Objectives
Kita‐Kyushu lung cancer antigen‐1 (KK‐LC‐1) is a cancer/testis antigen reactivated in several human malignancies. So far, the major focus of studies on KK‐LC‐1 has been on its potential as ...diagnostic biomarker and immunotherapy target. However, its biological functions and molecular mechanisms in cancer progression remain unknown.
Materials and Methods
Expression of KK‐LC‐1 in HCC was analysed using RT‐qPCR, Western blot and immunohistochemistry. The roles of KK‐LC‐1 on HCC progression were examined by loss‐of‐function and gain‐of‐function approaches. Pathway inhibitor DAPT was employed to confirm the regulatory effect of KK‐LC‐1 on the downstream Notch signalling. The interaction of KK‐LC‐1 with presenilin‐1 was determined by co‐immunoprecipitation. The association of CpG island methylation status with KK‐LC‐1 reactivation was evaluated by methylation‐specific PCR, bisulphite sequencing PCR and 5‐Aza‐dC treatment.
Results
We identified that HCC tissues exhibited increased levels of KK‐LC‐1. High KK‐LC‐1 level independently predicted poor survival outcome. KK‐LC‐1 promoted cell growth, migration, invasion and epithelial‐mesenchymal transition in vitro and in vivo. KK‐LC‐1 modulated the Notch1/Hes1 pathway to exacerbate HCC progression through physically interacting with presenilin‐1. Upregulation of KK‐LC‐1 in HCC was attributed to hypomethylated CpG islands.
Conclusions
This study identified that hypomethylation‐induced KK‐LC‐1 overexpression played an important role in HCC progression and independently predicted poor survival. We defined the KK‐LC‐1/presenilin‐1/Notch1/Hes1 as a novel signalling pathway that was involved in the growth and metastasis of HCC.
Purpose: This study was designed to evaluate the efficacy and safety of microwave ablation (MWA) in the treatment of intraoperative life-threatening tumour haemorrhage during hepatic surgeries.
...Methods: Three cases of MWA application in the emergent control of life-threatening hepatic tumour haemorrhage were analysed and reported.
Results: Satisfactory hemostasis for hepatic tumour rupture was achieved by MWA in all three cases. No major complications, such as post-operative haemorrhage, bile duct injury, liver abscess, colon perforation, skin burns, tumour seeding or renal dysfunction, were identified.
Conclusions: MWA may be a feasible, effective and simple strategy for the emergent control of intraoperative hepatic tumour bleeding. To the best of our knowledge, this study represents the first reported cases of this novel application of MWA.
Summary Background IL-11 is a multifunctional cytokine that belongs to the IL-6 family. Previous studies have demonstrated that IL-11 has underlying anti-inflammatory and anti-apoptotic properties. ...In this study, we evaluated the potential effects of IL-11 on mouse liver WI/Rp injury. Methods For in vivo experiments, mice were randomly divided into four main experimental groups ( n = 5 each): (1) normal group – anesthesia; (2) sham group– laparotomy; (3) I/R group– liver WI/Rp; and (4) IL-11 pretreatment (500 μg/kg, tail vein injection) group– administration of RhIL-11 2 h before liver WI/Rp induced in the same manner as in group 3. For in vitro experiments, cells were divided into two groups: (1) H/R group– H/R; and (2) IL-11 pretreatment group– pretreatment with RhIL-11 (2 μg/mL for 12 h) before the induction of H/R. For both groups, three periods of reoxygenation were examined (2 h, 6 h, and 12 h). Results In the in vivo experiments, IL-11 protected mouse livers from WI/Rp by reducing liver enzyme levels and cellular degeneration. In the in vitro experiments, IL-11 significantly reduced hepatocyte apoptosis. In both the in vivo and in vitro experiments, IL-11 pre-treatment significantly reduced the expression of TNF-α and IL-1β. In addition, NF-κB, a target of IL-11, was suppressed in macrophages after IL-11 pre-treatment. Conclusions Pre-treatment with IL-11 protects mouse livers from WI/Rp injury by suppressing NF-kB activity.
Acute rejection is commonly encountered for long‐term survival in liver transplant (LT) recipients and may impact their long‐term survival if rejection is severe or recurrent. The aim of this study ...is to examine the therapeutic potential of transforming growth factor (TGF‐β)‐overexpressing mesenchymal stem cells (MSCs) in inducing a local immunosuppression in liver grafts after transplantation. MSCs were transduced with a lentiviral vector expressing the human TGF‐β1 gene; TGF‐β1‐overexpressing MSCs (designated as TGF/MSCs) were then transfused into the liver grafts via the portal vein of a rat LT model of acute rejection. Rejection severity was assessed by clinical and histologic analysis. The immunity suppression effects and mechanism of TGF/MSCs were tested, focusing on their ability to induce generation of regulatory T cells (Tregs) in the liver grafts. Our findings demonstrate that transfusion of TGF/MSCs prevented rejection, reduced mortality, and improved survival of rats after LT. The therapeutic effects were associated with the immunosuppressive effects of MSCs and TGF‐β1. Their reciprocal effects on Tregs induction and function resulted in more CD4 + Foxp3 + Helios‐ induced Tregs, fewer Th17 cells, and improved immunosuppressive effects in local liver grafts. Thus, TGF/MSCs can induce a local immunosuppressive effect in liver grafts after transplantation. The immunomodulatory activity of TGF‐β1 modified MSCs may be a gateway to new therapeutic approaches to prevent organ rejection in clinical transplantation. Stem Cells 2016;34:2681–2692
Circular
RNA
s (circ
RNA
s), a novel class of non‐coding
RNA
s, have emerged as indispensable modulators in human malignancies. Aberrant cellular senescence is a phenotype observed in various ...cancers. The association of circ
RNA
s with cellular senescence in tumors is yet to determined. Here, we investigated the role of circ
LARP
4 in cellular senescence and cell proliferation in hepatocellular carcinoma (
HCC
). Downregulated circ
LARP
4 level was observed in
HCC
tissues and cell lines. Low expression level of circ
LARP
4 independently predicted poor survival outcome. Gain‐of‐function and loss‐of‐function assays demonstrated that circ
LARP
4 suppressed
HCC
cell proliferation, mediated cell cycle arrest and induced senescence in vitro. Levels of p53 and p21, 2 key regulatory molecules in cellular senescence, were increased in circ
LARP
4‐overexpressed
HCC
cells and decreased in circ
LARP
4‐silenced
HCC
cells. In vivo experiments further confirmed the tumor‐suppressing activity of circ
LARP
4. Further mechanistic studies showed that circ
LARP
4 dampened
HCC
progression by sponging miR‐761, thereby promoting the expression level of
RUNX
3 and activating the downstream p53/p21 signaling. Our study revealed the role of circ
LARP
4/miR‐761/
RUNX
3/p53/p21 signaling in
HCC
progression, providing a potential survival predictor and therapeutic candidate for
HCC
.
Aggravated liver injury has been reported in aged ischemia/reperfusion-stressed livers; however, the mechanism of aged macrophage inflammatory regulation is not well understood. Here, we found that ...the adaptor protein TRIB1 plays a critical role in the differentiation of macrophages and the inflammatory response in the liver after ischemia/reperfusion injury. In the present study, we determined that aging promoted macrophage-mediated liver injury and that inflammation was mainly responsible for lower M2 polarization in liver transplantation-exposed humans post I/R. Young and aged mice were subjected to hepatic I/R modeling and showed that aging aggravated liver injury and suppressed macrophage TRIB1 protein expression and anti-inflammatory function in I/R-stressed livers. Restoration of TRIB1 is mediated by lentiviral infection-induced macrophage anti-inflammatory M2 polarization and alleviated hepatic I/R injury. Moreover, TRIB1 overexpression in macrophages facilitates M2 polarization and anti-inflammation by activating MEK1-ERK1/2 signaling under IL-4 stimulation. Taken together, our results demonstrated that aging promoted hepatic I/R injury by suppressing TRIB1-mediated MEK1-induced macrophage M2 polarization and anti-inflammatory function.
The dysregulation of micro (mi)RNAs is associated with cancer development. The miRNA miR-145 is downregulated in intrahepatic cholangiocarcinoma (ICC); however, its precise role in tumor progression ...has not yet been elucidated. Novel (nua) kinase family (NUAK)1 functions as an oncogene in various cancers and is a putative target of miR-145 regulation. In this study, we investigated the regulation of NUAK1 by miR-145 in ICC. We found that miR-145 level was significantly decreased in ICC tissue and cell lines, which corresponded with an increase in NUAK1 expression. NUAK1 was found to be a direct target of miR-145 regulation. The overexpression of miR-145 in ICC cell lines inhibited proliferation, growth, and invasion by suppressing NUAK1 expression, which was associated with a decrease in Akt signaling and matrix metalloproteinase protein expression. Similar results were observed by inhibiting NUAK1 expression. These results demonstrate that miR-145 can prevent ICC progression by targeting NUAK1 and its downstream effectors, and can therefore be useful for clinical diagnosis and targeted therapy of ICC.
•MiR-145 suppresses ICC proliferation and invasion abilities.•We demonstrated that miR-145 directly targets NUAK1 in ICC.•MiR-145 expression in ICC was associated with Akt signaling and MMPs expression.
Hepatic ischemia-reperfusion injury is a significant complication of partial hepatic resection and liver transplantation, impacting the prognosis of patients undergoing liver surgery. The protein ...proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily synthesized by hepatocytes and has been implicated in myocardial ischemic diseases. However, the role of PCSK9 in hepatic ischemia-reperfusion injury remains unclear. This study aims to investigate the role and mechanism of PCSK9 in hepatic ischemia-reperfusion injury.
We first examined the expression of PCSK9 in mouse warm ischemia-reperfusion models and AML12 cells subjected to hypoxia/reoxygenation. Subsequently, we explored the impact of PCSK9 on liver ischemia-reperfusion injury by assessing mitochondrial damage and the resulting inflammatory response.
Our findings reveal that PCSK9 is up-regulated in response to ischemia-reperfusion injury and exacerbates hepatic ischemia-reperfusion injury. Blocking PCSK9 can alleviate hepatocyte mitochondrial damage and the consequent inflammatory response mediated by ischemia-reperfusion. Mechanistically, this protective effect is dependent on mitophagy.
Inhibiting PCSK9 in hepatocytes attenuates the inflammatory responses triggered by reactive oxygen species and mitochondrial DNA by promoting PINK1-Parkin–mediated mitophagy. This, in turn, ameliorates hepatic ischemia-reperfusion injury.
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The prognostic significance of insurance status has been investigated in many types of malignancies, however, its impact on gallbladder cancer is yet not known. The purpose of this study was to ...determine the relationship between insurance status and gallbladder cancer survival. We searched the Surveillance, Epidemiology, and End Results dataset, and identified 1,729 gallbladder cancer cases. Kaplan-Meier methods and multivariable Cox regression models were used to analyze survival outcomes and risk factors. We found that individuals who had non-Medicaid insurance were more likely to be male, older, from wealthier area, and better-educated. Insurance status was confirmed as an independent prognostic factor for gallbladder cancer patients. Stratified analysis revealed that the uninsured status independently predicted unfavorable survival outcome at localized tumor stage and in white individuals. To conclude, insurance status is an important predictive factor for gallbladder cancer, and uninsured individuals are at the highest risk of death.
All-trans retinoic acid (ATRA) has been proved to protect liver from ischemia/reperfusion (IR) injury, however, its mechanism is still unclear. This study is to investigate the mechanism of effect of ...ATRA on innate immunity in mice liver IR injury. Before operation, mice were gavaged by ATRA at 15mg/kg/d for two weeks, and then the liver was underwent 70% ischemia (90min) and reperfusion (6h). Liver function was assessed by serum alanine aminotransferase (sALT), serum aspartate aminotransferase (sAST). Real-time PCR and Western blot were to detect the level of mRNA and protein. In vitro, RAW264.7 macrophages were treatment with ATRA (1μM) or LE540 (5μM, a retinoic acid receptor α(RARα) receptor antagonist) before lipopolysaccharide (100ng/mL) stimulation. In vivo, ATRA protected the liver from IR injury by improving hepatocellular function (sALT and sAST), decreasing cell apoptosis and inhibiting inflammatory response (i.e., the level of toll-like receptor 4, transcription factor nuclear factor-кBp65, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α). When RARα was blocked by LE540 in RAW264.7 macrophages, the inflammatory cytokines were enhancing, along with a decline of Akt phosphorylation but Forkhead box o (Foxo) 1, compared with the ATRA group. In summary, ATRA regulates in part the innate immunity to protect liver from IR injury by RARα/Akt/Foxo1 pathway.
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