Background: Hepatitis B viral infection-induced hepatocellular carcinoma (HCC) is a major threat to human health in China. Hepatitis B virus X protein (HBX), an HBV protein, has been reported to be involved in regulating the cellular activities of the host cells and is responsible for HCC oncogenesis. Methods and Results: In this study, we performed real-time PCR in tumor tissue samples collected from 53 HCC patients (25 HBV-positive cases and 28 HBV-negative cases) to screen the candidate miRNAs that have previously been reported to be aberrantly expressed in HBV-associated HCC and found that miR-145 was significantly downregulated. The following computational analysis identified CUL5 and RAB5C as virtual targets of miR-145, whereas only CUL5 was verified as a validated target gene of miR-145 in liver cells via luciferase reporter assay. In line with this result, we found that both the mRNA and protein expression levels of CUL5 were significantly higher in HBV-positive than in HBV-negative HCC. An in vitro experiment demonstrated a significant decrease in the expression of miRNA-145, a substantial increase in the mRNA and protein expression of CUL5, and an enhanced proliferation of HBX over-expressing HepG2 cells compared with the control. In HepG2.2.15, we found significant decreases in both the expression of CUL5 and the cell growth rate of H cells transfected with 60 nM miR-145 mimics compared with the scramble controls. Conclusion: HBV infection promotes cell growth, at least partially, through the HBX-induced downregulation of miRNA-145 expression, which is responsible for the oncogenesis of HBV-associated HCC.

Trans-arterial chemoembolization for hepatic cellular carcinoma (HCC) is a recommended treatment schedule for stage B patients under the Barcelona-Clinic Liver Cancer (BCLC) diagnostic and treatment strategy system. Data from treatments with embolization performed with different embolizing microparticle reagents either alone or in combination with different chemotherapeutic agents showed favorable safety profile and significant efficacy in tumor control. In addition, recombinant adenoviral human p53 gene (rAd-p53) therapy has been shown effective in the treatment of many solid tumors and some pre-cancerous lesions such as oral leukoplakia, while also presenting a favorable safety profile. To date, no data are available regarding the safety and efficacy of trans-catheter treatment of HCC with embolizing microparticles combined with rAd-p53 in the world. In this study, we demonstrated the safety and efficacy of trans-arterial embolization combined with rAd-p53 gene therapy (TAGE) in the treatment of patients with BCLC stage B HCC. In this retrospective study, 15 HCC patients with BCLC stage B were received TAGE. Fifteen males were included with an average age of 65 (53-89) years and with Child-Pugh score A or B (12 or 3, respectively). The embolic agent used in TAE was gelatin sponge microparticles of diameter 350-560 µm, and 3-5 × 10(12) viral of rAd-p53 was diluted with physiological saline into 15 ml suspension. The study endpoints included response rate, 1 year survival, liver function, and adverse effects. With a median follow-up time of 15.5 months, 15 HCC patients received a total number of 64 TAGE treatments without any significant complication. Based on the modified response evaluation criteria in solid tumors, complete response (CR) was observed in four, six, and six patients at 1, 3, and 6 months after the first treatment, respectively. The objective tumor response (CR + PR) rates at 1, 3, and 6 months were 100.0, 93.3, and 80.0%. The total survival rates of 6 and 12 months in 15 patients were 100%, 100% respectively. The median survival time was 32 months in all. Mild or median fever was observed in all 15 patients, which occurred 4-12 h after treatment and lasted for 12-24 h. Transient abdominal pain, nausea, and cholecystitis were the common side effects with a frequency of 46.7, 33.3, and 26.7%, respectively, and three cases (20%) showed decrease in platelet count. However, other severe (grade 3 or 4) adverse events associated with TAGE were not observed. TAGE is a safe and effective treatments for HCC with BCLC stage B HCC patients.

PLT was elevated and MPV was decreased in SAT patients. A negative correlation between PLT and MPV was found.

Background Portal hypertension (PH) is the main cause of complications and death in liver cirrhosis. The effect of oral administration of octreotide (OCT), a drug that reduces PH by the constriction of mesenteric arteries, is limited by a remarkable intestinal first-pass elimination. Methods The bile duct ligation (BDL) was used in rats to induce liver cirrhosis with PH to examine the kinetics and molecular factors such as P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and cytochrome P450 3A4 (CYP3A4) influencing the intestinal OCT absorption via in situ and in vitro experiments on jejunal segments, transportation experiments on Caco-2 cells and experiments using intestinal microsomes and recombinant human CYP3A4. Moreover, RT-PCR, western blot, and immunohistochemistry were performed. Results Both in situ and in vitro experiments in jejunal segments showed that intestinal OCT absorption in both control and PH rats was largely controlled by P-gp and, to a lesser extent, by MRP2. OCT transport mediated by P-gp and MRP2 was demonstrated on Caco-2 cells. The results of RT-PCR, western blot, and immunohistochemistry suggested that impaired OCT absorption in PH was in part due to the jejunal upregulation of these two transporters. The use of intestinal microsomes and recombinant human CYP3A4 revealed that CYP3A4 metabolized OCT, and its upregulation in PH likely contributed to impaired drug absorption. Conclusions Inhibition of P-gp, MRP2, and CYP3A4 might represent a valid option for decreasing intestinal first-pass effects on orally administered OCT, thereby increasing its bioavailability to alleviate PH in patients with cirrhosis.

Abstract. The aim of the present study was to increase the intestinal transport of octreotide (OCT) by targeting the first-pass impact to identify a potential method for decreasing portal vein pressure (PVP) using oral OCT. Thus, the bioavailability of intestinally absorbed OCT was evaluated in normal rats and rats with portal hypertension (PH) that had been administered P-glycoprotein/multidrug resistance-associated protein 2/cytochrome P450 3A4 (P-gp/MRP2/CYP3A4) inhibitors. The mRNA and protein expression levels of P-gp, MRP2 and CYP3A4 were evaluated in normal and PH rats with or without OCT and the inhibitors using RT-PCR, western blot and immunohistochemical analyses. The potential effects of the inhibitor administration on PVP were also examined. The results suggest that P-gp, MRP2 and CYP3A4 play important roles in prohibiting the enteral absorption of OCT, particularly under a PH environment. Moreover, inhibitors of P-gp, MRP2 and CYP3A4 decrease the first-pass effects of OCT and effectively reduce PVP under PH conditions. Therefore, the present results suggest P-gp, MRP2 and CYP3A4 are key factors in the intestinal absorption of OCT. The inhibition of P-gp, MRP2 and CYP3A4 can markedly decrease the first-pass effects of OCT, and their use may facilitate the use of orally administered OCT.