HBx and c-MYC Cooperate to Induce URI1 Expression in HBV-Related Hepatocellular Carcinoma

Unconventional prefoldin RNA polymerase II subunit 5 interactor (URI1) has emerged as an oncogenic driver in hepatocellular carcinoma (HCC). Although the hepatitis B virus (HBV) represents the most common etiology of HCC worldwide, it is unknown whether URI1 plays a role in HBV-related HCC (HCC-B). In the present study, we investigated URI1 expression and its underlying mechanism in HCC-B tissues and cell lines. URI1 gene-promoter activity was determined by a luciferase assay. Human HCC-B samples were used for a chromatin immunoprecipitation assay. We found that c-MYC induced URI1 expression and activated the URI1 promoter through the E-box in the promoter region while the HBx protein significantly enhanced it. The positivity of URI1 expression was significantly higher in HCC-B tumor tissues than in non-HBV-related HCC tumor tissues, suggesting that a specific mechanism underlies URI1 expression in HCC-B. In tumor tissues from HCC-B patients, a significantly higher level of c-MYC was recruited to the E-box than in non-tumor tissues. These results suggest that HBx and c-MYC are involved in URI1 expression in HCC-B. URI1 expression may play important roles in the development and progression of HCC-B because HBx and c-MYC are well-known oncogenic factors in the virus and host, respectively

NEAT1 is Required for the Expression of the Liver Cancer Stem Cell Marker CD44

CD44, a cancer stem cell (CSC) marker, is required for maintaining CSC properties in hepatocellular carcinoma (HCC). Nuclear enriched abundant transcript 1 (NEAT1), a long noncoding RNA (lncRNA), is an oncogenic driver in HCC. In the present study, we investigated the significance of the NEAT1 gene in association with CD44 expression in liver CSCs of human HCC cell lines. The CSC properties were evaluated by spheroid culture, CSC marker expression, and sensitivity to anti-cancer drugs. The expression of both NEAT1 variant 1 (NEAT1v1) and variant 2 (NEAT1v2) as well as CD44 was significantly increased in the spheroid culture, compared with that in monolayer culture. Overexpression of Neat1v1, but not Neat1v2, enhanced the CSC properties, while knockout of the NEAT1 gene suppressed them. CD44 expression was increased by the overexpression of Neat1v1 and abrogated by NEAT1 knockout. The overexpression of NEAT1v1 restored the CSC properties and CD44 expression in NEAT1-knockout cells. NEAT1v1 expression in HCC tissues was correlated with poor prognosis and CD44 expression. These results suggest that NEAT1v1 is required for CD44 expression. To our surprise, NEAT1v1 also restored the CSC properties even in CD44-deficient cells, suggesting that NEAT1v1 maintains the properties of CSCs in a CD44-independent manner

CD44 standard isoform is involved in maintenance of cancer stem cells of a hepatocellular carcinoma cell line

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. Cancer stem cells (CSCs) have attracted attention as a novel therapeutic target for cancer because they play important roles in the development and aggravation of cancer. CD44 is expressed as a standard isoform (CD44s) and several variant isoforms. CD44v is a major isoform expressed on CSCs of a variety of tumors and has been extensively studied. However, HCC tissues dominantly express CD44s, whose function in CSCs remains unclear. In the present study, we investigated the roles of CD44s in CSCs of HCC. Knock-out of the CD44 gene in HuH7 HCC cells on which only CD44s is expressed resulted in decreased spheroid formation and increased drug sensitivity. The expression of CSC marker genes, including CD133 and EpCAM, was significantly downregulated in the spheroids of CD44-deficient cells compared with those in the spheroids of HuH7 cells. In addition, CD44 deficiency impaired antioxidant capacity, concomitant with downregulation of glutathione peroxidase 1 (GPX1) and thioredoxin. Because GPX1 uses the reduced form of glutathione (GSH) to regenerate oxidized cellular components, GSH levels were significantly increased in the CD44-deficient cells. We also found that NOTCH3 and its target genes were downregulated in the spheroids of CD44-deficient cells. NOTCH3 expression in HCC tissues was significantly increased compared with that in adjacent nontumor liver tissues and was correlated with CD44 expression. These results suggest that CD44s is involved in maintenance of CSCs in a HCC cell line, possibly through the NOTCH3 signaling pathway

Utility and Limitation of Preoperative Neutrophil Lymphocyte Ratio as a Prognostic Factor in Hepatocellular Carcinoma

【Background】 The neutrophil lymphocyte ratio (NLR) has been proposed to be a surrogate marker of inflammation and immunological status and to have prognostic value in various malignancies. This study was conducted to clarify the prognostic significance of preoperative NLR in hepatocellular carcinoma (HCC). 【Methods】 We enrolled 135 patients with histologicallyproven HCC who underwent initial curative hepatectomy. Based on the median NLR values, patients were divided into: NLR ? 2.0 (NLR-high, n = 69) and NLR < 2.0 (NLR-low, n = 66). 【Results】 In univariate analysis, the 5-year overall survival (OS) rates were 59.8 % ± 6.7% and 75.6% ± 6.5% (P = 0.028) in the NLR-high and NLR-low groups, respectively. Furthermore, the 5-year disease specific survival rates were 68.6% ± 6.7%, and 81.2 ± 6.4% (P = 0.048) in the NLR-high and NLR-low groups, respectively. 【Conclusion】 Our results showed that high NLR was an independent predictor for OS in hepatectomy-treated HCC, suggesting that NLR may be a novel prognostic biomarker for HCC. On the other hand, NLR also has a limitation to predict postoperative prognosis of HCC patients by itself

Clinical Significance of Serum Antithrombin III Activity After Hepatectomy for Hepatocellular Carcinoma

[Background] As antithrombin III (AT-III) is produced in the hepatocytes, its serum activity decreases at the time of liver failure, in addition to ischemia reperfusion injury, vascular endothelial dysfunction, and disseminated intravascular coagulation (DIC). Here, we examined whether the serum AT-III value after hepatectomy could be a prognostic factor for hepatocellular carcinoma (HCC). [Methods] Of 141 patients who underwent hepatectomy for HCC, data for 101 patients in whom serum AT-III activity was measured on the first postoperative day were extracted. Patients with serum AT-III activity > 50% and ? 50% were assigned to high value (72 cases) and low value (29 cases) groups, respectively. We examined the clinical and prognostic differences between these two groups. [Results] The average age of enrolled patients (83 men and 18 women) was 68.0 years. The 5-year overall survival rate was 88% and 60% in the high and low value groups, respectively (P < 0.01). Furthermore, the 2-year relapse-free survival rate was 71% and 54% in the high and low value groups, respectively (P = 0.03). [Conclusion] This is the first study to demonstrate that serum AT-III levels on the first postoperative day may serve as a prognostic factor in HCC patients

Portal Vein Stenting for Portal Vein Stenosis After Pancreatoduodenectomy : A Case Report

Portal vein stenosis, which results in serious clinical conditions such as gastrointestinal variceal bleeding and liver failure, is caused by hepatobiliary pancreatic cancer or major postoperative complications after hepatobiliary pancreatic surgery. In recent years, portal vein stenting under interventional radiology has been applied as a more useful treatment method for portal vein stenosis than invasive surgery. We herein report the successful use of a vascular stent for portal vein stenosis after pancreatoduodenectomy. A 66-year-old man with distal cholangiocarcinoma underwent subtotal stomach-preserving pancreatoduodenectomy with resection of the portal vein because of direct invasion to the main portal vein at our hospital. The portal vein was reconstructed without a venous graft. He developed jejunal bleeding near the pancreatojejunostomy on postoperative day (POD) 2. Although embolization of the responsible vessel achieved hemostasis, an intraoperatively inserted drainage tube was needed for a long period of time postoperatively because the embolized afferent jejunum was perforated. He was discharged on POD 39 after removal of the drainage tube. On POD 282, he was readmitted with melena and severe fatigue. Computed tomography revealed an obstruction of the reconstructed portal vein and varices at the hepaticojejunostomy site. We diagnosed variceal bleeding and performed percutaneous transhepatic stenting in the obstructed portal vein. The patient was discharged in good clinical condition on day 15 after stenting. In conclusion, portal vein stenting is a useful and less invasive therapy for portal vein stenosis

Traumatic Gastric Perforation Associated with Cardiopulmonary Resuscitation: A Case Report

Sternal and rib fractures are well-known complications of cardiopulmonary resuscitation (CPR). We experienced a rare case of traumatic gastric perforation associated with CPR that required emergency laparotomy. In this case, we examined whether surgery is essential for gastric perforation associated with CPR. A 67-year-old man experienced cardiopulmonary arrest in the workplace, and bystander CPR was performed by his colleagues. He was then transported by ambulance to our hospital. A large amount of free air was found in the peritoneal cavity on computed tomography at presentation, and perforation of the gastrointestinal tract was suspected. During emergency laparotomy, a 2-cm serosal-muscular layer tear was found in the gastric lesser curvature. The damaged stomach wall was repaired, the abdominal cavity was lavaged, and surgery was completed by placing a drainage tube. The patient’s postoperative course was good and he was discharged on the 26th postoperative day. Emergency laparotomy has been performed frequently for traumatic gastric perforation associated with CPR. However, emergency laparotomy may be avoided by conservative treatment in some cases. Traumatic gastric perforation associated with CPR is a serious complication; however, the life prognosis of cardiopulmonary arrest patients depends on the original disease and the success of CPR. Traumatic gastric perforation associated with CPR is rarely fatal, and bystanders should not hesitate to initiate CPR