Background & Aims De novo lipogenesis is believed to be involved in oncogenesis. We investigated the role of aberrant lipid biosynthesis in the pathogenesis of human hepatocellular carcinoma (HCC). Methods We evaluated expression of enzymes that regulate lipogenesis in human normal liver tissues and HCC and surrounding, nontumor, liver tissues from patients using real-time reverse transcription polymerase chain reaction, immunoblotting, immunohistochemistry, and biochemical assays. Effects of lipogenic enzymes on human HCC cell lines were evaluated using inhibitors and overexpression experiments. The lipogenic role of the proto-oncogene AKT was assessed in vitro and in vivo. Results In human liver samples, de novo lipogenesis was progressively induced from nontumorous liver tissue toward the HCC. Extent of aberrant lipogenesis correlated with clinical aggressiveness, activation of the AKT−mammalian target of rapamycin signaling pathway, and suppression of adenosine monophosphate−activated protein kinases. In HCC cell lines, the AKT−mammalian target of rapamycin complex 1−ribosomal protein S6 pathway promoted lipogenesis via transcriptional and post-transcriptional mechanisms that included inhibition of fatty acid synthase ubiquitination by the USP2a de-ubiquitinase and disruption of the SREBP1 and SREBP2 degradation complexes. Suppression of the genes adenosine triphosphate citrate lyase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, or sterol regulatory element-binding protein 1, which are involved in lipogenesis, reduced proliferation, and survival of HCC cell lines and AKT-dependent cell proliferation. Overexpression of an activated form of AKT in livers of mice induced lipogenesis and tumor development. Conclusions De novo lipogenesis has pathogenic and prognostic significance for HCC. Inhibitors of lipogenic signaling, including those that inhibit the AKT pathway, might be useful as therapeutics for patients with liver cancer.

Background & Aims Cancer cells often lose contact inhibition to undergo anchorage-independent proliferation and become resistant to apoptosis by inactivating the Hippo signaling pathway, resulting in activation of the transcriptional co-activator yes-associated protein (YAP). However, the oncogenic mechanisms of YAP activity are unclear. Methods By using cross-species analysis of expression data, the Notch ligand Jagged-1 (Jag-1) was identified as a downstream target of YAP in hepatocytes and hepatocellular carcinoma (HCC) cells. We analyzed the functions of YAP in HCC cells via overexpression and RNA silencing experiments. We used transgenic mice that overexpressed a constitutively activated form of YAP (YAP^S127A), and measured protein levels in HCC, colorectal and pancreatic tumor samples from patients. Results Human HCC cell lines and mouse hepatocytes that overexpress YAP^S127A up-regulated Jag-1, leading to activation of the Notch pathway and increased proliferation. Induction of Jag-1, activation of Notch, and cell proliferation required binding of YAP to its transcriptional partner TEA domain family member 4 (TEAD4); TEAD4 binding required the Mst1/2 but not β-catenin signaling. Levels of YAP correlated with Jag-1 expression and Notch signaling in human tumor samples and correlated with shorter survival times of patients with HCC or colorectal cancer. Conclusions The transcriptional regulator YAP up-regulates Jag-1 to activate Notch signaling in HCC cells and mouse hepatocytes. YAP-dependent activity of Jag-1 and Notch correlate in human HCC and colorectal tumor samples with patient survival times, suggesting the use of YAP and Notch inhibitors as therapeutics for gastrointestinal cancer. Transcript profiling: microarray information was deposited at the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=jxepvsumwosqkve&acc=GSE35004).

Our study demonstrates that, compared with multiphasic 64-section multidetector CT, gadoxetate disodium–enhanced MR imaging yields significantly higher diagnostic accuracy and sensitivity for the detection of hepatocellular carcinoma in patients with cirrhosis (P = .001 for both comparisons). Purpose To prospectively compare gadoxetate disodium–enhanced magnetic resonance (MR) imaging with multiphasic 64-section multidetector computed tomography (CT) in the detection of hepatocellular carcinoma (HCC) in patients with cirrhosis. Materials and Methods Institutional review board approval and informed patient consent were obtained for this prospective study. Fifty-eight patients (39 men, 19 women; mean age, 63 years; age range, 35–84 years) underwent gadoxetate disodium–enhanced MR imaging and multiphasic 64-section multidetector CT. The imaging examinations were performed within 30 days of each other. The two sets of images were qualitatively analyzed in random order by three independent readers in a blinded and retrospective fashion. Using strict diagnostic criteria for HCC, readers classified all detected lesions with use of a four-point confidence scale. The reference standard was a combination of pathologic proof, conclusive imaging findings, and substantial tumor growth at follow-up CT or MR...

Research from JAMA Surgery — Surgical Treatment of Pancreatic Head Carcinoma in Elderly Patients