Oxidative stress and inflammation are the most important pathogenic events in the development and progression of liver diseases. Nuclear erythroid 2-related factor 2 (Nrf2) is the master regulator of the cellular protection via induction of anti-inflammatory, antioxidant, and cyto-protective genes expression. Multiple studies have shown that activation or suppression of this transcriptional factor significantly affect progression of liver diseases. Comprehensive understanding the roles of Nrf2 activation/expression and the outcomes of its activators/inhibitors are indispensable for defining the mechanisms and therapeutic strategies against liver diseases. In this current review, we discussed recent advances in the function and principal mechanisms by regulating Nrf2 in liver diseases, including acute liver failure, hepatic ischemia–reperfusion injury (IRI), alcoholic liver disease (ALD), viral hepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC).

Osteopontin (OPN), a multifunctional protein, is involved in numerous pathological conditions including inflammation, immunity, angiogenesis, fibrogenesis and carcinogenesis in various tissues. Extensive studies have elucidated the critical role of OPN in cell signaling such as regulation of cell proliferation, migration, inflammation, fibrosis and tumor progression. In the liver, OPN interacts with integrins, CD44, vimentin and MyD88 signaling, thereby induces infiltration, migration, invasion and metastasis of cells. OPN is highlighted as a chemoattractant for macrophages and neutrophils during injury in inflammatory liver diseases. OPN activates hepatic stellate cells (HSCs) to exert an enhancer in fibrogenesis. The role of OPN in hepatocellular carcinoma (HCC) has also generated significant interests, especially with regards to its role as a diagnostic and prognostic factor. Interestingly, OPN acts an opposing role in liver repair under different pathological conditions. This review summarizes the current understanding of OPN in liver diseases. Further understanding of the pathophysiological role of OPN in cellular interactions and molecular mechanisms associated with hepatic inflammation, fibrosis and cancer may contribute to the development of novel strategies for clinical diagnosis, monitoring and therapy of liver diseases.

Intrahepatic cholangiocarcinoma is a highly fatal tumor characterized by an abundant stromal environment. Cancer‐associated fibroblasts play key roles in tumor growth and invasiveness and have been regarded as a potential therapeutic target. This study was designed to isolate human primary cancer‐associated fibroblasts of intrahepatic cholangiocarcinoma to study tumor‐stroma interactions and to analyze the clinical relevance of alpha‐smooth muscle actin ‐positive cancer‐associated fibroblasts in patients with intrahepatic cholangiocarcinoma. The isolated cancer‐associated fibroblasts were positive for alpha‐smooth actin, fibroblast‐specific protein‐1, fibroblast activation protein, and PDGFR‐β. In addition, cancer‐associated fibroblasts were found to increase proliferation, migration, and invasion of cholangiocarcinoma cells in vitro and promote tumor growth of mice in vivo. Moreover, alpha‐smooth muscle actin‐positive expression of cancer‐associated fibroblasts predicted unfavorable prognosis in patients with intrahepatic cholangiocarcinoma and showed correlation with presence of lymph node metastasis. This study may provide a useful tool to investigate further effect of cancer‐associated fibroblasts on the molecular mechanism of cholangiocarcinoma cells as well as contribution of cancer‐associated fibroblasts in lymphangiogenesis and lymph node metastasis.

MiRNA and lncRNA as biomarkers in cholangiocarcinoma(CCA) miRNA and lncRNA as biomarkers in cholangiocarcinoma(CCA)

Previous nomograms for intrahepatic cholangiocarcinoma (ICC) were conducted to predict overall survival, which could be influenced by various factors. Herein, we conducted our nomogram to predict recurrence of the tumor only after hepatic resection. The nomogram was established with prognostic factors for the relapse-free survival (RFS) analyzed from our single center cohort and was evaluated by comparing with the American Joint Committee on Cancer (AJCC) staging system for the predictive accuracy. Seropositivity of hepatitis B surface antigen (hazard ratio [HR], 0.505; 95% confidence interval [CI], 0.279 to 0.914; P = 0.024), tumor size of larger than 5 cm (HR, 1.947; 95% CI, 1.177 to 3.219; P = 0.009), Child-Pugh score of B (HR, 3.067; 95% CI, 1.293 to 7.275; P = 0.011), and lymph node metastasis (HR, 2.790; 95% CI, 1.628 to 4.781; P < 0.001) were found to be independent prognostic factors that significantly affected RFS. The calibration curve for the prediction revealed excellent agreement between estimation by our stratification system and actual RFS. The concordance C index of the nomogram (0.71; 95% CI, 0.65 to 0.77) revealed to be significantly higher than the AJCC staging system (0.66; 95% CI, 0.60 to 0.72). In the validation cohort, our risk stratification system (C-index 0.65; 95% CI, 0.59 to 0.71) also revealed more precise prediction than the AJCC staging system (C-index, 0.57; 95% CI, 0.50 to 0.64). Our nomogram could more accurately predict recurrence of ICC after hepatic resection than the AJCC staging system.

Seogsong Jeong, Yun Hwan Oh, Seulggie Choi, Jooyoung Chang, Sung Min Kim, Joung Sik Son, Gyeongsil Lee, Won Kim, and Sang Min Park. Gut and Liver 2022;16:589-98. https://doi.org/10.5009/gnl210256