Abstract
Hepatocellular carcinoma (HCC) is a serious threat to human health. HCC is a malignant tumor and its invasion and metastasis are the result of multigene interactions. Matrix metalloproteinase-2 (MMP-2) is capable of degrading the majority of components of the extracellular matrix and is regarded to closely correlate with tumor invasion and metastasis. Furthermore, the hypoxia-inducible factor 1α (HIF-1α) is an important transcription factor, which is closely associated with the process of tumor growth. The aim of the present study was to investigate the expression of MMP2 and HIF-1α) in HCC, and the relationship between MMP2/HIF-1α protein expression and the clinical/pathological characteristics of HCC. The mRNA levels of MMP2 and HIF-1α were detected in 32 cases of HCC and the corresponding normal adjacent tissues with fluorescence-based quantitative polymerase chain reaction (qPCR). The protein expression of MMP2 and HIF-1α was assessed in 45 HCC cases and 33 cases of corresponding normal adjacent tissue, using immunohistochemical methods. The association between MMP2/HIF-1α and pathological features of HCC, and the correlation between MMP2 and HIF-1α were analyzed. The Kaplan-Meier method was used to assess the impact of MMP2 and HIF-1α expression on survival. The fluorescence-based qPCR demonstrated that MMP2 and HIF-1α mRNA expression levels in the HCC tissues were 0.84±0.17 and 0.87±0.11, respectively, which were significantly higher than those in the adjacent normal tissues (0.70±0.13 and 0.68±0.13, respectively; P<0.05). Immunohistochemical analysis revealed that MMP2 and HIF-1α protein expression in the HCC tissues was 63.1 and 70.8%, respectively, which was also higher than that in the adjacent normal tissues (34.2 and 36.8%, respectively). There was no significant correlation between the expression of MMP2 or HIF-1α protein and the age or gender of patients with HCC (P>0.05). However, there was significant correlation between MMP2 or HIF-1α protein expression and tumor size, metastasis, presence of a capsule and clinical TNM staging of HCC. Their expression also had a significant effect on patient survival time. In conclusion, MMP2 and HIF-1α are overexpressed in HCC, and the MMP2 signaling pathway may promote the development of HCC together with HIF-1α.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common and rapidly fatal malignant tumors worldwide
Matrix metalloproteinases (MMPs) are a group of proteolytic enzymes, which can break down the extracellular matrix and basement membrane, and promote tumor invasion and metastasis
Matrix metalloproteinase 2 (MMP2) is a type IV collagenase and is secreted as a zymogen, which is proteolytically processed to the active form, which contributes to degradation and damage of the extracellular matrix and basement membrane
Summary
Hepatocellular carcinoma (HCC) is one of the most common and rapidly fatal malignant tumors worldwide. Its invasion and metastasis are the main factors that influence the prognosis. Previous studies have indicated that the invasion and metastasis of HCC are the combined results of multiple genes. Hypoxia‐inducible factor 1α (HIF‐1α) is a transcription regulation factor that is closely associated with the development of malignant tumors. Tumor oxygen condition and gene variation have been found to synergistically regulate the expression levels and activity of HIF‐1α [1]. Matrix metalloproteinase 2 (MMP2) is capable of degrading the majority of components of the extracellular matrix. It is widely believed that the effect of MMP2 on the extracellular matrix is closely associated with tumor invasion and metastasis [3,4,5,6,7,8,9]. This study has contributed to investigating the pathogenesis of HCC, and provides guidance for the clinical diagnosis and prognosis determination of HCC in the future
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