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Correlative Study Of NGX6 Gene With Angiogenesis And Contrast-Enhanced Ultrasound Features In Hepatocellular Carcinoma

Posted on:2009-08-21Degree:DoctorType:Dissertation
Country:ChinaCandidate:J D XiaoFull Text:PDF
GTID:1114360278454208Subject:Internal Medicine
Abstract/Summary:PDF Full Text Request
Angiogenesis is actually the outcome of the balance between stimulatory and inhibitory factors. The delicate balance can be regulated by oncogenes and tumor suppressor genes. Hepatocellular carcinoma is multiple gene disease. The study on gene aspects can provide theoretical basis for prevention,diagnosis, treatment ,and prognosis in hepatocellular carcinoma. NGX6 is a candidate tumor suppressor gene which was isolated by location candidate cloning strategy (GenBank accession Number AF188239). Previous study showed that the expression of NGX6 was associated with invasion and metastasis. Contrast-enhanced ultrasound is known as noninvasive microcirculation angiography and is new advance of ultrasonic medicine. Combining molecular biotechnology and imaging, this correlative study on the relationship of gene expression of NGX6 and contrast-enhanced ultrasound features with angiogenesis in hepatocellular carcinoma may play an important role in guiding targeted gene therapy and understanding the rules of angiogenesis in many aspects.Objective:1.To examine the expression of NGX6 gene and to investigate its association with the clinico-pathological characteristics in hepatocellular carcinoma(HCC). 2.To study the relationship between the expression of NGX6 and MVD(Microvessel density), microvascular morphology, VEGFmRNA. To explore the role of NGX6 in tumor angiogenesis.3.To study the correlation of contrast-enhanced ultrasound features and expression of VEGF,MVD,microvascular morphology .aiming at elucidating the molecular pathologic basis of imaging in angiogenesis and tumor invasion and metastasis.4.To study the correlation of contrast-enhanced ultrasound features and the expression of NGX6 in order to finding a theoretical basis for targeting therapy and imaging studies of angiogenesis, tumor invasion and metastasis on the gene level.Methods:45 patients with hepatocellular carcinoma confirmed by surgery and pathology between january 2006 and October 2007 were included in this study. Acuson Sequoia 512 color Doppler sonography system equipped with 2-6MHz frequency transducer and contrast pulse sequencing (CPS) software was used. The whole enhancing process of the tumors was recorded on the hard disk synchronously using microbubble SonoVue and analyzed by QONTRAST-QRADIO software. Then, the fresh samples in vitro were collected during surgery. RT-PCR was used to detect the expression of NGX6,VEGF mRNA in the hepatocellular carcinoma and the surround tissues (distance is more than 2cm from cancer to normal tissues) . The expression levels of VEGF in hepatocellular carcinoma and matched paracancerous tissues were analyzed by immunostainning and Western-blotting. MVD and microvascular morphology were studied by anti-CD34 immunostaining. Statistical analysis was performed on correlation of contrast-enhanced ultrasound features and expression of NGX6,VEGF, MVD, microvascular morphology.Results1. The positive rates of NGX6 in the hepatocellular carcinoma and the matched adjacent tissues were 35.5% (16/45) and 77.8% (35/45), respectively. There was statistical significance between the groups (x~2= 16.335, P<0.01). The expression of NGX6 gene in hepatocellular carcinoma was related with lymph node metastasis (x~2=5.237,P=0.022).2. There was a significant correlation between expression of NGX6 and the value of MVD (x~2=3.919, P <0.05), expression of VEGFmRNA (x~2=10.132, P<0.01). No correlation was shown between expression of NGX6 and microvascular morphology.3.VEGF (r_s=-0.335) and MVD (r_s=-0.477) were negatively correlated with TIP (time to peak). VEGF (r_s=0.566) and MVD (r_s=0.569) were positively correlated with peak value (PEAK).4. There was significant difference between two types of microvascular morphology of hepatocellular carcinoma on the time becoming hypo-enhancing (t=2.059, P <0.05) . The incidence of hypo-enhancement in portal phase and the pattern of ultrasound contrast agent clearance with quick wash-out was higher in microvascular morphology of loop-and-strip type than that of point-and-line type. Enhanced manifestations in portal phase and the pattern of ultrasound contrast agent clearance were correlated with the type of microvascular morphology ( x~2=11.948,P<0.01, contingency coefficient=0.458) .5. Tumor enhancing margin(x~2=7.032,P<0.01,contingency coefficient =0.368),enhancing area(x~2=5.38, P<0.05, contingency coefficient=0.327) and enhancement of portal vein tumor thrombus (x~2=4.148, P<0.05, contingency coefficient=0.291)were correlated with MVD. Tumor enhancing margin (x~2=3.90, P<0.05, contingency coefficient =0.282) , enhancing area (x~2=6.544,P<0.05,contingency coefficient=0.356 )and enhancement of portal vein tumor thrombus (x~2=7.039, P<0.01, contingency coefficient=0.368) were correlated with VEGF.6. Tumor enhancing margin (x~2=10.499,P<0.01, contingency coefficient=0.435) , enhancing area in the tumor (x~2=5.867, P<0.05, contingency coefficient=0.34) and enhancement of portal vein tumor thrombus (x~2=6.749, P<0.01,contingency coefficient=0.361 ) were correlated the expression of NGX6 mRNA. No correlation was shown between NGX6 and. the pattern of ultrasound contrast agent clearance , enhancement completely or not, artery flow. Conclusions:1 There is the positive expression of NGX6 in hepatocellular carcinoma and matched paracancerous tissues. The low-expression or no-expression of NGX6 gene play an important role in the gene transcription level in hepatocellular carcinogenesis. The expression of NGX6 gene in hepatocellular carcinoma is related with lymph node metastasis.2. NGX6 plays a significant role involved in regulation of angiogenesis in hepatocellular carcinoma. No correlation is shown between NGX6 and microvascular morphology.3.TTP and PEAK can reflect situation of angiogenesis in hepatocellular carcinoma. .The time of hepatocellular carcinoma becoming hypo-enhancing, enhanced manifestations in portal phase and the pattern of ultrasound contrast agent clearance are correlated with microvascular morphology type which is one of the morphological basis on enhanced-ultrasounography characterization.4.Margin, the range of tumor and enhancement of portal vein tumor thrombus are correlated with microvessel density (MVD)and the expression of VEGF which provide reliable basis for judging angiogenesis ,infiltrating growth and metastasis in tumors with clinical imaging method by connecting molecular characteristics with ultrasonic enhanced imaging. 5. The level of the NGX6 expression is correlated with margin and range of increases in the tumor and enhancement of portal vein tumor thrombus which provides a imaging theory basis for exploring invasion and metastasis in hepatocellular carcinoma.
Keywords/Search Tags:hepatocellular carcinoma, ngx6, contrast-enhanced ultrasound, angiogenesis, vascular endothelial growth factor
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