Chemokine receptor CXCR4 expression in hepatocellular carcinoma patients increases the risk of bone metastases and poor survival

Xiang, Zuo-Lin; Zeng, Zhao‐Chong; Tang, Zhao–You; Fan, Jia; Zhuang, Peng–Yuan; Li, Ying; Tan, Yaohong; He, Jian

doi:10.1186/1471-2407-9-176

Cited by 91 publications

(89 citation statements)

References 29 publications

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“…The immunohistochemistry protocols are described elsewhere (13)(14)(15). Primary antibodies were mouse antihuman monoclonal antibodies against hypoxia-inducible factor-1a (HIF-1a), VEGF (Santa Cruz Biotechnology), and matrix metalloproteinase-2 (MMP-2; R&D Systems).…”

Section: Immunohistochemistrymentioning

confidence: 99%

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Gene Expression Profiling of Fixed Tissues Identified Hypoxia-Inducible Factor-1α, VEGF, and Matrix Metalloproteinase-2 as Biomarkers of Lymph Node Metastasis in Hepatocellular Carcinoma

Xiang

Ren

Fan

et al. 2011

Clinical Cancer Research

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112

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Purpose: Hepatocellular carcinoma (HCC) most often develops in patients infected with hepatitis B or hepatitis C virus. Differential gene expression profiling is useful for investigating genes associated with lymph node metastasis (LNM). We screened genes to identify potential biomarkers for LNM in HCC.Experimental Design: RNA was extracted from formalin-fixed specimens of paired intratumoral and peritumoral tissues of patients with lymph node-positive (n ¼ 36) or negative (n ¼ 36) HCC. A cDNAmediated annealing, selection, extension, and ligation assay was done with an array of 502 known cancerrelated genes to identify differentially expressed genes in 20 pairs of patients with or without LNM. Candidate biomarkers were evaluated by using immunohistochemistry and tissue microarrays in an independent cohort of 309 HCC patients who had undergone hepatectomy. Of the 309 patients, 235 (76.1%) patients were infected with hepatitis B.Results: Compared with lymph node-negative patients, lymph node-positive patients had 17 overexpressed genes and 19 underexpressed genes in intratumoral tissues, and 25 overexpressed genes and 22 underexpressed genes in peritumoral tissues. Hypoxia-inducible factor (HIF)-1a, VEGF, and matrix metalloproteinase (MMP)-2 were selected for analysis in the cohort of 309 HCC patients. We found that intratumoral protein levels of HIF-1a, VEGF, and MMP-2 were independent risk factors for developing LNM.Conclusion: We identified 83 cancer genes that were differentially expressed in lymph node-positive and lymph node-negative HCC. Our findings show that the combination of intratumoral HIF-1a, VEGF, and MMP-2 may be useful as a molecular prediction model for LNM.

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Section: Immunohistochemistrymentioning

confidence: 99%

“…A tissue microarray (TMA) was constructed as described previously (13)(14)(15). H&E-stained slides were screened to identify optimal intratumoral and peritumoral tissue for analysis.…”

Section: Tissue Microarraymentioning

confidence: 99%

Gene Expression Profiling of Fixed Tissues Identified Hypoxia-Inducible Factor-1α, VEGF, and Matrix Metalloproteinase-2 as Biomarkers of Lymph Node Metastasis in Hepatocellular Carcinoma

Xiang

Ren

Fan

et al. 2011

Clinical Cancer Research

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112

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“…Its expression is elevated in breast cancer and leukemia (13). Previous studies have reported that CXCR4 expression in hepatocellular carcinoma (HCC) might correlate with the progress of the cancer and its lymphatic and distant metastasis (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Stemness-Related Transcriptional Factors and Homing Gene Expression Profiles in Hepatic Differentiation and Cancer

Toraih

Fawzy

El-Falouji

et al. 2016

Mol Med

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and 6 Pulmonologist, Ministry of Health, EgyptStem cell transcriptional signature activation is an essential event in the development of cancer. This study aimed to investigate the differential expression profiles of three pluripotency-associated genes, OCT4, NANOG and SOX2, G-protein-coupled chemokine receptor 4 (CXCR4) and the ligand CXCL2, and alpha-fetoprotein (AFP) in hepatogenic differentiated stem cells and in sera of hepatitis C virus (HCV) and HCV-induced hepatocellular carcinoma (HCC) patients. Mesenchymal stem cells derived from umbilical cord blood were differentiated using hepatogenic differentiation media. Serum specimens were collected from 96 patients (32 cirrhotic HCV, 32 early HCC and 32 late HCC) and 96 controls. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed for relative quantification of the six target genes using the Livak method. In silico network analysis was also executed to explore the pluripotency and tumorigenetic regulatory circuits in liver cancer. The expression levels of all genes declined gradually during the stages of stem cell differentiation. On univariate and multivariate analyses, NANOG, CXCR4 and AFP were significantly upregulated in late clinical stage HCC patients. In contrast, SOX2 and CXCL2 were markedly overexpressed in cirrhotic patients and could be used for clear demarcation between cirrhotic and HCC patients in our cases. In conclusion, our data highlight the potential role of the SOX2 stem cell marker and CXCL2 chemokine in liver cell degeneration and fibrogenesis in HCV-induced hepatic cirrhosis in our sample of the Egyptian population. In addition, the significant association of NANOG and CXCR4 high expression with late HCC could contribute to the acquisition of stem celllike properties in hepatic cancer and dissemination in late stages, respectively. Taken together, our results could have potential application in HCC prognosis and treatment.

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“…Different tumor types have distinct chemokine receptor expression profiles, with CXCR4 and CCR7 extensively investigated (3). Notably, CXCR4 is widely expressed in at least 23 different cancer types including HCCs and is associated with more aggressive disease and poorer patient prognosis (3,9,10). The CXCL12-CXCR4 axis is therefore of particular importance in cancer metastasis and currently represents the top target for therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

CXCR6 Upregulation Contributes to a Proinflammatory Tumor Microenvironment That Drives Metastasis and Poor Patient Outcomes in Hepatocellular Carcinoma

Gao

Zhao²,

Wang³

et al. 2012

Cancer Research

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149

116

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CXC chemokines and their cognate receptors have been implicated widely in cancer pathogenesis. In this study, we report a critical causal relationship between CXCR6 expression and tumorigenesis in the setting of human hepatocellular carcinoma (HCC). Among the CXC chemokine receptors, only CXCR6 was detected in all the hepatoma cell lines studied. Moreover, in HCC tissue, CXCR6 expression was significantly higher than in noncancerous liver tissues. Reduction of CXCR6 or its ligand CXCL16 in cancer cells reduced cell invasion in vitro and tumor growth, angiogenesis, and metastases in vivo. Importantly, loss of CXCR6 led to reduced Gr-1þ neutrophil infiltration and decreased neoangiogenesis in hepatoma xenografts via inhibition of proinflammatory cytokine production. Clinically, high expression of CXCR6 was an independent predictor of increased recurrence and poor survival in HCCs. Human HCC samples expressing high levels of CXCR6 also contained an increased number of CD66bþ neutrophils and microvessels, and the combination of CXCR6 and neutrophils was a superior predictor of recurrence and survival than either marker used alone. Together, our findings suggest that elevated expression of CXCR6 promotes HCC invasiveness and a protumor inflammatory environment and is associated with poor patient outcome. These results support the concept that inhibition of the CXCR6-CXCL16 pathway may improve prognosis after HCC treatment. Cancer Res; 72(14); 3546-56. Ó2012 AACR.

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Chemokine receptor CXCR4 expression in hepatocellular carcinoma patients increases the risk of bone metastases and poor survival

Cited by 91 publications

References 29 publications

Gene Expression Profiling of Fixed Tissues Identified Hypoxia-Inducible Factor-1α, VEGF, and Matrix Metalloproteinase-2 as Biomarkers of Lymph Node Metastasis in Hepatocellular Carcinoma

Gene Expression Profiling of Fixed Tissues Identified Hypoxia-Inducible Factor-1α, VEGF, and Matrix Metalloproteinase-2 as Biomarkers of Lymph Node Metastasis in Hepatocellular Carcinoma

Stemness-Related Transcriptional Factors and Homing Gene Expression Profiles in Hepatic Differentiation and Cancer

CXCR6 Upregulation Contributes to a Proinflammatory Tumor Microenvironment That Drives Metastasis and Poor Patient Outcomes in Hepatocellular Carcinoma

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