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Background and aims: Liver regeneration retardation post partial hepatectomy (PH) is a common clinical problem after liver transplantation. Identification of key regulators in liver regeneration post PH may be beneficial for clinically improving the prognosis of patients after liver transplantation. This study aimed to clarify the function of junctional protein‐associated with coronary artery disease (JCAD) in liver regeneration post PH and to reveal the underlying mechanisms. Methods: JCAD knockout (JCAD‐KO), liver‐specific JCAD‐KO (Jcad△Hep) mice and their control group were subjected to 70% PH. RNA sequencing was conducted to unravel the related signalling pathways. Primary hepatocytes from KO mice were treated with epidermal growth factor (EGF) to evaluate DNA replication. Fluorescent ubiquitination‐based cell cycle indicator (FUCCI) live‐imaging system was used to visualise the phases of cell cycle. Results: Both global and liver‐specific JCAD deficiency postponed liver regeneration after PH as indicated by reduced gene expression of cell cycle transition and DNA replication. Prolonged retention in G1 phase and failure to transition over the cell cycle checkpoint in JCAD‐KO cell line was indicated by a FUCCI live‐imaging system as well as pharmacologic blockage. JCAD replenishment by adenovirus reversed the impaired DNA synthesis in JCAD‐KO primary hepatocyte in exposure to EGF, which was abrogated by a Yes‐associated protein (YAP) inhibitor, verteporfin. Mechanistically, JCAD competed with large tumour suppressor 2 (LATS2) for WWC1 interaction, leading to LATS2 inhibition and thereafter YAP activation, and enhanced expression of cell cycle‐associated genes. Conclusion: JCAD deficiency led to delayed regeneration after PH as a result of blockage in cell cycle progression through the Hippo–YAP signalling pathway. These findings uncovered novel functions of JCAD and suggested a potential strategy for improving graft growth and function post liver transplantation. Key Points: JCAD deficiency leads to an impaired liver growth after PH due to cell division blockage.JCAD competes with LATS2 for WWC1 interaction, resulting in LATS2 inhibition, YAP activation and enhanced expression of cell cycle‐associated genes.Delineation of JCADHippoYAP signalling pathway would facilitate to improve prognosis of acute liver failure and graft growth in living‐donor liver transplantation. [ABSTRACT FROM AUTHOR]

Background and aims: Treatment of non‐alcoholic steatohepatitis (NASH) is challenging, because suppressing fibrotic progression has not been achieved consistently by drug candidates currently in clinical trials. The aim of this study was to investigate the molecular interplays underlying NASH‐associated fibrosis in a mouse NASH model and human specimens. Methods: Mice were divided into 4 groups: Controls; NASH (high fat/Calorie diet plus high fructose and glucose in drinking water, HFCD‐HF/G) for 16 weeks; HFCD‐HF/G plus docosahexaenoic acid (DHA) for 16 or 8 weeks. Results: Along with NASH progression, fibrotic deposition was documented in HFCD‐HF/G‐fed mice. Liver succinate content was significantly increased along with decreased expression of succinate dehydrogenase‐A (SDH‐A) in these mice; whereas, GPR‐91 receptor expression was much enhanced in histology compared to control mice, and co‐localized histologically with hepatic stellate cells (HSCs). Succinate content was increased in fatty acid‐overloaded primary hepatocytes with significant oxidant stress and lipotoxicity. Exposure to succinate led to up‐regulation of GPR‐91 receptor in primary and immortalized HSCs. In contrast, suppression of GPR‐91 receptor expression abolished succinate stimulatory role in GPR‐91 expression and extracellular matrix production in HSCs. All these changes were minimized or abrogated by DHA supplementation in vivo or in vitro. Moreover, GPR‐91 receptor expression correlates with severity of fibrosis in human NASH biopsy specimens. Conclusion: Succinate accumulation in steatotoic hepatocytes may result in HSC activation through GPR‐91 receptor signalling in NASH progression, and the cross‐talk between hepatocytes and HSC through GPR‐91 signalling is most likely to be the molecular basis of fibrogenesis in NASH. [ABSTRACT FROM AUTHOR]

We aimed to investigate the expression of RACK1 in breast cancer, evaluate its role in predicting prognosis and compare with commonly used biomarkers: Ki67, ER, PR and HER-2 for patients with breast cancer. The RACK1 expression and its clinical significance were examined in 160 breast carcinoma patients using immunohistochemistry. Correlations of RACK1 expression with other commonly used biomarkers and survival analyses were assessed. Immunohistochemistry results showed that the number of RACK1 cases scoring 0, 1, and 2 were 66, 54, and 40, respectively. RACK1 staining was strongly related to clinical stage, histological grade, Ki67, ER, PR and HER-2 (all p < 0.05). Consistently, all of the cases exhibiting RACK1 staining score 0 were survivors, whereas the majority (55.0%) of those exhibiting RACK1 staining score 2 were deaths. Kaplan-Meier survival analysis of 160 cases revealed a correlation between higher RACK1 expression levels and shorter overall survival times ( p < 0.001). Univariate and multivariate analyses revealed that RACK1, tumor size, lymph node metastasis, and HER-2 were independent prognostic factors (all p < 0.05). Interestingly, receiver operator characteristic (ROC) curves showed that the ROC areas for RACK1, Ki67, ER, PR and HER-2 were 0.833, 0.766, 0.446, 0.387, and 0.689, respectively, and the superiority of RACK1 in sensitivity and specificity as biomarker was demonstrated. To our knowledge, it is the first time to investigate the expression of RACK1, and identified that RACK1 is a superior independent biomarker for diagnosis and prognosis comparing with currently widely used diagnostic index in breast carcinoma. [ABSTRACT FROM AUTHOR]

Special AT-rich sequence binding protein (SATB) 1 has been proposed to act as a determinant for the acquisition of metastatic activity by controlling expression of a specific set of genes that promote metastatic activity. Here we found that SATB1 expression is upregulated in multidrug-resistant breast cancer cells that exhibit higher invasive potential than the parental cells. Apart from accelerating metastasis and inducing epithelial–mesenchymal transition, SATB1 was demonstrated to confer resistance to both P-glycoprotein-related and P-glycoprotein-non-related drugs on MCF7 cells, which was accompanied by decreasing accumulation of adriamycin in SATB1-overexpressing transfectants. SATB1 depletion could partially reverse the multidrug resistance (MDR) phenotype of MCF7/ADR in vitro and in vivo. The SATB1-induced P-glycoprotein-mediated MDR could be reversed by treatment with anti-P-glycoprotein mAb. Moreover, SATB1 plays an important role in anti-apoptotic activity in MCF7/ADR cells in response to adriamycin treatment, which suggests another mechanism contributing to SATB1-related MDR of breast cancers. These data provide new insights into the mode by which breast tumors acquire the MDR phenotype and also imply a role for SATB1 in this process. ( Cancer Sci 2009) [ABSTRACT FROM AUTHOR]

To determine whether p53 expression is different in intestinal and diffuse types of gastric carcinoma, we investigated p53 immunohistochemical expression in 178 primary gastric carcinomas. Overexpression of p53 was observed in 50 out of 100 intestinal-type tumors (50.0%) and in 27 out of 78 diffuse-type tumors (34.6%). A significant difference was found in the timing of p53 overexpression between the two types of carcinomas. Overexpression of p53 occurred often in the early stage of intestinal-type tumors, and there was no significant difference in expression between early and advanced cancers. In contrast, p53 overexpression did not occur often in the early stage of diffuse-type tumors, but it increased progressively as the tumor advanced. Analysis of patient survival revealed that p53 overexpression correlates significantly with a poor prognosis in diffuse-type gastric carcinoma (P = 0.003) but not in intestinal-type. Multivariate analysis showed that only pathological stage was an independent prognostic indicator. Our results suggest that p53 overexpression plays a different role in tumor carcinogenesis and progression of these two types of gastric cancers. [ABSTRACT FROM AUTHOR]

The cover image is based on the Original Article Succinate-GPR-91 Receptor Signaling Is Responsible for Nonalcoholic Steatohepatitis-Associated Fibrosis: Effects of DHA Supplementation by Jian Wu, Ying Wang, Li Xie et al., https://doi.org/10.1111/liv.14370. GLO:Q18/01apr20:liv14442-toc-0001.jpg PHOTO (COLOR): . gl. [Extracted from the article]