Expression and significance of NADPH oxidase DUOX1 in hepatocellular carcinoma after tumor resection
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Abstract:
Objective
To study the prognostic value of dual oxidase 1(DUOX1) gene in hepatocellular carcinoma(HCC).
Methods
Reverse transcription polymerase chain reaction (RT-PCR) analysis were used to detect the expression of DUOX1 mRNA in 7 HCC cell lines, one normal liver cell line, specimen of normal liver tissues in 30 cases and paired specimen of neoplastic with matched adjacent non-neoplastic liver tissues in 103 cases. The correlation of the DUOX1 mRNA expression in neoplastic tissues were analyzed with clinicopathological and prognostic factors.
Results
DUOX1 mRNA was expressed in MHCC-97H, MHCC-97L and BEL7402 cell lines, but not in HepG2, Hep3B, SMMC-7721, Chang liver and LO2 cell line. The expression of DUOX1 mRNA was not found in all 30 normal liver tissues. The positive rates of DUOX1 expression in neoplastic tissues was higher than in adjacent non-neoplastic tissues(53.4% vs 14.5%, P <0.01), respectively. Univariate analysis indicated that factors affecting overall survival were gender, age, tumor size, satellite nodule, tumor thrombus in the portal vein, TNM stage and DUOX1 expression status in neoplastic tissues. Multivariate analysis indicated that independent factors affecting overall survival were tumor size, tumor thrombus in the portal vein and DUOX1 expression status.
Conclusions
DUOX1 expression in HCC neoplastic tissues is an independent factor affecting the prognosis of patients with HCC after tumor resection. DUOX1 may play a role in liver carcinogenesis.
Key words:
NADPH oxidase; Hepatocellular Carcinoma; Prognosis; DUOX1To investigate the expression and clinical significance of HIF-1a protein in hepatocellular carcinoma (HCC) tissues.Immunohistochemistry (IHC), Western blotting and RT-PCR techniques were used to detect the expression of the HIF-1a gene protein in 35 HCC, 26 cirrhotic and 15 normal liver tissues. Their relationship with the pathological characteristics of the tumors were also analyzed.The positive rates of HIF-1a expression in HCC tissues was 94%, which was similar to the positive rates of HIF-1a expression in liver cirrhosis tissues of 92%, but was higher than that in normal hepatic tissues of 7%, but the residual proliferatic hepatic trabeculae among the necrotic liver cells and the fibrotic tissues expressed HIF-1a strongly in comparison with the cirrhotic liver tissues. The expression intensity of HIF-1a protein of the cirrhotic liver tissues was stronger than that in HCC; the results by Western blotting and RT-PCR were in accordance to that by IHC. In addition, the expression intensity in HCC had a negative correlation in differentiation degree and a positive correlation to intrahepatic and extrahepatic metastases but no correlation was found between HIF-1a expression and the existence of portal vein tumor emboli, prognosis and the status of HBsAg.HIF-1 protein was expressed in HCC and cirrhotic liver tissues, and was only affected by the factor of hypoxia. The expression of HIF-1a protein is associated with the differentiation of the tumor and its intrahepatic and extrahepatic metastases but was not related to the existence of portal vein tumor emboli, prognosis and the status of HBsAg. This phenomenon may provide a new idea for the treatment of liver cancer.
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The aim of the present study was to detect the expression levels of the human telomerase reverse transcriptase (hTERT) gene in hepatocellular carcinoma (HCC), and investigate its significance in the incidence and development of the cancer. HCC tissues and corresponding para-carcinoma liver tissues were surgically collected from 78 patients with HCC who presented to Shandong Provincial Hospital (Jinan, Shandong, China). hTERT expression at the protein and mRNA levels were detected by immunohistochemistry (streptavidin peroxidase method) and reverse transcription polymerase chain reaction, respectively, in the HCC tissues and corresponding para-carcinoma liver tissues of 78 HCC patients and in 12 samples of normal liver tissue. The data were analyzed using SPSS 17.0 statistical software, and employing χ2 tests and t-tests. hTERT protein was mainly expressed in the HCC cell cytoplasm, but was occasionally observed in the cell nucleus. The positive rates of hTERT protein and mRNA expression in the HCC patients were 84.62% (66/78) and 78.21% (61/78), respectively, which was significantly higher compared with the rates of 10.26% (8/78) and 8.97% (7/78) in the paired para-carcinoma liver tissues (P<0.01). hTERT protein and mRNA were not expressed in the normal liver tissues (0/12). χ2 test and t-test analysis revealed that hTERT gene expression was correlated with tumor grade, the presence/absence of a portal vein tumor thrombus, hepatitis B surface antigen positivity and a high α-fetoprotein level (P<0.05) rather than patient age, gender or tumor size. Expression of the hTERT gene may play a pivotal role in the incidence and development of HCC. The hTERT gene potentially serves as an important molecular and biological index for diagnosing and predicating the biological behavior of HCC.
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Objective To detect the tissue factor (TF) mRNA expression in hepatocellular carcinoma and to elucidate its significance. Methods TF mRNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) in 27 cases of human hepatocellular carcinoma tissue specimen with their adjacent tissues and in 27 non-tumorous process tissues. Then the relationship between mRNA expression and pathological data were analyzed. Results The expression and the relative expression intensity of TF in hepatocellular carcinoma tissues were 62.96(17/27) and 0.567±0.268 respectively, which were significantly higher than those in their adjacent tissues 〔33.33(9/27), 0.469±0.184〕 and in 27 non-tumorous process tissue 〔29.63(8/27), 0.353±0.121〕, P 0.05. The relative expression intensity of TF were associated with tumor size, intrahepatic and extrahepatic metastasis and portal vein invasion, but unrelated to gender, AFP level, differentiation, HBsAg, cirrhosis, number of tumor lesions, and lymph node metastasis (P0.05). Conclusion Expression of TF mRNA were significantly higher in hepatocellular carcinoma and in the invasive and metastatic tissue, which indicated that TF may play an important role in carcinogenesis, invasion and metastasis of hepatocellular carcinoma.
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To study the expression of cellular inhibitor of apoptosis protein-2 (C-IAP2) mRNA and protein in hepatocellular carcinoma (HCC) and its relationship with the clinical outcomes.Quantitative PCR and immunohistochemical staining were used to detect the expression of C-IAP2 mRNA and protein in the tumor tissues and corresponding adjacent non-cancerous tissues from HCC patients.The expression of C-IAP2 mRNA in HCC tissues was 2.70 folds higher than that in the non-cancerous tissues (P<0.001). The expression rate of C-IAP2 protein in HCC tissues was 70.8%, significantly higher than that in the non-cancerous tissues (27.8%, P=0.001). The expression of C-IAP2 mRNA and protein was associated with the tumor emboli, lymph node metastasis, AFP level, histological differentiation, TNM stage, postoperative recurrence and metastasis (P<0.05), but not with the patients' gender, age, HbsAg positivity, number of tumors, cirrhosis or the presence of tumor encapsulation (P>0.05).The expression of C-IAP2 in HCC is associated with tumor recurrence and metastasis, and can be a biological marker for prognostic evaluation of HCC.
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OBJECTIVE:To explore the expression and significance of the B-myb mRNA in human HCC (hepatocellular carcinoma) tissues. METHODS: Real time polymerase chain reaction (Real time PCR) was employed to determine the expression of B-myb mRNA in 70 HCC tissues and their adjacent liver tissues and 18 normal liver tissues. RESULTS: The expression level of B-myb mRNA in the HCC tissue (0.037 5±0.016 8) and the adjacent liver tissue (0.035 3±0.012 8) was markedly higher than in the normal liver tissues ( 0.026 5± 0.009 9 , P0.05). The expression level of B-myb mRNA were not significantly different in the HCC tissue than in the adjacent liver tissue (P0.05). The expression of B-myb in the HCC tissue was significantly correlated with the clinical stage, the presence of extrahepatic metastasis, and the recurrence of tumor, but not correlated with the Portal Vein Tumor Thrombus, the number of tumor, the diameter of tumor, the level of serum alpha-fetoprotein (AFP), and the differentiation of tumor. CONCLUSIONS: The results suggest that B-myb may be related to the initiation and progression of HCC.
MYB
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Expression and significance of NADPH oxidase DUOX1 in hepatocellular carcinoma after tumor resection
Objective To study the prognostic value of dual oxidase 1(DUOX1) gene in hepatocellular carcinoma(HCC). Methods Reverse transcription polymerase chain reaction (RT-PCR) analysis were used to detect the expression of DUOX1 mRNA in 7 HCC cell lines, one normal liver cell line, specimen of normal liver tissues in 30 cases and paired specimen of neoplastic with matched adjacent non-neoplastic liver tissues in 103 cases. The correlation of the DUOX1 mRNA expression in neoplastic tissues were analyzed with clinicopathological and prognostic factors. Results DUOX1 mRNA was expressed in MHCC-97H, MHCC-97L and BEL7402 cell lines, but not in HepG2, Hep3B, SMMC-7721, Chang liver and LO2 cell line. The expression of DUOX1 mRNA was not found in all 30 normal liver tissues. The positive rates of DUOX1 expression in neoplastic tissues was higher than in adjacent non-neoplastic tissues(53.4% vs 14.5%, P 0.01), respectively. Univariate analysis indicated that factors affecting overall survival were gender, age, tumor size, satellite nodule, tumor thrombus in the portal vein, TNM stage and DUOX1 expression status in neoplastic tissues. Multivariate analysis indicated that independent factors affecting overall survival were tumor size, tumor thrombus in the portal vein and DUOX1 expression status. Conclusions DUOX1 expression in HCC neoplastic tissues is an independent factor affecting the prognosis of patients with HCC after tumor resection. DUOX1 may play a role in liver carcinogenesis.
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AIM:To study the prognostic role of TAp73, p53, proliferating cell nuclear antigen (PCNA) and apoptosis in patients with hepatocellular carcinoma (HCC) after surgical tumor ablation. METHODS:Forty-seven human resected HCC tissues and 42 adjacent non-cancerous tissues were studied with 10 normal liver tissues as control group.TAp73, p53, and PCNA were detected with Elivision immunohistochemistry. Terminal deoxynucleotidyl transferase (TdT)-mediated d-UTP-biotin nick-end labeling (TUNEL) method was used to detect the apoptosis cells.All clinical and pathological materials were analyzed by SPSS10.0 statistical package. RESULTS:TAp73 overexpressed in HCC tissues (36.2%) when compared with adjacent non-cancerous tissues (2.38%, P<0.005) and normal liver tissues (0, P<0.01).Mutant type p53 (mt-p53) overexpressed in HCC tissues (38.3%) when contracted with adjacent non-cancerous tissues (16.7%, P<0.05) and normal liver tissues (0, P<0.01).Proliferation index (PI) level in HCC tissues was significantly higher than that in adjacent non-cancerous tissues (30.34%±4.46%vs 27.88%±5.89%,t, P = 0.028).Apoptosis index (AI) level in HCC tissues was higher than that in adjacent non-cancerous tissues (8.62%±2.28%vs 7.38%±2.61%,t, P = 0.019).Expression of TAp73 was associated with lymph node metastasis and mt-p53, with r = 0.407 and 0.265, respectively.Expression of mt-p53 was associated with Edmondson's stage and AFP, with r = 0.295 and -0.357, respectively.In Kaplan-Meier univariant analysis, TAp73, AFP, TNM stage, portal vein invasion, liver membrane invasion and HBsAg correlated with prognosis (log rank, P = 0.039, 0.012, 0.002, 0.000, 0.014, 0.007, respectively).Multivariant Cox regression analysis showed that TAp73, AFP, TNM stage, portal vein invasion, liver membrane invasion and age were independent factors of prognosis. CONCLUSION:These results suggest that TAp73 can be used as a prognostic indicator of patients with HCC undergoing surgical tumor ablation.AFP, TNM, portal vein invasion, liver membrane invasion and age also have a potency of predicting the prognosis of HCC.
Terminal deoxynucleotidyl transferase
2-Acetylaminofluorene
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Many studies have demonstrated the function of nitric oxide (NO) or nitric oxide synthase-2 (NOS-2) in cancer as pro-neoplastic or anti-neoplastic effectors, but the role of NO and NOS-2 in hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to investigate the levels of NO production and NOS-2 expression in HCC and adjacent non-tumor liver tissues and to clarify whether the levels of NO/NOS-2 are related to the clinicopathological features of HCC. The levels of NO production were examined in tumor and adjacent non-tumor liver tissues of 30 patients with HCC. The expression of NOS-2 was detected by real-time polymerase chain reaction (RT-PCR) and immunohistochemical analysis in HCC and/or adjacent non-tumor liver tissues. Mutant p53 and proliferating cell nuclear antigen (PCNA) were also immunohistochemically investigated in liver tissues. The levels of NO in HCC were significantly lower compared to adjacent non-tumor liver tissues (P<0.001). The relative mRNA and protein expression levels of NOS-2 in HCC were also significantly lower compared to adjacent non-tumor liver tissues (P<0.01 for both). We found that the levels of NO in patients suffering from HCC metastasis were lower compared to those without metastasis (P<0.05) and NOS-2 expression was correlated with tumor diameter (P<0.05) and metastasis (P<0.05). In addition, mutant p53 protein was expressed in the majority of HCC samples and the proliferation rate of HCC was significantly higher than that of adjacent non-tumor liver tissues. These data indicate that decreased levels of NO/NOS-2 may partially contribute to overexpression of the mutant p53 protein and excessive proliferation; this may be a potential mechanism in the development and progression of HCC.
Liver Cancer
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OBJECTIVE:To investigate the expression of signal transducer and activator of transcription 3(STAT3)protein in hepatocellular carcinoma(HCC)tissues and its significance in occurrence and development of HCC.METHODS:The expression of STAT3 protein was examined with immunohistochemical technique in the specimens from 56 HCC tissues and their para-carcinoma tissues,11 hepatic cirrhosis tissues and 11 normal liver tissues,and the expressions of VEGFR2 and EGFR were examind in 27 and 42 HCC tissues,respectively.RESULTS:The positive and strongly positive expressions of STAT3 protein in HCC tissues were in 23 and 9 cases respectively,the positive rate of STAT3 expression was significantly higher in HCC tissues than in the para-carcinoma tissues,its expression in para-carcinoma tissues was higher than that in hepatic cirrhosis tissues,and its expression in hepatic cirrhosis tissues was significantly higher than that in normal liver tissues,P0.01.The expression of STAT3 was correlated with the expression of AFP in HCC tissues,P0.05.There was no significant correlation between the expression of STAT3 protein and the expressions of VEGFR2 and EGFR in HCC tissues.CONCLUSIONS:The expression of STAT3 is closely correlated with the occurrence and development of HCC.
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