Calcyclin-binding protein contributes to cholangiocarcinoma progression by inhibiting ubiquitination of MCM2.

Background: Cholangiocarcinoma (CCA) represents the epithelial cell cancer with high aggressiveness whose five-year survival rate is poor with standard treatment. Calcyclin-binding protein (CACYBP) shows aberrant expression within several malignant tumors, but the role of CACYBP in CCA remains unknown. Methods: Immunohistochemical (IHC) analysis was used to identify CACYBP overexpression in clinical samples of CCA patients. Moreover, its correlation with clinical outcome was revealed. Furthermore, CACYBP's effect on CCA cell growth and invasion was investigated in vitro and in vivo using loss-of-function experiments. Results: CACYBP showed up-regulation in CCA, which predicts the dismal prognostic outcome. CACYBP had an important effect on in-vitro and in-vivo cancer cell proliferation and migration. Additionally, knockdown of CACYBP weakened protein stability by promoting ubiquitination of MCM2. Accordingly, MCM2 up-regulation partly reversed CACYBP deficiency's inhibition against cancer cell viability and invasion. Thus, MCM2 might drive CCA development by Wnt/ß-catenin pathway. Conclusions: CACYBP exerted a tumor-promoting role in CCA by suppressing ubiquitination of MCM2 and activating Wnt/ß-catenin pathway, hence revealing that it may be the possible therapeutic target for CCA treatment.

Role of the pre- to postoperative alpha-fetoprotein ratio in the prognostic evaluation of liver cancer after radiofrequency ablation.

OBJECTIVE: This study aimed to investigate the role of the alpha fetoprotein (AFP) ratio before and after radiofrequency ablation (RFA) in the prognosis of patients with liver cancer. METHODS: A total of 368 patients who underwent RFA for liver cancer in Shenzhen People's Hospital from 2010 to 2020 were randomly divided into the training group and the validation group. Levels of AFP before and after RFA were recorded and their ratios were calculated. RESULTS: Using the X-tile software, it was found that the optimal cut-off value of the AFP ratio in the training group was 37.9. Both in the training group and the validation group, the relapse-free survival and overall survival of patients with an AFP ratio <37.9 (high-risk group) were significantly shorter than those with an AFP ratio >37.9 (low-risk group) (training group, relapse-free survival, P = 0.0003; overall survival, P = 0.0186; validation group, relapse-free survival, P = 0.0490, overall survival, P = 0.0031). An AFP ratio <37.9 was an independent risk factor for recurrence and survival of liver cancer after RFA. CONCLUSION: The AFP ratio can predict the prognosis of patients with liver cancer after RFA. An AFP ratio <37.9 is an independent risk factor for tumor recurrence and survival after RFA.

Ubiquitin specific peptidase 1 promotes hepatic fibrosis through positive regulation of CXCL1 by deubiquitinating SNAIL.

BACKGROUND: Hepatic fibrosis is attributed to an imbalance of extracellular matrix production and lysis. Human hepatic stellate cells (HSCs) have been uncovered to converge through complex interactions with hepatocytes and immune cells, causing scarring in liver damage. AIMS: We aimed to investigate the expression status of ubiquitin specific peptidase 1 (USP1) and its potential mechanisms on HSCs and hepatic fibrosis. METHODS: Hepatic fibrosis animal and cell models were generated using mice with carbon tetrachloride (CCl4) treatment and HSCs LX-2 with TGF-ß1 treatment. Relationships among USP1, SNAIL, and CXCL1 were identified via dual-luciferase reporter gene assay, co-immunoprecipitation, and chromatin immunoprecipitation. With gain- and loss-of-experiments, CCK-8 and flow cytometry assays were employed for cell proliferation and apoptosis. RESULTS: USP1 upregulated SNAIL expression through deubiquitination to increase CXCL1 expression. USP1 downregulation decreased expressions of fibrosis-related genes, suppressed proliferation, and promoted apoptosis in TGF-ß1-induced LX-2 cells, which were reversed by SNAIL overexpression. The pro-fibrosis role caused by SNAIL upregulation was abolished by CXCL1 reduction. Promotive function of USP1/SNAIL/CXCL1 axis in hepatic fibrosis was further confirmed in vivo. CONCLUSION: These data supported siRNA-mediated silencing of USP1 improved hepatic fibrosis through inhibition of SNAIL and CXCL1, which yields a new therapeutic target for hepatic fibrosis treatment.

Extracellular vesicles-derived miR-150-5p secreted by adipose-derived mesenchymal stem cells inhibits CXCL1 expression to attenuate hepatic fibrosis.

Hepatic fibrosis (HF) is involved in aggravated wound-healing response as chronic liver injury. Extracellular vesicles (EVs) carrying microRNA (miR) have been reported as therapeutic targets for liver diseases. In this study, we set out to explore whether adipose-derived mesenchymal stem cells (ADMSCs)-derived EVs containing miR-150-5p affect the progression of HF. Carbon tetrachloride (CCl4 ) was firstly used to induce HF mouse models in C57BL/6J mice, and activation of hepatic stellate cells (HSCs) was achieved using transforming growth factor ß (TGF-ß). EVs were then isolated from ADMSCs and co-cultured with HSCs. The relationship between miR-150-5p and CXCL1 was identified using dual luciferase gene reporter assay. Following loss- and gain-function experimentation, HSC proliferation was examined by MTT assay, and levels of fibrosis-, HSC activation- and apoptosis-related genes were determined in vitro. Additionally, pathological scores, collagen volume fraction (CVF) as well as levels of inflammation- and hepatic injury-associated genes were determined in in vivo. Down-regulated miR-150-5p and elevated CXCL1 expression levels were detected in HF tissues. ADMSCs-derived EVs transferred miR-150-5p to HSCs. CXCL1 was further verified as the downstream target gene of miR-150-5p. Moreover, ADMSCs-EVs containing miR-150-5p markedly inhibited HSC proliferation and activation in vitro. Meanwhile, in vivo experiments also concurred with the aforementioned results as demonstrated by inhibited CVF, reduced inflammatory factor levels and hepatic injury-associated indicators. Both experiments results were could be reversed by CXCL1 over-expression. Collectively, our findings indicate that ADMSCs-derived EVs containing miR-150-5p attenuate HF by inhibiting the CXCL1 expression.

Advances in Diagnostic Imaging of Hepatopulmonary Syndrome.

Hepatopulmonary syndrome (HPS) is a serious pulmonary complication of progressive liver disease that leads to a poor clinical prognosis. Patients with HPS may develop acute respiratory failure, which requires intensive care and therapy. At present, the only effective treatment is liver transplantation; therefore, early diagnosis and timely treatment are of considerable significance. The three main features of HPS are liver disease, oxygenation disorder, and intrapulmonary vascular dilatation (IPVD). Diagnosing HPS is challenging due to the difficulty in detecting the presence or absence of IPVD. As such, imaging examination is very important for detecting IPVD. This paper reviews the imaging methods for diagnosing HPS such as ultrasound, dynamic pulmonary perfusion imaging, pulmonary angiography, and computed tomography.