Noriyuki Kitagawa

miR-148a plays a pivotal role in the liver by promoting the hepatospecific phenotype and suppressing the invasiveness of transformed cells.

MicroRNAs (miRNAs) are evolutionary conserved small RNAs that post‐transcriptionally regulate the expression of target genes. To date, the role of miRNAs in liver development is not fully understood. By using an experimental model that allows the induced and controlled differentiation of mouse fetal hepatoblasts (MFHs) into mature hepatocytes, we identified miR‐148a as a hepatospecific miRNA highly expressed in adult liver. The main finding of this study revealed that miR‐148a was critical for hepatic differentiation through the direct targeting of DNA methyltransferase (DNMT) 1, a major enzyme responsible for epigenetic silencing, thereby allowing the promotion of the “adult liver” phenotype. It was also confirmed that the reduction of DNMT1 by RNA interference significantly promoted the expression of the major hepatic biomarkers. In addition to the essential role of miR‐148a in hepatocyte maturation, we identified its beneficial effect through the repression of hepatocellular carcinoma (HCC) cell malignancy. miR‐148a expression was frequently down‐regulated in biopsies of HCC patients as well as in mouse and human HCC cell lines. Overexpressing miR‐148a led to an enhancement of albumin production and a drastic inhibition of the invasive properties of HCC cells, whereas miR‐148a silencing had the opposite consequences. Finally, we showed that miR‐148a exerted its tumor‐suppressive effect by regulating the c‐Met oncogene, regardless of the DNMT1 expression level. Conclusion: miR‐148a is essential for the physiology of the liver because it promotes the hepatospecific phenotype and acts as a tumor suppressor. Most important, this report is the first to demonstrate a functional role for a specific miRNA in liver development through regulation of the DNMT1 enzyme. (Hepatology 2013;53:1153–1165)

Downregulation of the microRNA biogenesis components and its association with poor prognosis in hepatocellular carcinoma

Genetic alterations and deregulation of the miRNA biogenesis pathway components have been reported in human tumors. Tissue‐specific deletion of the Dicer gene, which encodes an essential miRNA processing enzyme, promotes carcinogenesis in animal models. These features indicate that aberrant miRNA biogenesis components are directly associated with cancer. For the present study, we conducted quantitative RT‐PCR of 14 genes that are related to the miRNA biogenesis pathway in 47 paired samples of primary hepatocellular carcinoma (HCC) and matched non‐cancerous liver. Expression of seven genes (Dgcr8, p68, p72, Dicer, Ago3, Ago4 and Piwil4) was significantly decreased in primary HCC, especially in non‐viral HCC subtypes, compared to the non‐cancerous liver. Combinations of decreased expression of the miRNA biogenesis components in non‐cancerous liver were related to cigarette smoking, alcohol intake and diabetes, which are known to be risk factors for HCC, and were also associated with the occurrence of multicentric tumors. Reduction of two of these genes (Dicer and p68) in HCC was associated with poor prognosis. Trimethylation of histone H3 lysine 27 in the promoters is implicated in the deregulation of these miRNA‐biogenesis‐related genes in non‐HBV genome integrated HCC cell lines. In conclusion, deregulation of the miRNA biogenesis pathway components is frequently observed in non‐viral‐associated HCC and is linked to etiological risk factors and poor prognosis. Our study further showed that epigenetic regulation could be implicated in the deregulation of these genes during hepatocarcinogenesis.

Impact of advanced age on the short- and long-term outcomes in patients undergoing hepatectomy for hepatocellular carcinoma: a single-center analysis over a 20-year period

BACKGROUND The purpose of this study was to analyze the influence of age on both the risk of hepatectomy and the prognosis in patients with hepatocellular carcinoma (HCC). METHODS Patients undergoing an initial hepatectomy for HCC were classified into 2 age groups: 75 years or over (n = 113) and less than 75 years (n = 499). RESULTS A zero 90-day mortality was achieved in the elderly. Although the recurrence rate and recurrence sites were almost similar between the 2 groups, the 5-year survival rate in the elderly patients was significantly lower than that in the younger patients (46.0% vs 57.6%; P = .018), possibly because of the higher incidence of deaths from other causes (26.8% vs 10.4%; P = .011) in the elderly. CONCLUSION Selected elderly HCC patients can undergo a hepatectomy safely and can benefit from long-term HCC control comparable with that of their younger counterparts.

Hepatectomy preserving drainage veins of the posterior section for liver malignancy invading the right hepatic vein: an alternative to right hepatectomy.

BACKGROUND Although a right hepatectomy (RH) traditionally has been performed for liver tumors infiltrating the main trunk of the right hepatic vein (RHV), the presence of drainage veins of the posterior section (DVPS) beside the RHV provides a chance to preserve their draining area even if the main trunk of the RHV is removed. METHODS Since 2005, we systematically have performed DVPS-preserving hepatectomies whenever possible. In the present study, we describe our experience treating 12 consecutive patients who underwent this procedure. RESULTS We performed the following types of liver resections concomitant with the main trunk of the RHV without packed red cell transfusion, liver failure, or 90-day mortality: extended right anterior sectionectomy in 2 patients, extended segmentectomy 7 in 3, extended segmentectomy 8 in 2, and partial resection of segment 7 in 2 and segment 8 in 3. Postoperative morbidity was observed in 4 (33%) cases, all of which had pleural effusion requiring a tap. A free resection margin was obtained in all patients. CONCLUSIONS This procedure could be a useful alternative to RH, providing a chance for radical liver resection with minimal parenchymal sacrifice in selected patients with DVPS.

Cystic mixed adenoneuroendocrine carcinoma of the pancreas: A case report

Highlights • There are few reports about pancreatic MANEC with cystic features.• Mixed tumor of the pancreas may arise from totipotent stem cells.• The treatment strategy is unclear, but surgery may be the first choice if possible.

Tu1061 Impact of Multiple Tumors or Portal Hypertension on the Results of Second Hepatectomy for Recurrent Hepatocellular Carcinoma: A Single Center Experience

Background & Aims: Roayaie et al. reported a 5-year overall survival (OS) rate of 67% after second hepatectomy for recurrent hepatocellular carcinoma (HCC) in highly selected patients with a single nodule, preserved liver function, and noportal hypertension (PHT). The aim of this study was whether second liver resection can offer survival benefit for patients with multiple HCCs and/or PHT. Methods: We retrospectively studied 101 patients who had undergone second liver resection for recurrent HCC and stratified them into 3 groups according to the number of tumors and the presence of PHT, defined as a platelet count , 100,000/μL and/or the presence of esophageal varices: group A, patients with solitary tumor and no-PHT (n = 45); group B, those with either multiple tumor or PHT (n = 48); and Group C, those with both multiple tumor and PHT (n = 8). Overall survival (OS) and recurrence rate (RR) curves were constructed by the Kaplan-Meier method, and multivariate regression analysis was performed using the Cox proportional hazard model. Results: There was no 30-day mortality. The morbidity rate was comparable among the groups. The 5year OS rates and the 2-year recurrent rates were 67% and 60% in group A, 62%and 55% in group B, and 38% and 88% in group C, respectively, showing no significant differences among the three groups. In a multivariate analysis, neither multiple tumors nor presence of PHT was a predictive factor for poor prognosis. Conclusions: We can extend the indication of second hepatectomy for recurrent HCC, at least, to the patients with either multiple HCCs or PHT.