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

• Published in: Clinical cancer research Vol. 17; no. 16; pp. 5463 - 5472
• Main Authors: XIANG, Zuo-Lin, ZENG, Zhao-Chong, JIA FAN, TANG, Zhao-You, ZENG, Hai-Ying, GAO, Dong-Mei
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.08.2011
• Subjects: Analysis of Variance; Antineoplastic agents; Biological and medical sciences; biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; DNA microarrays; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gelatinase A; Gene expression; Gene Expression Profiling; Hematologic and hematopoietic diseases; Hepatitis B; Hepatitis C virus; Hepatocellular carcinoma; Humans; Hypoxia-inducible factor 1 alpha; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunohistochemistry; Kaplan-Meier Estimate; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lymph; Lymph nodes; Lymphatic Metastasis; Male; Matrix metalloproteinase; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Medical sciences; Metastases; Middle Aged; Molecular modelling; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; RNA; Tissue Array Analysis; Tissue Fixation; Transcriptome; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Enzyme; Biological marker; Malignant lymphadenopathy; Metalloendopeptidases; Hepatic disease; Hepatocellular carcinoma; Malignant hemopathy; Malignant tumor; Gelatinase A; Gene expression profile; Lymph node metastasis; Peptidases; Liver cancer; Vascular endothelium growth factor; Hydrolases; Digestive diseases; Transcription factor HIF1; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-10-3096

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. RNA was extracted from formalin-fixed specimens of paired intratumoral and peritumoral tissues of patients with lymph node-positive (n = 36) or negative (n = 36) HCC. A cDNA-mediated annealing, selection, extension, and ligation assay was done with an array of 502 known cancer-related 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. 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)-1α, 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-1α, VEGF, and MMP-2 were independent risk factors for developing LNM. 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-1α, VEGF, and MMP-2 may be useful as a molecular prediction model for LNM.