Medical Sciences, Wuhan University, No. 185 Donghu Road, Wuchang, Wuhan 430071, Hubei
Source of Support: None, Conflict of Interest: None
Background: Tyrosine kinase growth factor receptors (TKGFRs) play an important role in the progression of cancer. A variety of studies have investigated the clinicopathologic correlation of these receptors and their influences on patient survival in different types of cancer. As the members of TKGFRs, the biomarkers c-MET, epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER-2) have been extensively investigated in biliary tract cancer (BTC). However, their prognostic value is still controversial. Our study aimed to evaluate the prognostic significance of the three markers in BTC patients based on the published studies. The correlation between high expression of these markers and clinical parameters or overall survival (OS) has been assumed in this paper.
Materials and Methods: Including PubMed, EMBASE, China National Knowledge Infrastructure, and Springer, a comprehensive search for the related literature published in Chinese and English has been done. Finally, 31 studies were selected in our research.
Results: Surprisingly, the meta-analysis indicated that HER-2 high expression was not correlated with age, gender, primary tumor, tumor node metastasis (TNM) stage, lymph node status, and differentiation. We also found that EGFR high expression was not associated with the parameters, such as age, gender, TNM stage, differentiation, or lymph node status. c-MET high-expression was not associated with age, differentiation, gender, TNM stage, or lymph node status. In addition, our study showed that HER-2, EGFR, and c-MET high expression had an adverse influence on OS in BTC, the pooled hazard ratio for HER-2, EGFR, and c-MET was statistically significant.
Conclusion: The present meta-analysis indicated that EGFR and HER-2 high expression have little impact on OS in patients with BTC while c-MET high expression influenced OS in patients with BTC to a large extent. However, c-MET, EGFR, and HER-2 expression did not show any correlation with those clinical parameters. c-MET may be a potential therapeutic target for BTC.
Keywords: Biliary tract cancer, c-MET, epidermal growth factor receptor, human epidermal growth factor receptor 2, meta-analysis
|How to cite this article:|
Zhou W, Jiang C, Zhan N, Lv X, Fan L, Ninu M. Human epidermal growth factor receptor 2, epidermal growth factor receptor, and c-MET overexpression and survival in biliary tract cancer: A meta-analysis. J Can Res Ther 2018;14:28-35
|How to cite this URL:|
Zhou W, Jiang C, Zhan N, Lv X, Fan L, Ninu M. Human epidermal growth factor receptor 2, epidermal growth factor receptor, and c-MET overexpression and survival in biliary tract cancer: A meta-analysis. J Can Res Ther [serial online] 2018 [cited 2018 Nov 19];14:28-35. Available from: http://www.cancerjournal.net/text.asp?2018/14/8/28/206864
| > Introduction|| |
Biliary tract cancer (BTC) is one of the most common cancers among people, including cholangiocarcinoma, carcinoma of gallbladder, and ampulla cancer. The common sites of bile duct cancer were hilar bile duct, ductuli, and hepatic cuscommunis. Recently, the morbidity of BTC is approximately 1–10/10,000,,, presenting a rising trend. Patients with BTC have a poor prognosis. Many factors have been identified, such as tumor node metastasis (TNM) stage, the depth of tumor invasion, status of lymph nodes, and distant metastasis, perineural status, differentiation. However, distinguishing outcomes are commonly observed among patients with the same stage. Therefore, it is vital to understand the significance of expression of the three markers, human epidermal growth factor receptor 2 (HER-2), epidermal growth factor receptor (EGFR), and c-MET.
HER-2, EGFR, and c-MET are tyrosine growth factor family members. HER-2 is a 185-kDa transmembrane glycoprotein, encoded by proto-oncogene c-ErbB-2. Both HER-2 and EGFR belong to ErbB family and can be activated by hepatocyte growth factor (HGF) and EGF. The three markers share approximately 5% overall homology and are composed of an N-terminus extracellular, a transmembrane lipophilic segment, and a C-terminus intracellular region containing a tyrosine kinase domain. In c-MET, the N-terminus extracellular contains an alpha helix and a beta sheet, a transmembrane domain, and an intracellular tyrosine kinase.
The previous studies reported that biomarkers with tyrosine kinase domain, such as HER-2, EGFR, and c-MET, are associated with poor prognosis in diverse types of cancer, such as gastric cancer,, breast cancer, and lung cancer. Although similar results have been found in patients with BTC, some studies show that the three biomarkers did not affect prognosis in BTC. New chemotherapeutic agents, such as trastuzumab, cetuximab, and gefitinib, targeting tyrosine kinase growth factor receptors (TKGFRs) have not been widely applied in BTC. There seems to be no consensus on the prognostic significance of HER-2, EGFR, and c-MET. Therefore, in this study, we performed a systematic review to analyze the prognostic significance of the three markers expression in patients with BTC.
| > Materials And Methods|| |
Publication and literature search
The following terms and their combinations were used as keywords in literature search: c-MET, EGFR, HER-2, cholangiocarcinoma, gallbladder, ampulla, biliary, ErbB2, carcinoma, cancer. A comprehensive search was operated in PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and Springer with the criteria as listed below. The deadline of search is August 1, 2016.
The inclusion criteria for the selection of literature in this study were as follows:
- An original dependent study of the correlation between the three markers and the prognosis of patients with BTC
- HER-2, EGFR, and c-MET were examined using immunohistochemistry (IHC)
- Subjects in every study comprised patients with high-expression and low-expression controls
- When multiple studies used the same study subject and had similar study content, the study with the most comprehensive date was selected
- Relevant information was extracted from the full text
- Literature must provide the original data of HER-2, EGFR, and c-MET expression, clinicopathological parameters, or overall survival (OS) rate; or be able to obtain the above information by calculation
- The language of the publications was English or Chinese.
- Reviews, abstracts and conference papers, letters to the editors
- Literature before the year of 2000
- Studies with insufficient information or were of poor quality.
Data were independently extracted by two investigators from the full-length articles. General information extracted from these articles includes author, publication year, number of patients, cutoff value, detection method, the number of total patients, the number of high expression, hazard ratio (HR), and 95% confidence interval (CI) of OS. The quality of the eligible studies was individually assessed based on the Newcastle–Ottawa scale. Studies obtaining 7–9 stars were considered to be of “high quality,” 5–6 stars as “moderate quality,” and five stars below as “low quality.” The studies of low quality were excluded.
For clinical parameters, the odds ratio and 95% CI were used to present the statistical values derived from the efficacy analysis for dichotomous variables. We calculated HRs with their 95% CI, which takes into consideration the number and timing of events. To evaluate the relationships between HER-2, EGFR, c-MET, and OS, the significance of the pooled HR was determined by Z-test, and P < 0.05 was considered statistically significant. I2 was calculated to assess the impact of heterogeneity on results. When I2 was >50%, heterogeneity was considered significant; the random-effects model was used. Publication bias was investigated through a funnel plot by the Begg's tests, and P < 1.0 was regarded as statistically significant of publication bias. The Kaplan–Meier curves were read by Engauge Digitizer (Version 2.11; http://sourceforge.net). All the statistical analyses were performed by Stata software (Version 12.0; StataCorp LP, College Station, Texas, USA).
| > Results|| |
Characterization of eligible studies
The characteristics of 465 studies were reviewed from the four databases, PubMed, EMBASE, CNKI, and Springer. The process of retrieved eliminating was mentioned in the methods [Figure 1]. Finally, 32 literature were eligible in our study. Twenty-seven literature provided complete original date about clinicopathological parameters. Fourteen literature assessed the prognostic value of HER-2, EGFR, or c-MET expression for OS in BTC patients by the Kaplan–Meier method. We obtained relevant data by directly extracting original data or by indirectly calculating from these studies.
The main characteristics of the 32 eligible studies for aggregation are shown in [Table 1]. A total of 2885 BTC patients were included in this meta-analysis. In all the 32 studies, the expression of HER-2, c-MET, and EGFR was confirmed by IHC.
Correlation of human epidermal growth factor receptor 2, epidermal growth factor receptor, and c-MET high expression and overall survival
Based on the previous report, a combined HR >1 indicated a worse OS but HR >2 is considered strongly predictive. In our study, HER-2, EGFR, and c-MET high expression were statistically significant with the OS in BTC patients, the pooled HRs value were 1.65 (95% CI, 1.11–2.45) [Figure 2], 1.59 (95% CI, 1.14–2.21) [Figure 3], and 2.24 (95% CI, 1.45–3.45) [Figure 4], they were negatively related to BTC patients survival. Subgroup analyses were performed after stratifying the data by region. In the Asian subgroup, HER-2 high expression had a mild negative effect on OS with the pooled HR of 1.62 (95% CI, 0.92–2.85); EGFR high expression also slightly but adversely affected OS in BTC patients, with the pooled HR of 1.31 (95% CI, 0.94-1.82); however, the Z-test revealed no statistical significance either in HER-2 or in EGFR. In the non-Asian subgroup, the pooled HR for HER-2 and EGFR was 1.88 (95% CI, 1.21–2.92) and 2.99 (95% CI: 1.73–5.16), respectively, suggesting that HER-2 and EGFR high expression were negatively related to BTC patient survival. Considering that all the c-MET studies enrolled were from Japan and China, two Asia countries, we did not divide data according to the region, but the overall HR indicated that c-MET was a reliable predictor for poor OS in patients with BTC.
|Figure 2: Meta-analysis for the association between human epidermal growth factor receptor 2 overexpression and biliary tract cancer survival and subgroup analysis of the Asian and non-Asian|
Click here to view
|Figure 3: Meta-analysis for the association between epidermal growth factor receptor overexpression and biliary tract cancer survival and subgroup analysis of the Japan and China|
Click here to view
|Figure 4: Meta-analysis for the association between c-MET overexpression and biliary tract cancer survival and subgroup analysis of the Asian and non-Asian|
Click here to view
Correlation of human epidermal growth factor receptor 2, epidermal growth factor receptor, and c-MET expression and clinicopathological parameters in biliary tract cancer patients
Our result showed that HER-2 high expression did not correlate with age (P = 0.791), gender (P = 0.741), primary tumor (P = 0.940), TNM stage (P = 0.381), lymph node status (P = 0.487), and differentiation (P = 0.277). EGFR high expression was not associated with these elements, including age (P = 0.586), gender (P = 0.52), TNM stage (P = 0.224), differentiation (P = 0.167), and lymph node status (P = 0.723). c-MET high expression showed no association with age (P = 0.261), gender (P = 0.727), differentiation (P = 0.371), TNM stage (P = 0.286), lymph node status (P = 0.739), and perineural invasive status (P = 0.929) as well, no statistical significance was found. Detailed information was exhibited in [Table 2], [Table 3], [Table 4].
|Table 2: Relationships between human epidermal growth factor receptor 2 and clinicopathological parameters|
Click here to view
|Table 3: Relationships between epidermal growth factor receptor and clinicopathological parameters|
Click here to view
Evaluation of publication bias in overall survival
The estimation of publication bias was based on the OS by Begg's funnel plot and the P value. The result of publication bias for HER-2, EGFR, and c-MET was P = 0.230 [Figure 5]a, P = 0.592 [Figure 5]b, and P = 0.308 [Figure 5]c, respectively, showing no significant publication bias in OS.
|Figure 5: Begg's funnel plot (a) ErbB-2, (b) epidermal growth factor receptor, (c) c-MET|
Click here to view
To test whether the inclusion criteria of the meta-analysis affected the final results, we deleted one single study from the overall pooled analysis each time to check the influence of the removed data set to the overall HRs. The results of sensitivity analysis are shown in [Figure 6]. We found that no study had an obvious impact on our overall results and verified the stability and reliability of our results.
|Figure 6: Sensitivity analysis (a) ErbB-2, (b) epidermal growth factor receptor, (c) c-MET|
Click here to view
| > Discussion|| |
The result obtained from a meta-analysis considerably depends on the quality of the selected studies, and it is also substantially influenced by the results of previous studies. Therefore, we applied a strict screening of the related literature, trying to avoid bias and to obtain a reliable conclusion. The process of screening is presented in [Figure 1]. A total of 32 studies were included in this study according to the inclusion and exclusion criteria.
To date, among the various biomarkers associated with tumorigenesis, many studies have demonstrated the correlation of biomarkers and prognosis, indicating that these makers may have complementary roles in improving the diagnosis and prognosis of cancers. Considering the prevalence of cancer, improving early detection, screening, and treatment is extremely important. Identifying the risk of mortality and disease recurrence in cancer patients is critical in guiding surveillance and selecting adjunctive therapies. It has been reported that HER-2, EGFR, and c-MET were related to clinicopathological parameters and OS in breast cancer or colon cancer.
In our systematic review, most of the selected articles came from Asia, indicating an obvious region differences. We found that EGFR, HER-2, and c-MET high expression were not related to age, differentiation, TNM stage, gender, or lymph node status. High expression of the three markers was associated with poor OS in BTC patients in different degree. Our findings indicated that the expression levels of TKGFRs, like the three markers that we studied, were not associated with clinicopathological parameters but correlated with the OS. Understanding the precise mechanisms of HER-2, EGFR, and c-MET in BTC pathogenesis could help to develop a new treatment for BTC patients although the molecular mechanism of the three markers associated with prognosis of BTC remains to be determined.
In regard to EGFR, it was enhanced in human cholangiocarcinoma, the activation of EGFR by bile acids can induce cox-2 expression via mitogen-activated protein Kinase (MAPK) cascade that may play a role in the progression of cholangiocarcinoma. The activation of EGFR also activates other transduction pathways, such as Ras/Ras/MAPK and Akt/mammalian target of rapamycin, that can influence cell proliferation, motility, and apoptosis., Inhibition of EGFR pathway leads to suppression of tumor growth, inhibition of angiogenesis, and induction of antimetastatic apoptosis properties in cholangiocarcinoma., In addition, EGF/EGFR axis contributes to the progression of cholangiocarcinoma through the induction of an epithelial-mesenchymal transition. Hepatic myofibroblasts promote the progression of human cholangiocarcinoma through activation of EGFR. c-MET, combined with HGF, regulates VEGF and heparanase expression via PI3K/Akt/MAPK/STAT3 and PI3K/Akt/NF-Kβ signaling pathways for cancer metastasis and growth., This c-MET/HGF pathway plays an important role in cancer invasion. HER-2 regulates cancer cell proliferation, increases metastatic potential, and affects adhesion or invasion of the cancer cell.
Several limitations of this study should be mentioned. First, limited numbers of available articles and the data quality. Although we have searched most pertinent articles in four different databases, the number of eligible studies in this meta-analysis is still limited due to the rarity of BTC. In some literature, the selected study period, the retrieved publications, and blinding design were not described precisely. In addition, some articles were a retrospective study. Therefore, the present results concerning the prognostic role of the three markers in BTC need to be further confirmed by high-quality studies. Second, heterogeneity among some of these studies was relatively large, which might be caused by baseline characteristics of the patients, such as age, different counties, histological type of cancer, adjuvant treatment, the duration of follow-up, and adjustments for other factors. Third, the location of the BTC was not taken into account, which may influence the accuracy of results. Fourth, if these statistics were not reported by the authors, we extrapolated them from the survival curves, necessarily making assumptions about the censoring process which introduced an element of decreased reliability. Moreover, the detection method of biomarkers should be further optimized. All the studies in our meta-analysis relied on IHC to assess HER-2, EGFR, and c-MET expression due to its convenience. However, IHC is a semiquantitative method, which can be easily influenced by the subjective perceptions of the pathologist. The various primary antibodies used and the experimental designs may also lead to inconsistency. In addition, the cutoff for determining the three makers high expression differed widely among studies, from 0% to 50%, and there is no widely accepted scoring system to evaluate EGFR, HER-2, and c-MET expression of BTC. Given all these limitations, an objective gold standard in determining the three markers high expression is expected. Even though, the relationship between EGFR overexpression and its mutations is still obscure and often leads to false-overexpression results.
Given that TKGFRs play major roles in biliary tract carcinogenesis in animal models,, HER-2, EGFR, and c-MET, as the representatives of TKGFRs, may play important roles in biliary tract carcinogenesis as well. To better understand and use HER-2, EGFR, and c-MET as biomarkers in the clinical, further research with standardized, unbiased methods, and large worldwide sample sizes are required. Targeting c-MET in BTC may be a new therapeutic strategy in future.
| > Conclusion|| |
The evidence from the meta-analysis indicated that HER-2, EGFR, and c-MET high expression were relatively associated with worse OS of BTC although it needs to be considered with caution due to the limitations as we described.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Lepage C, Cottet V, Chauvenet M, Phelip JM, Bedenne L, Faivre J, et al.
Trends in the incidence and management of biliary tract cancer: A French population-based study. J Hepatol 2011;54:306-10.
Patel T. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2002;2:10.
Taylor-Robinson SD, Toledano MB, Arora S, Keegan TJ, Hargreaves S, Beck A, et al.
Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968-1998. Gut 2001;48:816-20.
Akiyama T, Sudo C, Ogawara H, Toyoshima K, Yamamoto T. The product of the human c-erbB-2 gene: A 185-kilodalton glycoprotein with tyrosine kinase activity. Science 1986;232:1644-6.
Yamamoto T, Ikawa S, Akiyama T, Semba K, Nomura N, Miyajima N, et al.
Similarity of protein encoded by the human c-erb-B-2 gene to epidermal growth factor receptor. Nature 1986;319:230-4.
Vigna E, Naldini L, Tamagnone L, Longati P, Bardelli A, Maina F, et al.
Hepatocyte growth factor and its receptor, the tyrosine kinase encoded by the c-MET proto-oncogene. Cell Mol Biol (Noisy-le-grand) 1994;40:597-604.
Xie SD, Xu CY, Shen JG, Jiang ZN, Shen JY, Wang LB. HER 2/neu protein expression in gastric cancer is associated with poor survival. Mol Med Rep 2009;2:943-6.
Guo T, Yang J, Yao J, Zhang Y, Da M, Duan Y. Expression of MACC1 and c-Met in human gastric cancer and its clinical significance. Cancer Cell Int 2013;13:121.
Schillaci R, Guzmán P, Cayrol F, Beguelin W, Díaz Flaqué MC, Proietti CJ, et al.
Clinical relevance of ErbB-2/HER2 nuclear expression in breast cancer. BMC Cancer 2012;12:74.
Li F, Liu Y, Chen H, Liao D, Shen Y, Xu F, et al.
EGFR and COX-2 protein expression in non-small cell lung cancer and the correlation with clinical features. J Exp Clin Cancer Res 2011;30:27.
Harder J, Waiz O, Otto F, Geissler M, Olschewski M, Weinhold B, et al.
EGFR and HER2 expression in advanced biliary tract cancer. World J Gastroenterol 2009;15:4511-7.
Yoshikawa D, Ojima H, Iwasaki M, Hiraoka N, Kosuge T, Kasai S, et al.
Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer 2008;98:418-25.
Zheng J, Zhu YM. Expression of c-erbB-2 proto-oncogene in extrahepatic cholangiocarcinoma and its clinical significance. Hepatobiliary Pancreat Dis Int 2007;6:412-5.
Joo HH, Song EY, Jin SH, Oh SH, Choi YK. Expressions and clinical significances of c-met, c-erbB-2, COX-2, and IL-6 in the biliary tract cancers. Korean J Gastroenterol 2007;50:370-8.
Tong SX, Wu MH. Expression and significance of estrogen, progesterone receptor and C-erbB-2 in primary gallbladder carcinoma. Fudan Univ J Med Sci 2002;2:116-8.
Wang YB, Zhou NX, Wang DJ, Huang ZQ. Expression and significance of p16, nm23H1 and C-erbB-2 gene in cholangiocarcinoma. Chin J Gen Surg 2001;8:46-8.
Niu AH, Wang Z, Hou GY. Expression and clinical significance of c-erbB-2, p53 and nm23H1 protein in bile duct carcinoma. Shandong Med J 2009;35:40-2.
Wang P, He Y, Ma XD, Sun BW, Huang YB, Zhu CH, et al
. The clinical significance of erbB family protein expression in intrahepatic cholangiocarcinoma with stones. J Nanjing Med Univ 2016;4:466-9.
Shafizadeh N, Grenert JP, Sahai V, Kakar S. Epidermal growth factor receptor and HER-2/neu status by immunohistochemistry and fluorescence in situ
hybridization in adenocarcinomas of the biliary tree and gallbladder. Hum Pathol 2010;41:485-92.
Huang F, Chen RF, Zhou QB, Li HG. Expression and significance of NF- kappa B and EGFR in intrahepatic bile duct stones with intrahepatic bile duct carcinoma. Chin J Bases Clin Gen Surg 2010;11:1158-63.
Zhou YM, LI YM, Cao N. Expression and significance of nm23H1 and EGFR gene in bile duct carcinoma. Chin J Curr Adv Gen Surg 2002;3:172-3.
Kim HJ, Yoo TW, Park DI, Park JH, Cho YK, Sohn CI, et al.
Gene amplification and protein overexpression of HER-2/neu in human extrahepatic cholangiocarcinoma as detected by chromogenic in situ
hybridization and immunohistochemistry: Its prognostic implication in node-positive patients. Ann Oncol 2007;18:892-7.
Chaube A, Tewari M, Garbyal RS, Singh U, Shukla HS. Preliminary study of p53 and c-erbB-2 expression in gallbladder cancer in Indian patients. BMC Cancer 2006;6:126.
Nakazawa K, Dobashi Y, Suzuki S, Fujii H, Takeda Y, Ooi A. Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers. J Pathol 2005;206:356-65.
Gu HP, Zhou CL, Shang PZ. Expression and correlation of CD15 and c-erbB-2 in gallbladder carcinoma. J Hepatobiliary Surg 2000;1:20-1.
Wu JH, Zhang QH, Wang L, Cai R. Expression and significance of c-erbB-2 and nm23H_1 gene products in gallbladder carcinoma. Chin J Hepatobiliary Surg 2001;2:23-5.
Lee HJ, Chung JY, Hewitt SM, Yu E, Hong SM. HER3 overexpression is a prognostic indicator of extrahepatic cholangiocarcinoma. Virchows Arch 2012;461:521-30.
Ogo Y, Nio Y, Yano S, Toga T, Koike M, Hashimoto K, et al.
Immunohistochemical expression of HER-1 and HER-2 in extrahepatic biliary carcinoma. Anticancer Res 2006;26:763-70.
Roa I, de Toro G, Schalper K, de Aretxabala X, Churi C, Javle M. Overexpression of the HER2/neu gene: A new therapeutic possibility for patients with advanced gallbladder cancer. Gastrointest Cancer Res 2014;7:42-8.
Kumari N, Kapoor VK, Krishnani N, Kumar K, Baitha DK. Role of C-erbB2 expression in gallbladder cancer. Indian J Pathol Microbiol 2012;55:75-9. [Full text]
Doval DC, Azam S, Sinha R, Batra U, Mehta A. Expression of epidermal growth factor receptor, p53, Bcl2, vascular endothelial growth factor, cyclooxygenase-2, cyclin D1, human epidermal receptor-2 and Ki-67: Association with clinicopathological profiles and outcomes in gallbladder carcinoma. J Carcinog 2014;13:10.
] [Full text]
Sergeant G, Lerut E, Ectors N, Hendrickx T, Aerts R, Topal B. The prognostic relevance of tumor hypoxia markers in resected carcinoma of the gallbladder. Eur J Surg Oncol 2011;37:80-6.
Aishima SI, Taguchi KI, Sugimachi K, Shimada M, Sugimachi K, Tsuneyoshi M. c-erbB-2 and c-Met expression relates to cholangiocarcinogenesis and progression of intrahepatic cholangiocarcinoma. Histopathology 2002;40:269-78.
Wang J, Zhao YJ, Cui GB, Shang PZ. The clinical significance of HGF and C-Met protein expression in cholangiocarcinoma. Chongqing Med 2016;17:2362-4.
Miyamoto M, Ojima H, Iwasaki M, Shimizu H, Kokubu A, Hiraoka N, et al.
Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma. Br J Cancer 2011;105:131-8.
Huang XY, Ke AW, Shi GM, Ding ZB, Devbhandari RP, Gu FM, et al.
Overexpression of CD151 as an adverse marker for intrahepatic cholangiocarcinoma patients. Cancer 2010;116:5440-51.
Lu MS, Wang DY, Zhang YT, Zhang QW. Study on the relationship between c-Met and intrahepatic bile duct cancer with the gallstone. Chin J Curr Adv Gen Surg 2013;4:290-2.
Wu J. Expression of c-MET and hypoxia-inducible-factor-1a in cholangiocarcinoma. Cent S Univ 2014.
Mao ZY, Zhu GQ, Ren L, Guo XC, Su D, Bai L. Prognostic value of C-met expression in cholangiocarcinoma. Technol Cancer Res Treat 2016;15:227-33.
Choi HJ, Kim HJ, Choi JH. Expression of c-erbB-2 and cyclooxygenase-2 in intrahepatic cholangiocarcinoma. Hepatogastroenterology 2009;56:606-9.
Gu MJ, Choi JH. Clinicopathological significance of E-cadherin, ß-catenin and epidermal growth factor receptor expression in intrahepatic cholangiocarcinoma. Hepatogastroenterology 2012;59:1241-4.
Pais-Costa SR, Farah JF, Artigiani-Neto R, Martins SJ, Goldenberg A. Evaluation of P53, E-cadherin, Cox-2, and EGFR protein immunoexpression on prognostic of resected gallbladder carcinoma. Arq Bras Cir Dig 2014;27:126-32.
Hayes DF, Isaacs C, Stearns V. Prognostic factors in breast cancer: Current and new predictors of metastasis. J Mammary Gland Biol Neoplasia 2001;6:375-92.
Ahmad M, Attoub S, Singh MN, Martin FL, El-Agnaf OM. Gamma-synuclein and the progression of cancer. FASEB J 2007;21:3419-30.
Mann CD, Neal CP, Garcea G, Manson MM, Dennison AR, Berry DP. Prognostic molecular markers in hepatocellular carcinoma: A systematic review. Eur J Cancer 2007;43:979-92.
Yoon JH, Gwak GY, Lee HS, Bronk SF, Werneburg NW, Gores GJ. Enhanced epidermal growth factor receptor activation in human cholangiocarcinoma cells. J Hepatol 2004;41:808-14.
Yoon JH, Higuchi H, Werneburg NW, Kaufmann SH, Gores GJ. Bile acids induce cyclooxygenase-2 expression via the epidermal growth factor receptor in a human cholangiocarcinoma cell line. Gastroenterology 2002;122:985-93.
Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW. Epidermal growth factor receptor: Mechanisms of activation and signalling. Exp Cell Res 2003;284:31-53.
Kari C, Chan TO, Rocha de Quadros M, Rodeck U. Targeting the epidermal growth factor receptor in cancer: Apoptosis takes center stage. Cancer Res 2003;63:1-5.
Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 2002;20 18 Suppl: 1S-13S.
Wiedmann M, Feisthammel J, Blüthner T, Tannapfel A, Kamenz T, Kluge A, et al.
Novel targeted approaches to treating biliary tract cancer: The dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib. Anticancer Drugs 2006;17:783-95.
Clapéron A, Mergey M, Nguyen Ho-Bouldoires TH, Vignjevic D, Wendum D, Chrétien Y, et al.
EGF/EGFR axis contributes to the progression of cholangiocarcinoma through the induction of an epithelial-mesenchymal transition. J Hepatol 2014;61:325-32.
Claperon A, Mergey M, Aoudjehane L, Thanh HN, Wendum D, Prignon A, et al
. Hepatic myofibroblasts promote the progression of human cholangiocarcinoma through activation of epidermal growth factor receptor. Hepatology 2014;60:770.
Hao NB, Tang B, Wang GZ, Xie R, Hu CJ, Wang SM, et al.
Hepatocyte growth factor (HGF) upregulates heparanase expression via the PI3K/Akt/NF-κB signaling pathway for gastric cancer metastasis. Cancer Lett 2015;361:57-66.
Matsumura A, Kubota T, Taiyoh H, Fujiwara H, Okamoto K, Ichikawa D, et al.
HGF regulates VEGF expression via the c-Met receptor downstream pathways, PI3K/Akt, MAPK and STAT3, in CT26 murine cells. Int J Oncol 2013;42:535-42.
Leelawat K, Leelawat S, Tepaksorn P, Rattanasinganchan P, Leungchaweng A, Tohtong R, et al.
Involvement of c-Met/hepatocyte growth factor pathway in cholangiocarcinoma cell invasion and its therapeutic inhibition with small interfering RNA specific for c-Met. J Surg Res 2006;136:78-84.
Wang W, Tu Y, Wang S, Xu S, Xu L, Xiong Y, et al.
Role of HER-2 activity in the regulation of malignant meningioma cell proliferation and motility. Mol Med Rep 2015;12:3575-82.
Tome-Garcia J, Li D, Ghazaryan S, Shu L, Wu L. ERBB2 increases metastatic potentials specifically in androgen-insensitive prostate cancer cells. PLoS One 2014;9:e99525.
Jeon M, Lee J, Nam SJ, Shin I, Lee JE, Kim S. Induction of fibronectin by HER2 overexpression triggers adhesion and invasion of breast cancer cells. Exp Cell Res 2015;333:116-26.
Radaeva S, Ferreira-Gonzalez A, Sirica AE. Overexpression of C-NEU and C-MET during rat liver cholangiocarcinogenesis: A link between biliary intestinal metaplasia and mucin-producing cholangiocarcinoma. Hepatology 1999;29:1453-62.
Kiguchi K, Carbajal S, Chan K, Beltrán L, Ruffino L, Shen J, et al.
Constitutive expression of ErbB-2 in gallbladder epithelium results in development of adenocarcinoma. Cancer Res 2001;61:6971-6.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4]