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ORIGINAL ARTICLE
CD44v6 expression is associated with a poor prognosis in Chinese hepatocellular carcinoma patients: A meta-analysis Yong Fu a,1, Ying Geng b,1, Ning Yang c, Nan Zhu c, Chang-Zheng Wang c, Xin-Cheng Su c, Hai-Bin Zhang c,∗ a
Hepatobiliary Surgery Department, Tianyou Hospital, Tongji University, 200311 Shanghai, PR China Tongji Hospital Affiliated to Tongji University, 200065 Shanghai, PR China c Fifth Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, PR China b
Summary Background: The role of CD44v6 in hepatocellular carcinoma (HCC) remains controversial. To clarify the association of CD44v6 with survival in HCC, we performed a meta-analysis of the literature with meta-analysis. Methods: Trials were selected for further analysis if they provided an independent assessment of CD44v6 in HCC and reported the survival data in the context of CD44v6 status. Sensitivity analyses were conducted using the patient’s disease stage, IHC cut-off value, and ethnicity. Results: A total of nine trials, which comprised 942 patients, were included in the metaanalysis. The combined hazard ratio (HR) of 2.13 [95% CI, 1.58—2.88; test for heterogeneity P = 0.061] suggests that high CD44v6 expression has an impact on patient survival. When the studies were restricted to Chinese patients, high levels of CD44v6 expression were correlated with reduced survival (HR 2.27, 95% CI = 1.79—2.86; P = 0.544 for heterogeneity). In addition, the heterogeneity disappeared when the analysis was restricted to Chinese. Conclusion: CD44v6 expression is associated with poor prognosis for Chinese HCC patients. © 2015 Elsevier Masson SAS. All rights reserved.
Introduction ∗
Corresponding author. Fifth Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, PR China. Tel.:/fax: +86 2181 875292. E-mail address: twj [email protected] (H.-B. Zhang). 1 First coauthors.
Hepatocellular carcinoma (HCC) is a common and rapidly fatal cancer ranking third among the leading causes of cancer-related deaths [1]. It is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths [2,3]. The assessment of prognosis is an important factor affecting the selection of an appropriate treatment
http://dx.doi.org/10.1016/j.clinre.2015.03.001 2210-7401/© 2015 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Fu Y, et al. CD44v6 expression is associated with a poor prognosis in Chinese hepatocellular carcinoma patients: A meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.03.001
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regimen for each HCC patient. The variables that are associated with prognosis can be grouped into the following categories: tumor related, such as the primary site, cell type, and extent of disease; patient related, such as sex, comorbidity, and performance status; and environmental factors, such as nutrition and the choice of treatment [4]. Many predictive and prognostic markers have been assessed in HCC [5—7]. CD44 is a multi-structural and multi-functional transmembrane glycoprotein, and it was initially characterized as a receptor for hyaluronan and lymphocytehoming receptor [8]. In 1990s, it was found that the CD44 variant exon 6 (CD44v6) was the chief variant isoform to regulate tumor invasion, progression, and metastasis [9]. It has been reported that CD44v6 can contribute to both PI3K/Akt and MAPK activation, which can regulate the extracellular matrix, promote cell motility, and suppress cancer apoptosis [10,11]. The effects of CD44v6 expression in prognosis of cancer have been investigated [12—14]. The prognostic value of CD44v6 expression in patients with HCC has been evaluated in many studies, but the results are controversial. Therefore, we performed a meta-analysis of published studies to quantitatively review the effect of elevated CD44v6 expression in tumor tissue on the survival of patients with HCC.
Methods Publication search The PubMed, Embase, Web of Science, and CNKI (China National Knowledge Infrastructure) electronic databases were used to search for the studies. The terms used to search these databases were ‘‘CD44v6’’, and ‘‘hepatocellular carcinoma’’. The most recent research included was from before October 31, 2014, but we did not apply a limit on how far in the past the research had been published. The published studies that were eligible for inclusion in this meta-analysis met the following criteria: • measured CD44v6 expression in HCC tissue rather than in other specimens, using immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), or reverse transcription-polymerase chain reaction (RT-PCR);
Table 1
• provided information on patient survival. Studies that did not meet the inclusion criteria were excluded from this analysis.
Data extraction The key characteristics of each study, such as the authors, year of publication, country in which the research was conducted, ethnic group of the study population, number of patients, and cut-off value of CD44v6, were noted.
Statistical analysis Survival outcome data were synthesized using the timeto-event HR (a benefit of survival would be represented by an HR < 1). When HR values were not provided in a paper, the data were extracted from the relevant KaplanMeier curves to calculate HR values [15]. To account for the inherent heterogeneity between the included studies, we assumed the presence of statistical heterogeneity and used a random effects model before pooling the data. The random-effects model incorporates the variability of the results among trials and provides a more conservative estimate of the effect size by increasing the confidence intervals (CIs) [16]. Heterogeneity between the studies was tested using Q-statistics. Heterogeneity was considered statistically significant at P < 0.10. Funnel plot asymmetry was assessed using the Egger’s linear regression test, and the significance of the intercept was determined by the Egger’s t-test (P < 0.05 indicated a statistically significant publication bias). All calculations were performed using STATA 10.0.
Results Study characteristics Nine of the studies identified met the inclusion criteria. They were published between 2000 and 2013, and 942 patients were included in the pooled analysis [17—25]. Table 1 lists the identified studies and their main characteristics. Within these studies, the sample sizes ranged from 50 to 323 patients. Immunohistochemistry (IHC) was used to determine the CD44v6 expression status in all of the
Characteristic of the studies included in the meta-analysis for the interaction between CD44v6 levels and HCs.
First author, year of publication
Country
Patient Ethnicity
Number of patients
Deng, 2011 Deng, 2012 Endo, 2000 Huang, 2001 Mima, 2012 Zhang, 2008 Zheng, 2000 Zheng, 2007 Zhou, 2013
China China Japan China Japan China China China China
East East East East East East East East East
78 30 107 51 150 50 66 87 323
Asian Asian Asian Asian Asian Asian Asian Asian Asian
Positive cases n (%) 59 19 36 25 46 15 26 45 162
(75.6) (63.3) (33.6) (49.0) (30.7) (30.0) (39.4) (51.7) (50.2)
Methods
Cut-off (%)
HR (95%CI)
IHC IHC IHC IHC IHC IHC IHC IHC IHC
5 25 1 NR 1 5 5 25 NR
2.30 (1.13—4.61) 3.74 (1.35—10.34) 2.70 (1.50—4.89) 4.35 (1.52—12.39) 1.08 (0.70—1.66) 3.31 (1.33—8.25) 2.35 (1.14—4.83) 1.23 (0.47—3.21) 2.06 (1.51—2.82)
Please cite this article in press as: Fu Y, et al. CD44v6 expression is associated with a poor prognosis in Chinese hepatocellular carcinoma patients: A meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.03.001
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CD44v6 and HCC
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Discussion
Figure 1 Forest plot of the HR. The size of the squares reflects each study’s relative weight and the diamond ( ) represents the aggregate HR and 95% CI.
included studies. Different cut-off values for the CD44v6 expression level were used.
Meta-analysis results The main results of this meta-analysis are summarized in Fig. 1. The overall HR was 2.13 [95% CI 1.58—2.88; test for heterogeneity P = 0.061]. Sensitivity analyses were conducted to evaluate whether modifying the inclusion criteria of this meta-analysis affected the outcome or eliminated heterogeneity. Modifications to the inclusion criteria involved limiting the meta-analysis to studies that included more than 100 patients, a cut-off value ≥ 5%, Chinese patients, and Japanese patients. These results are shown in Table 2. Two chinese researches which did not report the cut-off value were excluded from the subgroup analyses [20,25].
Publication bias The Egger’s test (P = 0.354) and Bgger’s test (P = 0.370) results indicate that the publication bias had insignificant funnel plot asymmetry, which was determined by comparing the HR in all patients.
Table 2
Several studies have indicated that HCC patients with high CD44v6 expression have a worse survival prognosis than those with low CD44v6-expressing tumors. To address the prognosis value of CD44v6 expression, we performed a metaanalysis of previously published studies to derive an overall, pooled assessment of the relationship between CD44v6 expression and patient survival. Based on our results, CD44v6 high expression is a prognostic factor for poor survival in HCC patients. Specifically in Chinese populations, a significant association was found for CD44v6 levels in the prognosis of HCC, which may reveal ethnic-specific differences in the prognostic value of CD44v6 levels. Ethnicity is a valuable prognostic factor in HCC [26,27]. There were only two studies of Japanese patients, and they had conflicting results [19,21]. More studies are necessary to accurately define the impact of CD44v6 among Japanese. CD44 and CD44 variant isoforms are involved in a variety of physiological and pathological processes, including tumor development and progression. In addition, CD44v6 is associated with poor clinical outcome for HCC patients and is significantly related to vascular microvascular invasion [19,25], preoperative c-glutamyl transferase levels and TNM stage [25]. The mechanism of CD44v6 promoting the metastasis of cancer may be attributed to its interactions with various components of the extracellular matrix, and its involvement in cell adhesion and critical signaling pathways. Jung et al. found the CD44v6 could activate the MAPK and the PI3K/Akt pathways, and then the two pathways could activate anti-apoptotic proteins and inactivate proapoptotic proteins [11]. This meta-analysis also has some limitations, and the results should be interpreted with caution. First, due to the lack of relevant information in the original studies, we could not perform subgroup analyses according to the patients’ comorbidity, sex, performance status, and nutrition; thus, it is unclear whether CD44v6 is an independent prognostic factor. Second, heterogeneity is a potential problem when interpreting the results of our meta-analysis. The presence of heterogeneity can result from differences factors. Third, all studies taken into the meta-analysis are based on immunohistochemistry. ISH is very subjective and not a suitable quantification tool. Moreover, use of different cutoff values in different studies makes the evaluation much more difficult and the reliability of the data questionable.
Sensitivity analysis according to the study characteristics. I2 (%)
HR Random effects (95% CI) Total Patient number > 100 Chinese Japanese Cutoff ≥ 5%
2.13 1.78 2.27 1.67 2.39
(1.58—2.88) (1.08—2.94) (1.79—2.86) (0.68—4.09) (1.64—3.47)
46.3 74.7 0 83.4 0
P value Q test
0.061 0.019 0.544 0.014 0.544
Please cite this article in press as: Fu Y, et al. CD44v6 expression is associated with a poor prognosis in Chinese hepatocellular carcinoma patients: A meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.03.001
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Y. Fu et al.
A somewhat more reliable comparison would be to compare tumors with the same histology, same stage and mode of therapy. In conclusion, our results support that CD44v6 is a prognostic factor among Chinese patients with HCC.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgement This study was supported by a grant from Shanghai Municipal Commission of Health and Family Planning (201440445).
References [1] Gandhi S, Khubchandani S, Iyer R. Quality of life and hepatocellular carcinoma. J Gastrointest Oncol 2014;5(4): 296—317. [2] Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55(2):74—108. [3] El-Serag HB, Marrero JA, Rudolph L, Reddy KR. Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology 2008;134(6):1752—63. [4] Gospodarowicz MK, O’Sullivan B, Sobin LH. Prognostic factors in cancer. 3rd ed. New Jersey, USA: Wiley-Liss; 2006. [5] Mínguez B, Lachenmayer A. Diagnostic and prognostic molecular markers in hepatocellular carcinoma. Dis Markers 2011;31(3):181—90. [6] Milazzo M, Fornari F, Gramantieri L. MicroRNA and hepatocellular carcinoma: biology and prognostic significance. Minerva Gastroenterol Dietol 2011;57(3):257—71. [7] Schmidt C, Marsh JW. Molecular signature for HCC: role in predicting outcomes after liver transplant and selection for potential adjuvant treatment. Curr Opin Organ Transplant 2010;15(3):277—82. [8] Naor D, Sionov RV, Ish-Shalom D. CD44: structure, function, and association with the malignant process. Adv Cancer Res 1997;71:241—319. [9] Günthert U, Hofmann M, Rudy W, Reber S, Zöller M, Haussmann I, et al. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell 1991;65(1):13—24. [10] Marhaba R, Bourouba M, Zöller M. CD44v6 promotes proliferation by persisting activation of MAP kinases. Cell Signal 2005;17(8):961—73. [11] Jung T, Gross W, Zöller M. CD44v6 coordinates tumor matrixtriggered motility and apoptosis resistance. J Biol Chem 2011;286(18):15862—74. [12] Jiang H, Zhao W, Shao W. Prognostic value of CD44 and CD44v6 expression in patients with non-small cell lung cancer: metaanalysis. Tumour Biol 2014;35(8):7383—9.
[13] Chen J, Li T, Liu Q, Jiao H, Yang W, Liu X, et al. Clinical and prognostic significance of HIF-1␣, PTEN, CD44v6, and survivin for gastric cancer: a meta-analysis. PLoS One 2014;9(3):e91842. [14] Chai L, Liu H, Zhang Z, Wang F, Wang Q, Zhou S, et al. CD44 expression is predictive of poor prognosis in pharyngolaryngeal cancer: systematic review and meta-analysis. Tohoku J Exp Med 2014;232(1):9—19. [15] Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007;8:16. [16] Berlin JA, Laird NM, Sacks HS, Chalmers TC. A comparison of statistical methods for combining event rates from clinical trials. Stat Med 1989;8:141—51. [17] Deng WJ, Chen D, Qian SK, Lin H, Hu H, Li Q, et al. Study of significancer of E-selectin, sLEX, sLeA and CD44v6 expression in hepatocellular carcinoma. Guangdong Yixue 2011;32(7):891—4 [In Chinese]. [18] Deng B, Fang JQ, Wang HH, Lv Y. Study of significancer of OPN and CD44v6 expression in hepatocellular carcinoma with prognosis if patients underwent liver transplantation. Guoji Xiaohuabing Zazhi 2012;32(3):176—9 [In Chinese]. [19] Endo K, Terada T. Protein expression of CD44 (standard and variant isoforms) in hepatocellular carcinoma: relationships with tumor grade, clinicopathologic parameters, p53 expression, and patient survival. J Hepatol 2000;32(1):78—84. [20] Huang KH, Yuan SZ. Study of significancer of CD44v6 expression in hepatocellular carcinoma. Aizhen 2001;20(2):200—1 [In Chinese]. [21] Mima K, Okabe H, Ishimoto T, Hayashi H, Nakagawa S, Kuroki H, et al. The expression levels of CD44v6 are correlated with the invasiveness of hepatocellular carcinoma in vitro, but do not appear to be clinically significant. Oncol Lett 2012;3(5):1047—51. [22] Zhang KL, Wang ZM, Wei SD, Chen NZ, Li YD, Wei W, et al. Significancer of CD44v6 and c-Met expression in hepatocellular carcinoma. Zhongguo Putongwaike Zazhi 2008;17(1):94—7 [In Chinese]. [23] Zheng JM, Ni CR, Zheng WQ, Zhu MH, Wang Y, Bao JZ, et al. Adhesive molecule expression in relation to invasion and metastas is in human hepatocellular carcinoma. Linchuangyushiyan Binglixue Zazhi 2000;16(5):381—4 [In Chinese]. [24] Zheng WH, Yang WB, Fu CB, Li XR, Yang ZF, Yi JL. Expression of KAI1 protein and its relationship with CD44v6 in HCC. Zhongguo Xiandai Yixue 2007;17(20):2481—4 [In Chinese]. [25] Zhou ZJ, Dai Z, Zhou SL, Fu XT, Zhao YM, Shi YH, et al. Overexpression of HnRNP A1 promotes tumor invasion through regulating CD44v6 and indicates poor prognosis for hepatocellular carcinoma. Int J Cancer 2013;132(5):1080—9. [26] Ly CL, Wong LL. Ethnicity as a predictive factor for hepatocellular carcinoma screening among patients in Hawaii. Ethn Dis 2014;24(3):376—81. [27] Artinyan A, Mailey B, Sanchez-Luege N, Khalili J, Sun CL, Bhatia S, et al. Race, ethnicity, and socioeconomic status influence the survival of patients with hepatocellular carcinoma in the United States. Cancer 2010;116(5):1367—77.
Please cite this article in press as: Fu Y, et al. CD44v6 expression is associated with a poor prognosis in Chinese hepatocellular carcinoma patients: A meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.03.001
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Clinics and Research in Hepatology and Gastroenterology (2015) xxx, xxx—xxx
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ORIGINAL ARTICLE
CD44v6 expression is associated with a poor prognosis in Chinese hepatocellular carcinoma patients: A meta-analysis Yong Fu a,1, Ying Geng b,1, Ning Yang c, Nan Zhu c, Chang-Zheng Wang c, Xin-Cheng Su c, Hai-Bin Zhang c,∗ a
Hepatobiliary Surgery Department, Tianyou Hospital, Tongji University, 200311 Shanghai, PR China Tongji Hospital Affiliated to Tongji University, 200065 Shanghai, PR China c Fifth Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, PR China b
Summary Background: The role of CD44v6 in hepatocellular carcinoma (HCC) remains controversial. To clarify the association of CD44v6 with survival in HCC, we performed a meta-analysis of the literature with meta-analysis. Methods: Trials were selected for further analysis if they provided an independent assessment of CD44v6 in HCC and reported the survival data in the context of CD44v6 status. Sensitivity analyses were conducted using the patient’s disease stage, IHC cut-off value, and ethnicity. Results: A total of nine trials, which comprised 942 patients, were included in the metaanalysis. The combined hazard ratio (HR) of 2.13 [95% CI, 1.58—2.88; test for heterogeneity P = 0.061] suggests that high CD44v6 expression has an impact on patient survival. When the studies were restricted to Chinese patients, high levels of CD44v6 expression were correlated with reduced survival (HR 2.27, 95% CI = 1.79—2.86; P = 0.544 for heterogeneity). In addition, the heterogeneity disappeared when the analysis was restricted to Chinese. Conclusion: CD44v6 expression is associated with poor prognosis for Chinese HCC patients. © 2015 Elsevier Masson SAS. All rights reserved.
Introduction ∗
Corresponding author. Fifth Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 200438 Shanghai, PR China. Tel.:/fax: +86 2181 875292. E-mail address: twj [email protected] (H.-B. Zhang). 1 First coauthors.
Hepatocellular carcinoma (HCC) is a common and rapidly fatal cancer ranking third among the leading causes of cancer-related deaths [1]. It is the fifth most common cancer worldwide and the third leading cause of cancer-related deaths [2,3]. The assessment of prognosis is an important factor affecting the selection of an appropriate treatment
http://dx.doi.org/10.1016/j.clinre.2015.03.001 2210-7401/© 2015 Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Fu Y, et al. CD44v6 expression is associated with a poor prognosis in Chinese hepatocellular carcinoma patients: A meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.03.001
+Model
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Y. Fu et al.
regimen for each HCC patient. The variables that are associated with prognosis can be grouped into the following categories: tumor related, such as the primary site, cell type, and extent of disease; patient related, such as sex, comorbidity, and performance status; and environmental factors, such as nutrition and the choice of treatment [4]. Many predictive and prognostic markers have been assessed in HCC [5—7]. CD44 is a multi-structural and multi-functional transmembrane glycoprotein, and it was initially characterized as a receptor for hyaluronan and lymphocytehoming receptor [8]. In 1990s, it was found that the CD44 variant exon 6 (CD44v6) was the chief variant isoform to regulate tumor invasion, progression, and metastasis [9]. It has been reported that CD44v6 can contribute to both PI3K/Akt and MAPK activation, which can regulate the extracellular matrix, promote cell motility, and suppress cancer apoptosis [10,11]. The effects of CD44v6 expression in prognosis of cancer have been investigated [12—14]. The prognostic value of CD44v6 expression in patients with HCC has been evaluated in many studies, but the results are controversial. Therefore, we performed a meta-analysis of published studies to quantitatively review the effect of elevated CD44v6 expression in tumor tissue on the survival of patients with HCC.
Methods Publication search The PubMed, Embase, Web of Science, and CNKI (China National Knowledge Infrastructure) electronic databases were used to search for the studies. The terms used to search these databases were ‘‘CD44v6’’, and ‘‘hepatocellular carcinoma’’. The most recent research included was from before October 31, 2014, but we did not apply a limit on how far in the past the research had been published. The published studies that were eligible for inclusion in this meta-analysis met the following criteria: • measured CD44v6 expression in HCC tissue rather than in other specimens, using immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), or reverse transcription-polymerase chain reaction (RT-PCR);
Table 1
• provided information on patient survival. Studies that did not meet the inclusion criteria were excluded from this analysis.
Data extraction The key characteristics of each study, such as the authors, year of publication, country in which the research was conducted, ethnic group of the study population, number of patients, and cut-off value of CD44v6, were noted.
Statistical analysis Survival outcome data were synthesized using the timeto-event HR (a benefit of survival would be represented by an HR < 1). When HR values were not provided in a paper, the data were extracted from the relevant KaplanMeier curves to calculate HR values [15]. To account for the inherent heterogeneity between the included studies, we assumed the presence of statistical heterogeneity and used a random effects model before pooling the data. The random-effects model incorporates the variability of the results among trials and provides a more conservative estimate of the effect size by increasing the confidence intervals (CIs) [16]. Heterogeneity between the studies was tested using Q-statistics. Heterogeneity was considered statistically significant at P < 0.10. Funnel plot asymmetry was assessed using the Egger’s linear regression test, and the significance of the intercept was determined by the Egger’s t-test (P < 0.05 indicated a statistically significant publication bias). All calculations were performed using STATA 10.0.
Results Study characteristics Nine of the studies identified met the inclusion criteria. They were published between 2000 and 2013, and 942 patients were included in the pooled analysis [17—25]. Table 1 lists the identified studies and their main characteristics. Within these studies, the sample sizes ranged from 50 to 323 patients. Immunohistochemistry (IHC) was used to determine the CD44v6 expression status in all of the
Characteristic of the studies included in the meta-analysis for the interaction between CD44v6 levels and HCs.
First author, year of publication
Country
Patient Ethnicity
Number of patients
Deng, 2011 Deng, 2012 Endo, 2000 Huang, 2001 Mima, 2012 Zhang, 2008 Zheng, 2000 Zheng, 2007 Zhou, 2013
China China Japan China Japan China China China China
East East East East East East East East East
78 30 107 51 150 50 66 87 323
Asian Asian Asian Asian Asian Asian Asian Asian Asian
Positive cases n (%) 59 19 36 25 46 15 26 45 162
(75.6) (63.3) (33.6) (49.0) (30.7) (30.0) (39.4) (51.7) (50.2)
Methods
Cut-off (%)
HR (95%CI)
IHC IHC IHC IHC IHC IHC IHC IHC IHC
5 25 1 NR 1 5 5 25 NR
2.30 (1.13—4.61) 3.74 (1.35—10.34) 2.70 (1.50—4.89) 4.35 (1.52—12.39) 1.08 (0.70—1.66) 3.31 (1.33—8.25) 2.35 (1.14—4.83) 1.23 (0.47—3.21) 2.06 (1.51—2.82)
Please cite this article in press as: Fu Y, et al. CD44v6 expression is associated with a poor prognosis in Chinese hepatocellular carcinoma patients: A meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.03.001
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CD44v6 and HCC
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Discussion
Figure 1 Forest plot of the HR. The size of the squares reflects each study’s relative weight and the diamond ( ) represents the aggregate HR and 95% CI.
included studies. Different cut-off values for the CD44v6 expression level were used.
Meta-analysis results The main results of this meta-analysis are summarized in Fig. 1. The overall HR was 2.13 [95% CI 1.58—2.88; test for heterogeneity P = 0.061]. Sensitivity analyses were conducted to evaluate whether modifying the inclusion criteria of this meta-analysis affected the outcome or eliminated heterogeneity. Modifications to the inclusion criteria involved limiting the meta-analysis to studies that included more than 100 patients, a cut-off value ≥ 5%, Chinese patients, and Japanese patients. These results are shown in Table 2. Two chinese researches which did not report the cut-off value were excluded from the subgroup analyses [20,25].
Publication bias The Egger’s test (P = 0.354) and Bgger’s test (P = 0.370) results indicate that the publication bias had insignificant funnel plot asymmetry, which was determined by comparing the HR in all patients.
Table 2
Several studies have indicated that HCC patients with high CD44v6 expression have a worse survival prognosis than those with low CD44v6-expressing tumors. To address the prognosis value of CD44v6 expression, we performed a metaanalysis of previously published studies to derive an overall, pooled assessment of the relationship between CD44v6 expression and patient survival. Based on our results, CD44v6 high expression is a prognostic factor for poor survival in HCC patients. Specifically in Chinese populations, a significant association was found for CD44v6 levels in the prognosis of HCC, which may reveal ethnic-specific differences in the prognostic value of CD44v6 levels. Ethnicity is a valuable prognostic factor in HCC [26,27]. There were only two studies of Japanese patients, and they had conflicting results [19,21]. More studies are necessary to accurately define the impact of CD44v6 among Japanese. CD44 and CD44 variant isoforms are involved in a variety of physiological and pathological processes, including tumor development and progression. In addition, CD44v6 is associated with poor clinical outcome for HCC patients and is significantly related to vascular microvascular invasion [19,25], preoperative c-glutamyl transferase levels and TNM stage [25]. The mechanism of CD44v6 promoting the metastasis of cancer may be attributed to its interactions with various components of the extracellular matrix, and its involvement in cell adhesion and critical signaling pathways. Jung et al. found the CD44v6 could activate the MAPK and the PI3K/Akt pathways, and then the two pathways could activate anti-apoptotic proteins and inactivate proapoptotic proteins [11]. This meta-analysis also has some limitations, and the results should be interpreted with caution. First, due to the lack of relevant information in the original studies, we could not perform subgroup analyses according to the patients’ comorbidity, sex, performance status, and nutrition; thus, it is unclear whether CD44v6 is an independent prognostic factor. Second, heterogeneity is a potential problem when interpreting the results of our meta-analysis. The presence of heterogeneity can result from differences factors. Third, all studies taken into the meta-analysis are based on immunohistochemistry. ISH is very subjective and not a suitable quantification tool. Moreover, use of different cutoff values in different studies makes the evaluation much more difficult and the reliability of the data questionable.
Sensitivity analysis according to the study characteristics. I2 (%)
HR Random effects (95% CI) Total Patient number > 100 Chinese Japanese Cutoff ≥ 5%
2.13 1.78 2.27 1.67 2.39
(1.58—2.88) (1.08—2.94) (1.79—2.86) (0.68—4.09) (1.64—3.47)
46.3 74.7 0 83.4 0
P value Q test
0.061 0.019 0.544 0.014 0.544
Please cite this article in press as: Fu Y, et al. CD44v6 expression is associated with a poor prognosis in Chinese hepatocellular carcinoma patients: A meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.03.001
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Y. Fu et al.
A somewhat more reliable comparison would be to compare tumors with the same histology, same stage and mode of therapy. In conclusion, our results support that CD44v6 is a prognostic factor among Chinese patients with HCC.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgement This study was supported by a grant from Shanghai Municipal Commission of Health and Family Planning (201440445).
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Please cite this article in press as: Fu Y, et al. CD44v6 expression is associated with a poor prognosis in Chinese hepatocellular carcinoma patients: A meta-analysis. Clin Res Hepatol Gastroenterol (2015), http://dx.doi.org/10.1016/j.clinre.2015.03.001
