Cytohesin-2 as a novel prognostic marker for hepatocellular carcinoma

Xu,Kedong; Gao,Jie; Yang,Xue; Yao,Yingmin; Liu,Qingguang

doi:10.3892/or.2013.2366

Cytohesin-2 as a novel prognostic marker for hepatocellular carcinoma

Authors:
- Kedong Xu
- Jie Gao
- Xue Yang
- Yingmin Yao
- Qingguang Liu
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, The First Hospital of Xi'an Jiaotong University, College of Medicine, Xi'an, Shaanxi 710061, P.R. China
Published online on: March 26, 2013 https://doi.org/10.3892/or.2013.2366
Pages: 2211-2218

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

Cytohesin-2 is overexpressed in human lung cancer and it activates cytoplasmic ErbB receptors. Inhibition of cytohesin-2 by SecinH3 reduces growth of EGFR-dependent lung cancer xenografts and improves the treatment of primarily EGFR-TKI-resistant lung cancers. Cytohesin-2 promotes HepG2 proliferation through the IGF pathway, and VEGF-dependent initiation of angiogenesis by regulation of VEGFR-2 internalization in endothelial cells, vessel permeability and ultimately endothelial proliferation. The purpose of this study was to evaluate the effects of cytohesin-2 in hepatocellular carcinoma (HCC) . In the current study, we collected 40 HCC tissues and detected cytohesin-2 mRNA expression in the 40 HCC tissues by using quantitative real-time polymerase chain reaction (qRT-PCR), as well as its protein expression by using immunohistochemistry and western blot analysis. We found that cytohesin-2 was more highly expressed in HCC compared to adjacent non-tumorous liver tissues, and cytohesin-2 expression was significantly increased in specimens with high α-fetoprotein and vascular invasion. Both univariate and multivariate analyses indicated that there is an association between cytohesin-2 expression and overall survival (OS) and disease-free survival (DFS). Moreover, stratified analysis showed that patients in tumor-node-metastasis (TNM) stage I with higher cytohesin-2 levels had shorter OS and DFS than those with lower cytohesin-2 levels. In conclusion, cytohesin-2 may identify low-and high-risk individuals with HCC and may be a valuable indicator for stratifying prognosis of TNM stage I patients. Cytohesin-2 may serve as a novel prognostic biomarker for HCC.

View Figures

View References

1	El-Serag HB and Rudolph L: Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 132:2557–2576. 2007. View Article : Google Scholar : PubMed/NCBI
2	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. Ca Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar
3	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. Ca Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
4	Kitisin K, Pishvaian MJ, Johnson LB and Mishra L: Liver stem cells and molecular signaling pathways in hepatocellular carcinoma. Gastrointest Cancer Res. 1(Suppl 2): S13–S21. 2007.PubMed/NCBI
5	Dragani TA: Risk of HCC: Genetic heterogeneity and complex genetics. J Hepatol. 52:252–257. 2010. View Article : Google Scholar : PubMed/NCBI
6	Bill A, Schmitz A, Albertoni B, et al: Cytohesins are cytoplasmic ErbB receptor activators. Cell. 143:201–211. 2010. View Article : Google Scholar : PubMed/NCBI
7	Bos JL, Rehmann H and Wittinghofer A: GEFs and GAPs: Critical elements in the control of small G proteins. Cell. 129:865–877. 2007. View Article : Google Scholar : PubMed/NCBI
8	Casanova JE: Regulation of arf activation: the sec7 family of guanine nucleotide exchange factors. Traffic. 8:1476–1485. 2007. View Article : Google Scholar : PubMed/NCBI
9	Kolanus W: Guanine nucleotide exchange factors of the cytohesin family and their roles in signal transduction. Immunol Rev. 218:102–113. 2007. View Article : Google Scholar : PubMed/NCBI
10	Kolanus W, Nagel W, Schiller B, et al: Alpha L beta 2 integrin/LFA-1 binding to ICAM-1 induced by cytohesin-1, a cytoplasmic regulatory molecule. Cell. 86:233–242. 1996. View Article : Google Scholar : PubMed/NCBI
11	Lim J, Zhou M, Veenstra TD and Morrison DK: The CNK1 scaffold binds cytohesins and promotes insulin pathway signaling. Genes Dev. 24:1496–1506. 2010. View Article : Google Scholar : PubMed/NCBI
12	Thomas M: Molecular targeted therapy for hepatocellular carcinoma. J Gastroenterol. 44:136–141. 2009. View Article : Google Scholar
13	Kannangai R, Sahin F and Torbenson MS: EGFR is phosphorylated at Ty845 in hepatocellular carcinoma. Mod Pathol. 19:1456–1461. 2006.PubMed/NCBI
14	Mannell HK, Pircher J, Chaudhry DI, et al: ARNO regulates VEGF-dependent tissue responses by stabilizing endothelial VEGFR-2 surface expression. Cardiovasc Res. 93:111–119. 2012. View Article : Google Scholar : PubMed/NCBI
15	Shirahata A, Fan W, Sakuraba K, et al: MACC 1 as a marker for vascular invasive hepatocellular carcinoma. Anticancer Res. 31:777–780. 2011.PubMed/NCBI
16	Wang L, Chen S, Zhang M, et al: Legumain: A biomarker for diagnosis and prognosis of human ovarian cancer. J Cell Biochem. 113:2679–2686. 2012. View Article : Google Scholar : PubMed/NCBI
17	Tu K, Zheng X, Zan X, Han S, Yao Y and Liu Q: Evaluation of Fbxw7 expression and its correlation with the expression of c-Myc, cyclin E and p53 in human hepatocellular carcinoma. Hepatol Res. 42:904–910. 2012. View Article : Google Scholar : PubMed/NCBI
18	Tan NS, Michalik L, Di-Poi N, et al: Essential role of Smad3 in the inhibition of inflammation-induced PPAR beta/delta expression. EMBO J. 23:4211–4221. 2004. View Article : Google Scholar : PubMed/NCBI
19	Chen XP, Qiu FZ, Wu ZD, et al: Effects of location and extension of portal vein tumor thrombus on long-term outcomes of surgical treatment for hepatocellular carcinoma. Ann Surg Oncol. 13:940–946. 2006. View Article : Google Scholar : PubMed/NCBI
20	Cherqui D, Laurent A, Mocellin N, et al: Liver resection for transplantable hepatocellular carcinoma: long-term survival and role of secondary liver transplantation. Ann Surg. 250:738–746. 2009. View Article : Google Scholar : PubMed/NCBI
21	Cammà C, Schepis F, Orlando A, et al: Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology. 224:47–54. 2002.PubMed/NCBI
22	Fujioka M, Nakashima Y, Nakashima O and Kojiro M: Immunohistologic study on the expressions of α-fetoprotein and protein induced by vitamin K absence or antagonist II in surgically resected small hepatocellular carcinoma. Hepatology. 34:1128–1134. 2001.
23	Hafner M, Schmitz A, Grüne I, et al: Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance. Nature. 444:941–944. 2006. View Article : Google Scholar : PubMed/NCBI