Background Hepatocellular carcinoma is a common and aggressive cancer that occurs mainly in men. We examined microRNA expression patterns, survival, and response to interferon alfa in both men and women with the disease. Methods We analyzed three independent cohorts that included a total of 455 patients with hepatocellular carcinoma who had undergone radical tumor resection between 1999 and 2003. MicroRNA-expression profiling was performed in a cohort of 241 patients with hepatocellular carcinoma to identify tumor-related microRNAs and determine their association with survival in men and women. In addition, to validate our findings, we used quantitative reverse-transcriptase–polymerase-chain-reaction assays to measure microRNAs and assess their association with survival and response to therapy with interferon alfa in 214 patients from two independent, prospective, randomized, controlled trials of adjuvant interferon therapy. Results In patients with hepatocellular carcinoma, the expression of miR-26a and miR-26b in nontumor liver tissue was higher in women than in men. Tumors had reduced levels of miR-26 expression, as compared with paired noncancerous tissues, which indicated that the level of miR-26 expression was also associated with hepatocellular carcinoma. Moreover, tumors with reduced miR-26 expression had a distinct transcriptomic pattern, and analyses of gene networks revealed that activation of signaling pathways between nuclear factor κB and interleukin-6 might play a role in tumor development. Patients whose tumors had low miR-26 expression had shorter overall survival but a better response to interferon therapy than did patients whose tumors had high expression of the microRNA. Conclusions The expression patterns of microRNAs in liver tissue differ between men and women with hepatocellular carcinoma. The miR-26 expression status of such patients is associated with survival and response to adjuvant therapy with interferon alfa.

For Child-Pugh class A patients with small HCC, hepatic resection is a reasonable first-line treatment associated with a favorable 5-year overall survival rate. A considerable proportion of patients may survive without recurrence for 5 or even 10 years; among those with recurrence, the majority may be eligible for salvage transplantation. These data suggest that primary resection and salvage transplantation may be a feasible and rational strategy for patients with small HCC and preserved liver function. Primary transplantation may be a preferable option for the subset of patients with oligonodular tumors in cirrhotic liver in view of the poor survival results after resection.

Perioperative outcome has improved despite extending the indication of hepatectomy to more high-risk patients. The role of hepatectomy in the management of hepatobiliary diseases can be expanded. Reduced perioperative transfusion is the main contributory factor for improved outcome.

Better understanding of human hepatocellular carcinoma (HCC) pathogenesis at the molecular level will facilitate the discovery of tumor initiating events. Herein, transcriptome sequencing revealed that adenosine (A)-to-inosine (I) RNA editing of antizyme inhibitor 1 (AZIN1) displays a high modification rate in HCC specimens. A-to-I editing of AZIN1 transcripts is specifically regulated by adenosine deaminase acting on RNA-1 (ADAR1). The serine (S) → glycine (G) substitution at residue 367, located in β-strand 15 (β15), predicted a conformational change, induced a cytoplasmic-to-nuclear translocation, and conferred “gain-of-function” phenotypes manifested by augmented tumor initiating potential and more aggressive behavior. Compared with wild-type AZIN1 protein, the edited form possesses stronger affinity to antizyme, and the resultant higher protein stability promotes cell proliferation via the neutralization of antizyme-mediated degradation of ornithine decarboxylase (ODC) and cyclin D1 (CCND1). Collectively, A-to-I RNA editing of AZIN1 may be a potential driver in the pathogenesis of human cancers, particularly HCC.

A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor, called tumor-initiating cells (TICs) or cancer stem cells (CSCs). Here we describe the identification and characterization of such cells from hepatocellular carcinoma (HCC) using the marker CD133. CD133 accounts for approximately 1.3%-13.6% of the cells in the bulk tumor of human primary HCC samples. When compared with their CD133⁻ counterparts, CD133(+) cells not only possess the preferential ability to form undifferentiated tumor spheroids in vitro but also express an enhanced level of stem cell-associated genes, have a greater ability to form tumors when implanted orthotopically in immunodeficient mice, and can be serially passaged into secondary animal recipients. Xenografts resemble the original human tumor and maintain a similar percentage of tumorigenic CD133(+) cells. Quantitative PCR analysis of 41 separate HCC tissue specimens with follow-up data found that CD133(+) tumor cells were frequently detected at low quantities in HCC, and their presence was also associated with worse overall survival and higher recurrence rates. Subsequent differential microRNA expression profiling of CD133(+) and CD133⁻ cells from human HCC clinical specimens and cell lines identified an overexpression of miR-130b in CD133(+) TICs. Functional studies on miR-130b lentiviral-transduced CD133⁻ cells demonstrated superior resistance to chemotherapeutic agents, enhanced tumorigenicity in vivo, and a greater potential for self renewal. Conversely, antagonizing miR-130b in CD133(+) TICs yielded an opposing effect. The increased miR-130b paralleled the reduced TP53INP1, a known miR-130b target. Silencing TP53INP1 in CD133⁻ cells enhanced both self renewal and tumorigenicity in vivo. Collectively, miR-130b regulates CD133(+) liver TICs, in part, via silencing TP53INP1.

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External drainage of pancreatic duct with a stent reduced leakage rate of pancreaticojejunostomy after pancreaticoduodenectomy.

A continuous improvement of survival outcomes after hepatectomy for HCC was achieved in the past 20 years even in patients with advanced diseases. Hepatectomy remains the treatment of choice for resectable HCC in a predominantly hepatitis B virus-based Asian population.