Abstract
Purpose
To investigate the expression and clinical significance of CADM2 in hepatocellular carcinomas (HCC).
Methods
The level of expression of CADM2 mRNA was assessed in frozen tumor specimens and adjacent noncancerous tissues from 30 HCC patients by real-time PCR. The protein level was determined by immunohistochemistry on a tissue microarray containing tumor and adjacent noncancerous tissues from 234 HCC patients. Clinicopathological characteristics associated analysis was performed through SPSS18 .
Results
CADM2 was strikingly down regulated in HCC. CADM2 expression was associated with differentiation (P = 0.000), serum alpha-fetoprotein (P = 0.003), vascular invasion (P = 0.001), and hepatitis B surface antigen (HBsAg, P = 0.038). Furthermore, patients with low CADM2 expression had significantly poorer recurrence-free survival (RFS) (40.8 and 34.2 % vs. 56.3 and 50.1 % in 3- and 5-year RFS, respectively, P = 0.005). Subgroup analysis revealed that the difference in RFS between groups with low- and high-CADM2 expression still existed among patients belonging to stage 0 or A of BCLC staging system (P = 0.008), patients with tumor ≤5 cm in size (P = 0.013), and alpha-fetoprotein-negative patients (P = 0.003). Moreover, low expression was more frequently observed in the early recurrence group (within 2 years, P = 0.007). Further multivariate Cox regression analysis indicated that CADM2 expression level, tumor size, tumor number, vascular invasion, HBsAg were independent risk factors for HCC recurrence.
Conclusion
CADM2 serves as a novel predictor of RFS in HCC patients after curative resection.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Chang G, Xu S, Dhir R et al (2010) Hypoexpression and epigenetic regulation of candidate tumor suppressor gene CADM-2 in human prostate cancer. Clin Cancer Res 16:5390–5401. doi:10.1158/1078-0432.ccr-10-1461
Edmondson HA, Steiner PE (1954) Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer 7:462–503
El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132:2557–2576. doi:10.1053/j.gastro.2007.04.061
Faraji F, Pang Y, Walker RC et al (2012) Cadm1 is a metastasis susceptibility gene that suppresses metastasis by modifying tumor interaction with the cell-mediated immunity. PLoS Genet 8:e1002926. doi:10.1371/journal.pgen.1002926
Ferlay J, Shin HR, Bray F et al (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127:2893–2917. doi:10.1002/ijc.25516
Fong Y, Sun RL, Jarnagin W et al (1999) An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg 229:790–799 (discussion 799–800)
Fukuhara H, Kuramochi M, Fukami T et al (2002) Promoter methylation of TSLC1 and tumor suppression by its gene product in human prostate cancer. Jpn J Cancer Res 93:605–609
Grazi GL, Ercolani G, Pierangeli F et al (2001) Improved results of liver resection for hepatocellular carcinoma on cirrhosis give the procedure added value. Ann Surg 234:71–78
Hoshida Y, Villanueva A, Kobayashi M et al (2008) Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med 359:1995–2004. doi:10.1056/NEJMoa0804525
Hu J, Xu Y, Shen ZZ et al (2009) High expressions of vascular endothelial growth factor and platelet-derived endothelial cell growth factor predict poor prognosis in alpha-fetoprotein-negative hepatocellular carcinoma patients after curative resection. J Cancer Res Clin Oncol 135:1359–1367. doi:10.1007/s00432-009-0577-5
Huang G, Yang Y, Shen F et al (2013) Early viral suppression predicts good postoperative survivals in patients with hepatocellular carcinoma with a high baseline HBV-DNA load. Ann Surg Oncol 20:1482–1490. doi:10.1245/s10434-012-2803-7
Imamura H, Matsuyama Y, Tanaka E et al (2003) Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol 38:200–207
Ito T, Shimada Y, Hashimoto Y et al (2003) Involvement of TSLC1 in progression of esophageal squamous cell carcinoma. Cancer Res 63:6320–6326
Ju MJ, Qiu SJ, Gao Q et al (2009) Combination of peritumoral mast cells and T-regulatory cells predicts prognosis of hepatocellular carcinoma. Cancer Sci 100:1267–1274. doi:10.1111/j.1349-7006.2009.01182.x
Kuramochi M, Fukuhara H, Nobukuni T et al (2001) TSLC1 is a tumor-suppressor gene in human non-small-cell lung cancer. Nat Genet 27:427–430. doi:10.1038/86934
Li D, Mallory T, Satomura S (2001) AFP-L3: a new generation of tumor marker for hepatocellular carcinoma. Clin Chim Acta 313:15–19
Llovet JM, Bru C, Bruix J (1999) Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 19:329–338. doi:10.1055/s-2007-1007122
Mann CD, Neal CP, Garcea G et al (2007) Prognostic molecular markers in hepatocellular carcinoma: a systematic review. Eur J Cancer 43:979–992. doi:10.1016/j.ejca.2007.01.004
Murakami Y (2005) Involvement of a cell adhesion molecule, TSLC1/IGSF4, in human oncogenesis. Cancer Sci 96:543–552. doi:10.1111/j.1349-7006.2005.00089.x
Nagata M, Sakurai-Yageta M, Yamada D et al (2012) Aberrations of a cell adhesion molecule CADM4 in renal clear cell carcinoma. Int J Cancer 130:1329–1337. doi:10.1002/ijc.26160
Raveh S, Gavert N, Spiegel I et al (2009) The cell adhesion nectin-like molecules (Necl) 1 and 4 suppress the growth and tumorigenic ability of colon cancer cells. J Cell Biochem 108:326–336. doi:10.1002/jcb.22258
Shiraki K, Takase K, Tameda Y et al (1995) A clinical study of lectin-reactive alpha-fetoprotein as an early indicator of hepatocellular carcinoma in the follow-up of cirrhotic patients. Hepatology 22:802–807
Takahashi Y, Iwai M, Kawai T et al (2012) Aberrant expression of tumor suppressors CADM1 and 4.1B in invasive lesions of primary breast cancer. Breast Cancer 19:242–252. doi:10.1007/s12282-011-0272-7
Takai Y, Irie K, Shimizu K et al (2003) Nectins and nectin-like molecules: roles in cell adhesion, migration, and polarization. Cancer Sci 94:655–667
Takayama T (2011) Surgical treatment for hepatocellular carcinoma. Jpn J Clin Oncol 41:447–454. doi:10.1093/jjco/hyr016
Tsukuma H, Hiyama T, Tanaka S et al (1993) Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 328:1797–1801. doi:10.1056/nejm199306243282501
Williams YN, Masuda M, Sakurai-Yageta M et al (2006) Cell adhesion and prostate tumor-suppressor activity of TSLL2/IGSF4C, an immunoglobulin superfamily molecule homologous to TSLC1/IGSF4. Oncogene 25:1446–1453. doi:10.1038/sj.onc.1209192
Wu CY, Chen YJ, Ho HJ et al (2012) Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection. JAMA 308:1906–1914
Acknowledgments
This study was supported by the Chinese Key Project for Infectious Diseases (2012ZX10002010, 2012ZX10002016), the Science Fund for Creative Research Groups, National Natural Science Foundation of China (NSFC; Grant No.: 81221061), and NFSC (Grant Nos.: 81071681, 81171935, 81201940). We thank Yang Yun in our department for genechip information support.
Conflict of interest
We certify that no actual or potential conflict of interest in relation to this article exists.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Sen Yang, Hong-Li Yan, and Qi-Fei Tao have contributed equally to this study.
Electronic supplementary material
Below is the link to the electronic supplementary material.
432_2013_1536_MOESM1_ESM.tif
Fig. S1 Representative immunohistochemistry pictures of respective semiquantitative score. a/b/c/d/e are representative immunohistochemistry pictures with score 0/1/2/3/4, respectively. The magnification is ×100. a/b are from tumor tissues, and c/d/e are from adjacent noncancerous tissues. (TIFF 4414 kb)
Rights and permissions
About this article
Cite this article
Yang, S., Yan, HL., Tao, QF. et al. Low CADM2 expression predicts high recurrence risk of hepatocellular carcinoma patients after hepatectomy. J Cancer Res Clin Oncol 140, 109–116 (2014). https://doi.org/10.1007/s00432-013-1536-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-013-1536-8