Lingli Chen

Liver cancer initiation is controlled by AP-1 through SIRT6-dependent inhibition of survivin

Understanding stage-dependent oncogenic mechanisms is critical to develop not only targeted therapies, but also diagnostic markers and preventive strategies. The mechanisms acting during cancer initiation remain elusive, largely owing to a lack of suitable animal models and limited availability of human precancerous lesions. Here we show using genetic mouse models specific for liver cancer initiation, that survival of initiated cancer cells is controlled by c-Jun, independently of p53, through suppressing c-Fos-mediated apoptosis. Mechanistically, c-Fos induces SIRT6 transcription, which represses survivin by reducing histone H3K9 acetylation and NF-κB activation. Importantly, increasing the level of SIRT6 or targeting the anti-apoptotic activity of survivin at the initiation stage markedly impairs cancer development. Moreover, in human dysplastic liver nodules, but not in malignant tumours, a specific expression pattern with increased c-Jun-survivin and attenuated c-Fos-SIRT6 levels was identified. These results reveal a regulatory network connecting stress response and histone modification in liver tumour initiation, which could be targeted to prevent liver tumorigenesis.Understanding stage-dependent oncogenic mechanisms is critical to develop not only targeted therapies, but also diagnostic markers and preventive strategies. The mechanisms acting during cancer initiation remain elusive, largely owing to a lack of suitable animal models and limited availability of human precancerous lesions. Here we show using genetic mouse models specific for liver cancer initiation, that survival of initiated cancer cells is controlled by c-Jun, independently of p53, through suppressing c-Fos-mediated apoptosis. Mechanistically, c-Fos induces SIRT6 transcription, which represses survivin by reducing histone H3K9 acetylation and NF-κB activation. Importantly, increasing the level of SIRT6 or targeting the anti-apoptotic activity of survivin at the initiation stage markedly impairs cancer development. Moreover, in human dysplastic liver nodules, but not in malignant tumours, a specific expression pattern with increased c-Jun–survivin and attenuated c-Fos–SIRT6 levels was identified. These results reveal a regulatory network connecting stress response and histone modification in liver tumour initiation, which could be targeted to prevent liver tumorigenesis.

Liver computed tomographic perfusion in the assessment of microvascular invasion in patients with small hepatocellular carcinoma.

ObjectivesDetecting microvascular invasion (mVI) in patients with hepatocellular carcinoma is a diagnostic challenge. The present study aimed to acquire a series of quantitative perfusion parameters from liver computed tomography (CT) with a 320-slice scanner in patients with small hepatocellular carcinoma (sHCC) and study its efficacy in identifying mVI. Materials and MethodsFifty-six patients who underwent hepatic resection for sHCC (⩽3 cm) were preoperatively examined with a 320-detector row CT scanner. Histopathological analyses of liver biopsies confirmed that 18 patients had sHCC with mVI and that 38 patients had sHCC without mVI. Hepatic artery flow, portal vein flow (PVF), and perfusion index were measured in both tumor and normal liver tissues. Nonparametric receiver operating characteristic curve analysis was performed to quantify the accuracy of the perfusion CT parameters. ResultsThe tumor PVF (PVFtumor), difference in PVF between tumor and liver tissue (&Dgr;PVF), and the &Dgr;PVF/liver PVF ratio (rPVF) were significantly higher in sHCC with mVI than in sHCC without mVI (P = 0.0094, P = 0.0018, and P = 0.0007, respectively; Wilcoxon signed rank test). The PVFtumor, &Dgr;PVF, and rPVF correctly predicted mVI in 73.2% (sensitivity, 66.7%; specificity, 76.3%; cutoff, 103.8 mL per 100 mL/min), 76.8% (sensitivity, 66.7%; specificity, 81.6%; cutoff, −53.65 mL per 100 mL/min), and 83.9% (sensitivity, 77.8%; specificity, 86.8%; cutoff, −0.38) of a total of 56 patients with sHCC, respectively. Other parameters were not significantly different between the groups. ConclusionsLiver CT perfusion provides a noninvasive, quantitative method that can predict mVI in patients with sHCC through measurement of 3 perfusion parameters: PVFtumor, &Dgr;PVF, and rPVF.

MRI of small intrahepatic mass-forming cholangiocarcinoma and atypical small hepatocellular carcinoma (≤3 cm) with cirrhosis and chronic viral hepatitis: a comparative study.

OBJECTIVE The objective was to identify the decision-making magnetic resonance (MR) features in differentiating small intrahepatic mass-forming cholangiocarcinoma (sIMCC) from atypical small hepatocellular carcinoma (sHCC) (≤3 cm) in patients with cirrhosis and chronic viral hepatitis. METHODS Signal features and relative contrast of sHCCs and sIMCCs in T2-weighted and dynamic enhanced imaging were analyzed. A subgroup comparison between the cirrhosis and noncirrhosis chronic viral hepatitis group was also made. RESULTS Univariate analysis revealed that tumor contours (P<.001), signals in T2-weighted (P<.001) and each phase of contrast-enhanced scanning (P<.001), enhancement patterns (P<.001), as well as accompanying findings of tumor capsule (P<.001), hepatic capsule retraction (P<.001), bile duct dilation (P=.031), and transient hepatic intensity difference (P=.002) were different between sIMCC and atypical sHCC. Multivariate analysis indicated that dynamic enhancement patterns (P<.001) and signals in T2-weighted images (P=.024) were independent predictors for differentiation. Confusing MR features were more often observed in the cirrhosis group compared with those in the noncirrhosis chronic viral hepatitis group. CONCLUSION Dynamic enhancement patterns and signals in T2-weighted images were the most important MR features to differentiate sIMCC from atypical sHCC with cirrhosis and chronic viral hepatitis.

Retrospective study of hepatocellular adenomas based on the phenotypic classification system: A report from China

A molecular and pathological classification system for hepatocellular adenomas (HCAs) was recently introduced in Europe, resulting in four major identified subgroups. Asian countries have a considerably lower incidence of HCA as well as a different etiology. We aimed to characterize HCAs in a Chinese population based on this new classification system. A series of 30 patients with HCA were analyzed based on the phenotypic classification system using immunohistochemical analysis. Investigated antigens included liver-fatty acid binding protein (L-FABP), glutamine synthetase (GS), β-catenin, serum amyloid A (SAA), and C-reactive protein (CRP). Of the 30 cases (20 female) included in this study, only one had a history of oral contraceptive use. We identified 9 (30%) hepatocyte nuclear factor (HNF)-1α-inactivated HCAs, 3 (10%) β-catenin-activated HCAs, 11 (36.7%) inflammatory HCAs, and 7 (23.3%) unclassified HCAs. In the inflammatory HCA group, 2 cases demonstrated concurrent β-catenin-activation. Homogeneous steatosis (6/9) and microadenomas (2/9) were more frequently observed in HNF1α-inactivated HCAs. A body mass index (BMI) of greater than 25 (5/11), alcohol use (4/11), and steatosis in background liver (3/11) were more frequent in inflammatory HCAs. β-catenin-activated HCAs were larger than those of other subgroups. Despite obvious differences in etiology and gender proportion compared with Western countries, the clinical and pathological characteristics of HCA subgroups in China are similar to those in Europe. The phenotypic classification system could be reliably applied to Chinese patients as a meaningful tool for HCA management.

Detection of Endogenous Iron Reduction during Hepatocarcinogenesis at Susceptibility-Weighted MR Imaging: Value for Characterization of Hepatocellular Carcinoma and Dysplastic Nodule in Cirrhotic Liver

Objective To investigate the value of susceptibility-weighted imaging (SWI) for characterization of hepatocellular carcinoma (HCC) and dysplastic nodule (DN). Materials and Methods Sixty-eight cirrhotic patients with 89 hepatocellular nodules underwent SWI. The radiological features of hepatocellular nodules on SWI were classified into three types: type A (iso- or hypointensity, and background liver siderosis), type B (hyperintensity, and background liver siderosis), or type C (hyperintensity, and no background liver siderosis). Intranodular and background liver iron content was quantified and correlated with SWI pattern. Prussian blue staining was performed to quantify intranodular and background liver iron content. Results Type A pattern (n = 12) contained 11 (91.7%) DNs and 1 (8.3%) HCC, Type B pattern (n = 66) comprised 1 (1.5%) DN and 65 (98.5%) HCCs (including 12 DN-HCCs and 53 overt HCCs), and type C pattern (n = 11) was exclusively seen in HCCs. The iron scores of DN-HCCs and overt HCCs were significantly lower than those of background livers [(0.091±0.30) VS (2.18±0.87), P = 0.000; (0.11±0.41) VS (2.16±0.97), P = 0.000; respectively]. There was no significant difference between iron scores of DNs and those of background livers [(1.92±0.29) VS (2.17±039), P = 0.191]. For lesion-based and patient-based analysis of HCCs (DN-HCCs and overt HCCs), type B pattern showed a sensitivity, specificity, accuracy, positive predicative value (PPV), and negative predicative value (NPV) of 84.4% and 84.4%, 91.7% and 75%, 85.4% and 83.8%, 98.5% and 98.2%, 47.8% and 23.1%, respectively. Conclusion SWI can provide valuable information for characterization of HCC and DN based on endogenous iron reduction during hepatocarcinogenesis.