ABSTRACT
BACKGROUND AND AIM: To explore the expression and role of activating transcription factor 3 in human hepatocellular carcinoma. METHODS: Immunohistochemistry, Western blot assay and Real-time PCR were used to evaluate activating transcription factor 3 protein and gene level in HCC clinical samples. RESULTS: Activating transcription factor 3 expression is lowest in HCC, and the protein level is lower in patients with capsule invasion, while there is no association with other main clinical pathological features. CONCLUSIONS: Low expression of ATF3 may function as a tumor suppressor during human hepatocellular oncogenesis and targeting ATF3 pathway might be beneficial for anti-HCC therapy.
Subject(s)
Activating Transcription Factor 3/metabolism , Carcinoma, Hepatocellular/metabolism , Gene Expression Regulation, Neoplastic , Liver Neoplasms/metabolism , Liver/metabolism , Activating Transcription Factor 3/genetics , Adult , Aged , Aged, 80 and over , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Female , Humans , Liver/pathology , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Middle AgedABSTRACT
Objective To detect the expression of KiSS-1, KiSS-1R and MMP-9 in hepatocellular carcinoma (HCC). To study the correlation of KiSS-1, KiSS-1R and MMP-9 expression with invasion and metastasis of HCC, and to explore the underlying mechanisms. Methods The expression of KiSS-1 , KiSS-1R mRNA in 33 HCC samples, 26 non-neoplastic adjacent liver tissue samples and 13 non-neoplastic distant liver tissue samples were detected by RT-PCR. Tissue chips were constructed by modified manual tools, which contained HCC, non-neoplastic adjacent liver tissues, non-neoplastic distant liver tissues, normal liver tissues and intrahepatic metastasis lesions. The expression of KiSS-1 and MMP-9 protein was determined by tissue chips, immunohistochemistry and semi-quantitative image analysis in 150 HCC, 137 non-neoplastic adjacent liver tissue, 98 non-neoplastic distant liver tissues, 16 normal liver tissues and 37 intrahepatic metastasis lesion samples. Results The results of RT-PCR showed that compared with the non-neoplastic adjacent liver tissues and the non-neoplastic distant liver tissues, the expression of KiSS-1 mRNA in HCC was significantly lower (P＜0.01). The expression of KiSS-1R mRNA did not changed in HCC and non-neoplastic liver tissues (P＞0.05). The expression of KiSS-1 protein was lower in HCC with metastasis and in clinical stage Ⅲ than that in those with non-metastasis, and in clinical stages Ⅰ and Ⅱ . It was also higher in the primary than in the metastasis lesions (P＜0.01, respectively). The expression of MMP-9 was higher in tumors having peplos invasion and metastasis than in those with negative peplos invasion and non-metastasis. It was lower in the primary than the metastasis lesions (P＜0. 01, respectively).Negative correlation between KiSS-1 and MMP-9 expression was found in HCC(r=- 0.340,P＜0.01). Conclusions The imbalance between KiSS-1 and MMP-9 expression might play an important role in enhancing the invasive and metastatic capacity of HCC. Loss of KiSS-1 expression might predict an aggressive clinical behavior and was associated with metastatic potential in HCC.
ABSTRACT
KiSS-1 has been identified as a putative metastasis-suppressor gene in human melanomas and breast cancer cell lines. Although loss of KiSS-1 expression has been associated with progression and poor prognosis of various cancers, the exact role of KiSS-1 expression in HCC is not well-defined. Our study investigated KiSS-1 expression levels in HCC and its role in invasion and metastasis of human HCC. The expression levels of KiSS-1 and MMP-9 protein were determined by tissue microarray (TMA) serial sections, immunohistochemistry and semi-quantitative image analysis. All clinical and histological data obtained were subjected to statistical analysis. The expression of KiSS-1 protein in HCC and intrahepatic metastasis lesions was significantly lower (P < 0.01) when compared with non-tumor liver tissue and normal liver tissue. Multivariate analysis revealed a significant inverse correlation between KiSS-1 expression and o1 TNM stage, (F = 7.113, P < 0.01) and o2 intrahepatic metastasis (t = 2.898, P < 0.01). Loss of KiSS-1 in intrahepatic metastasis versus primary carcinomas was statistically significant (P<0.01). We also found a negative correlation between KiSS-1 and MMP-9 expression in HCC (r = -0.506, P < 0.01). We conclude that loss of KiSS-1 during HCC metastasis, along with a concomitant upregulation of MMP-9 suggests a possible mechanism for cell motility and invasion during HCC metastasis, with KiSS-1 emerging as a possible therapeutic target during HCC metastasis.
