Transmembrane receptor CXCR7 increases the risk of extrahepatic metastasis of relatively well-differentiated hepatocellular carcinoma through upregulation of osteopontin

Xue,Tong-Chun; Chen,Rong-Xin; Ren,Zheng-Gang; Zou,Jing-Huai; Tang,Zhao-You; Ye,Sheng-Long

doi:10.3892/or.2013.2442

Transmembrane receptor CXCR7 increases the risk of extrahepatic metastasis of relatively well-differentiated hepatocellular carcinoma through upregulation of osteopontin

Authors:
- Tong-Chun Xue
- Rong-Xin Chen
- Zheng-Gang Ren
- Jing-Huai Zou
- Zhao-You Tang
- Sheng-Long Ye
View Affiliations

Affiliations: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
Published online on: May 1, 2013 https://doi.org/10.3892/or.2013.2442
Pages: 105-110

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

Recurrence and metastasis are the main obstacles to improving the survival of patients with post-resective hepatocellular carcinoma (HCC). Our previous study suggests a critical role of CXCR7 in the metastasis of HCC. In the present study, the effect of CXCR7 as a risk factor for metastasis of HCC was evaluated. Immunohistochemical assay was performed on tissue microarrays based on HCC with extrahepatic metastases after hepatectomy. Two categories based on staining scores were used to evaluate the risk effect of CXCR7, respectively. The effect of CXCR7 on osteopontin (OPN) was explored by RNA interference. Based on the results, in both categories, highly expressed CXCR7 was a dependent risk factor for extrahepatic metastasis because of the potential association with relatively good cell differentiation. Stratification analyses indicated that CXCR7 was a strong independent risk factor (OR, 3.40; 95% CI, 1.07-18.84; P=0.038 in category 1 and OR, 6.40; 95% CI, 1.64-24.92; P=0.007 in category 2, respectively) in patients with Edmondson grade 1/2. Furthermore, CXCR7 correlated well and positively with expression of OPN (P=0.019 and P<0.001 in two categories, respectively) in HCC cases with Edmondson grade 1/2. Immunocytochemistry and RT-PCR demonstrated downregulation of OPN in a highly metastatic HCC cell line following knockdown of CXCR7. Taken together, these findings suggest that high expression of CXCR7 increases the risk of metastasis in post-resective HCC patients with relatively good differentiated tumors, potentially through upregulation of OPN. This group of patients may acquire a survival benefit from early detection and treatment of recurrence and metastasis.

View Figures

View References

1	Zhou XD: Recurrence and metastasis of hepatocellular carcinoma: progress and prospects. Hepatobiliary Pancreat Dis Int. 1:35–41. 2002.PubMed/NCBI
2	Tang Z, Zhou X, Lin Z, et al: Surgical treatment of hepatocellular carcinoma and related basic research with special reference to recurrence and metastasis. Chin Med J. 112:887–891. 1999.PubMed/NCBI
3	Balabanian K, Lagane B, Infantino S, et al: The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem. 280:35760–35766. 2005. View Article : Google Scholar : PubMed/NCBI
4	Burns JM, Summers BC, Wang Y, et al: A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development. J Exp Med. 203:2201–2213. 2006. View Article : Google Scholar : PubMed/NCBI
5	Ben-Baruch A: Organ selectivity in metastasis: regulation by chemokines and their receptors. Clin Exp Metastasis. 25:345–356. 2008. View Article : Google Scholar : PubMed/NCBI
6	Wang J, Shiozawa Y, Wang Y, et al: The role of CXCR7/RDC1 as a chemokine receptor for CXCL12/SDF-1 in prostate cancer. J Biol Chem. 283:4283–4294. 2008. View Article : Google Scholar : PubMed/NCBI
7	Iwakiri S, Mino N, Takahashi T, et al: Higher expression of chemokine receptor CXCR7 is linked to early and metastatic recurrence in pathological stage I non small cell lung cancer. Cancer. 115:2580–2593. 2009. View Article : Google Scholar : PubMed/NCBI
8	Zheng K, Li HY, Su XL, et al: Chemokine receptor CXCR7 regulates the invasion, angiogenesis and tumor growth of human hepatocellular carcinoma cells. J Exp Clin Cancer Res. 29:312010. View Article : Google Scholar : PubMed/NCBI
9	Monnier J, Boissan M, L’Helgoualc’h A, et al: CXCR7 is up-regulated in human and murine hepatocellular carcinoma and is specifically expressed by endothelial cells. Eur J Cancer. 48:138–148. 2012. View Article : Google Scholar : PubMed/NCBI
10	Xue TC, Chen RX, Han D, et al: Down-regulation of CXCR7 inhibits the growth and lung metastasis of human hepatocellular carcinoma cells with highly metastatic potential. Exp Ther Med. 3:117–123. 2012.PubMed/NCBI
11	Sun HC, Zhuang PY, Qin LX, et al: Incidence and prognostic values of lymph node metastasis in operable hepatocellular carcinoma and evaluation of routine complete lymphadenectomy. J Surg Oncol. 96:37–45. 2007. View Article : Google Scholar : PubMed/NCBI
12	Simon R, Mirlacher M and Sauter G: Tissue microarrays. Methods Mol Med. 97:377–389. 2004.
13	Lugli A, Spichtin H, Maurer R, et al: EphB2 expression across 138 human tumor types in a tissue microarray: high levels of expression in gastrointestinal cancers. Clin Cancer Res. 11:6450–6458. 2005. View Article : Google Scholar
14	Dalby B, Cates S, Harris A, et al: Advanced transfection with Lipofectamine 2000 reagent: primary neurons, siRNA, and high-throughput applications. Methods. 33:95–103. 2004. View Article : Google Scholar : PubMed/NCBI
15	Brooks SA: Basic immunocytochemistry for light microscopy. Methods Mol Biol. 878:1–30. 2012. View Article : Google Scholar : PubMed/NCBI
16	Trevisani F, D’Intino PE, Morselli-Labate AM, et al: Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol. 34:570–575. 2001. View Article : Google Scholar : PubMed/NCBI
17	Chen RX, Xia YH, Cui JF, Xue TC and Ye SL: Osteopontin, a single marker for predicting the prognosis of patients with tumor-node-metastasis stage I hepatocellular carcinoma after surgical resection. J Gastroenterol Hepatol. 25:1435–1442. 2010. View Article : Google Scholar
18	Pan HW, Ou YH, Peng SY, et al: Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma. Cancer. 98:119–127. 2003. View Article : Google Scholar
19	Nishida N, Fukuda Y, Komeda T, et al: Prognostic impact of multiple allelic losses on metastatic recurrence in hepatocellular carcinoma after curative resection. Oncology. 62:141–148. 2002. View Article : Google Scholar : PubMed/NCBI
20	Sasaki A, Kai S, Endo Y, et al: Hepatitis B virus infection predicts extrahepatic metastasis after hepatic resection in patients with large hepatocellular carcinoma. Ann Surg Oncol. 14:3181–3187. 2007. View Article : Google Scholar
21	Emile JF, Lemoine A, Azoulay D, Debuire B, Bismuth H and Reynes M: Histological, genomic and clinical heterogeneity of clear cell hepatocellular carcinoma. Histopathology. 38:225–231. 2001. View Article : Google Scholar : PubMed/NCBI
22	Unsal H, Yakicier C, Marcais C, et al: Genetic heterogeneity of hepatocellular carcinoma. Proc Natl Acad Sci USA. 91:822–826. 1994. View Article : Google Scholar : PubMed/NCBI
23	Nathan H, Schulick RD, Choti MA and Pawlik TM: Predictors of survival after resection of early hepatocellular carcinoma. Ann Surg. 249:799–805. 2009. View Article : Google Scholar : PubMed/NCBI
24	An FQ, Matsuda M, Fujii H, et al: Tumor heterogeneity in small hepatocellular carcinoma: analysis of tumor cell proliferation, expression and mutation of p53 and β-catenin. Int J Cancer. 93:468–474. 2001.
25	Ben-Porath I, Thomson MW, Carey VJ, et al: An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet. 40:499–507. 2008. View Article : Google Scholar : PubMed/NCBI
26	Lee TI, Jenner RG, Boyer LA, et al: Control of developmental regulators by Polycomb in human embryonic stem cells. Cell. 125:301–313. 2006. View Article : Google Scholar : PubMed/NCBI
27	Jones SW, Brockbank SM, Mobbs ML, et al: The orphan G-protein coupled receptor RDC1: evidence for a role in chondrocyte hypertrophy and articular cartilage matrix turnover. Osteoarthritis Cartilage. 14:597–608. 2006. View Article : Google Scholar : PubMed/NCBI
28	Rajagopal S, Kim J, Ahn S, et al: Beta-arrestin- but not G protein-mediated signaling by the’decoy’ receptor CXCR7. Proc Natl Acad Sci USA. 107:628–632. 2010.
29	Ravindranath A, Yuen HF, Chan KK, et al: Wnt-β-catenin-Tcf-4 signalling-modulated invasiveness is dependent on osteopontin expression in breast cancer. Br J Cancer. 105:542–551. 2011.
30	Rohde F, Rimkus C, Friederichs J, et al: Expression of osteopontin, a target gene of de-regulated Wnt signaling, predicts survival in colon cancer. Int J Cancer. 121:1717–1723. 2007. View Article : Google Scholar : PubMed/NCBI