A Mouse Model of the Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy Procedure Aided by Microscopy.

Hepatectomy is widely regarded as the primary treatment for hepatic malignancies; yet, postoperative liver failure remains a major cause of perioperative mortality, severely impacting patient outcomes. In a robust hepatic environment, the future liver remnant (FLR) must exceed 25%, and in cases of cirrhosis, this requirement increases to over 40%. The inadequacy of FLR is currently a major obstacle in the progression of hepatic surgery. Traditional methods to enhance FLR hypertrophy mainly focus on portal vein embolization (PVE), but its effectiveness is considerably limited. In recent years, there have been numerous reports on a novel biphasic hepatectomy method involving hepatic partitioning and portal vein ligation, known as associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). ALPPS surpasses PVE in efficiently and considerably inducing FLR hypertrophy. However, the detailed mechanisms driving ALPPS-facilitated hepatic regeneration are not fully understood. Thus, replicating ALPPS in animal models is crucial to thoroughly investigate the molecular mechanisms of hepatic regeneration, offering valuable theoretical and practical insights.

CENPB promotes the proliferation of hepatocellular carcinoma and is directly regulated by miR-29a.

Hepatocellular carcinoma (HCC) is a significant global health concern as it ranks as the sixth most common malignant tumor and the third leading cause of cancer-related deaths. In this study, we analyzed the expression of centromere protein B (CENPB) mRNA in HCC using TCGA and GEO datasets. Immunohistochemistry (IHC) was performed to determine CENPB protein levels in 490 HCC patients. Our findings revealed higher expression of CENPB mRNA in HCC tissues across the three datasets. Additionally, as the pathological stage and histological grade advanced, CENPB expression increased. Patients with elevated levels of CENPB mRNA and protein demonstrated shorter overall survival (OS) and recurrence-free survival (OS). Notably, CENPB protein showed prognostic value in patients with stage I/II, AFP levels below 400 ng/ml, and tumor size less than 5 cm. Using multivariate regression analysis in 490 HCC patients, we developed nomograms to predict 1-year, 3-year, and 5-year OS and RFS. Knockdown of CENPB in Hep3B and MHCC97 cell lines resulted in significant inhibition of cell proliferation and invasion. Furthermore, bioinformatics analysis identified miR-29a as a potential negative regulator of CENPB expression, which was validated through a dual-luciferase reporter assay. In conclusion, our findings suggest that CENPB may serve as an oncogenic factor in HCC and is directly regulated by miR-29a, highlighting its potential as a promising therapeutic target.

High cathepsin A protein expression predicts poor prognosis and tumor recurrence of hepatocellular carcinoma patients after curative hepatectomy.

Cathepsin A (CTSA) is overexpressed in various types of cancer and is linked to poor clinical outcomes. However, the clinical application of CTSA in HCC has not been explored. In this study, we examined the protein level of CTSA in the archived HCC samples from 161 patients by Immunohistochemistry (IHC). The high protein level of CTSA was significantly correlated to the poor clinicopathological parameters, such as TNM stage, serum AFP level, tumor differentiation, liver cirrhosis, Child-Pugh class, vascular invasion, tumor encapsulation, tumor recurrence, and patient death. In addition, multivariate Cox regression analysis indicated that high CTSA expression was an independent prognostic factor of OS and RFS. We also analyzed the area under the curve (AUC) of the time-dependent receiver operating characteristic (ROC) of CTSA expression for 1-, 3-, and 5-year OS and RFS prediction. Furthermore, we constructed a nomogram that exhibited excellent prediction performance, which was validated by the calibration curve and decision curve analysis. Together, our study demonstrated that CTSA protein level is strongly associated with poor clinical outcome of HCC patients and may be used as a potential diagnostic and prognostic biomarker in HCC.

Elevated Small Nuclear Ribonucleoprotein Polypeptide an Expression Correlated With Poor Prognosis and Immune Infiltrates in Patients With Hepatocellular Carcinoma.

Background: Elevated Small Nuclear Ribonucleoprotein Polypeptide A (SNRPA) can enhance tumor cell growth and proliferation in various cancers. However, rarely studies focus on the comprehensive analysis of SNRPA in hepatocellular carcinoma (HCC). Methods: TCGA and GEO databases were used to analyze the mRNA expression of SNRPA in HCC. Protein expression of SNAPA was validated using immunohistochemistry. Stably transfected HCC cells were used to investigate the role of SNRPA in the progression of HCC. The functional enrichment analysis was utilized for the biological function prediction. The CIBERSORT and ssGSEA algorithms were used to evaluate the composition of the tumor microenvironment and immunocyte infiltration ratio. Results: The SNRPA expression was upregulated in HCC and positively correlated with tumor stage and grade. SNRPA overexpression were independent risk factors for poor overall survival (OS) and recurrence-free survival (RFS). In patients with early-stage disease, low alpha-fetoprotein expression, and better differentiation, SNRPA still exhibited the excellent prognostic value. Knockdown of SNRPA inhibited the proliferation and migration while promoting the apoptosis of HCC cells. Higher methylation of the CpG site cg16596691 correlated with longer OS in HCC patients. Genes co-expressed with SNRPA were overexpressed in HCC and correlated with shorter OS. The GO and KEGG enrichment analysis showed that SNRPA expression was related to mRNA splicing, spliceosome signaling. GSEA demonstrated that the main enrichment pathway of SNRPA-related differential genes was spliceosome signaling, cell cycle signaling, P53 signaling pathway, T cell receptor signaling pathway, natural killer cell-mediated signaling. CIBERSORT and ssGSEA algorithm revealed that SNRPA was mainly associated with the higher proportion of CD8+T cells, T cells follicular helper, T cells regulatory, Macrophages M0, and the lower proportion of T cells CD4 memory resting, NK cells resting, Monocytes, and Mast cells resting. Conclusion: Elevated SNRPA enhances tumor cell proliferation and correlated with poor prognosis and immune infiltrates in patients with HCC.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

Adult liver transplantation using pediatric donor livers after cardiac or brain death: A report of three cases.

The present study reports on the experience at Jiangxi Provincial People's Hospital (Nanchang, China) with liver transplantation in adults using pediatric donor livers, including indications, technique and results. A total of three cases of liver transplantation performed between April 2008 and May 2016 were retrospectively reviewed. Liver procurement and trimming, recipient selection, surgical tips, prevention and treatment of small-for-size syndrome, selection of immunosuppressive regimens, prevention and treatment of vascular complications and anticoagulant therapy were discussed. The three pediatric donors were 8, 8 and 10 years old. The three recipients were confirmed to have primary liver cancer. In recipient 1 (female; age, 39 years), jaundice persisted in the recipient after the liver transplantation. A reduced dose of FK506 was then given to gradually decrease the total bilirubin level to the normal range. Recipient 1 recovered and was discharged from hospital; however, the patient died of liver cancer recurrence and bone metastasis 6 years post-transplantation. In recipient 2 (male; age, 56 years), the recipient experienced sudden abdominal distension on postoperative day 7. The patient's clotting time was prolonged and the transaminase level was sharply increased, peaking on day 9. The patient was suspected of having small-for-size syndrome and was treated symptomatically. The patient experienced a significant improvement in symptoms on postoperative day 13 and regular postoperative follow-ups were performed until now and the patient is now in remission. In recipient 3 (male; age, 48 years), the recipient recovered well and the liver function returned to normal on postoperative day 3. The patient was discharged from hospital and has been in remission thus far. Adult liver transplantations from pediatric donors are feasible treatments. Systematic donor and recipient assessments, sound surgical skills and optimal postoperative treatments are essential for success in the transplantation of livers from pediatric donors into adult recipients. Considering the condition of the donor liver, the selection of recipients and appropriate surgical methods are particularly important in these cases.

MicroRNA-543 promotes cell invasion and impedes apoptosis in pituitary adenoma via activating the Wnt/ß-catenin pathway by negative regulation of Smad7.

Pituitary adenomas (PA) are commonly occurring benign neoplasms. Identification of molecular pathway resulting in pituitary tumorigenesis remains challenges in endocrine oncology. The present study was conducted with aim of investigating the role of microRNA-543 (miR-543) in PA development. Up-regulated miR-543 and downregulated Smad7 were observed in PA tissues. Afterwards, the specific mechanism of miR-543 and Smad7 in PA were determined with the use of ectopic expression, depletion and reporter assay experiments. Smad7 was confirmed as a target gene of miR-543. HP75 cells treated with overexpressed miR-543 exhibited increased cell proliferation, migration and invasion, while decreased cell apoptosis as well as expression of Cleaved caspase-3 and Cleaved caspase-8 were observed. Suppression of miR-543 contributed to an opposite trend to the above findings. Based on the findings, the inhibition of miR-543 was found to play a tumor suppressive role in PA through the down-regulation of Wnt/ß-catenin pathway by negatively regulating Smad7.

UNC119 promotes the growth and migration of hepatocellular carcinoma via Wnt/ß-catenin and TGF-ß/EMT signaling pathways.

PURPOSE: It has been reported that UNC119 is significantly up-regulated in liver cancer cells. However, the role of UNC119 in liver cancer and the clinical significance of reducing its expression in hepatocellular carcinoma (HCC) are not well understood. The aim of this study was to investigate the expression profile of UNC119 in HCC and its connection with the progression of HCC. METHODS: UNC119 expression in HCC cell lines and tissues was assessed using quantitative real-time PCR, western blot and immunohistochemical analyses. The biological functions of UNC119 during the proliferation, growth and other different life cycles of tumor cells were also analyzed both in vitro and in vivo. RESULTS: UNC119 expression was up-regulated in both HCC cell lines and tissues. A higher level of UNC119 not only promoted HCC cell proliferation, but also enhanced its ability of migration and invasion. UNC119 promoted the progression of cell cycles and significantly induced HCC cell growth through the Wnt/ß-catenin signaling pathway. In addition, UNC119 enhanced tumor migration and invasion through the TGF-ß/epithelial-mesenchymal transition (EMT) pathway. The antibody against UNC119 (Anti- UNC119) efficiently inhibited the proliferation, migration and invasion of HCC cells by blocking the Wnt/ß-catenin and TGF-ß/EMT signaling pathways, respectively. Anti- UNC119 not only facilitated tumor remission, but also extended long-term survival of HCC-bearing mice. CONCLUSION: UNC119 was significantly up-regulated in liver cancer cells and tissues. It promoted cell growth and migration through the Wnt/ß-catenin and TGF-ß/EMT signaling pathways, respectively. The anti-UNC119 treatment inhibited tumor cell proliferation, growth, migration and invasion by inhibiting the Wnt/ß-catenin and GF-ß/ EMT signaling pathways, respectively.

UNC119 promotes the growth and migration of hepatocellular carcinoma via Wnt/ß/catenin and TGF/ß-EMT signaling pathways.

PURPOSE: It has been reported that UNC119 is significantly up-regulated in liver cancer cells. However, the role of UNC119 in liver cancer and the clinical significance of reducing its expression in hepatocellular carcinoma (HCC) are not well understood. The aim of this study was to investigate the expression profile of UNC119 in HCC and its connection with the progression of HCC. METHODS: UNC119 expression in HCC cell lines and tissues was assessed using quantitative real-time PCR, western blot and immunohistochemical analyses. The biological functions of UNC119 during the proliferation, growth and other different life cycles of tumor cells were also analyzed both in vitro and in vivo. RESULTS: UNC119 expression was up-regulated in both HCC cell lines and tissues. A higher level of UNC119 not only promoted HCC cell proliferation, but also enhanced its ability of migration and invasion. UNC119 promoted the progression of cell cycles and significantly induced HCC cell growth through the Wnt/ß-catenin signaling pathway. In addition, UNC119 enhanced tumor migration and invasion through the TGF-ß/epithelial-mesenchymal transition (EMT) pathway. The antibody against UNC119 (Anti- UNC119) efficiently inhibited the proliferation, migration and invasion of HCC cells by blocking the Wnt/ß-catenin and TGF-ß/EMT signaling pathways, respectively. Anti- UNC119 not only facilitated tumor remission, but also extended long-term survival of HCC-bearing mice. CONCLUSION: UNC119 was significantly up-regulated in liver cancer cells and tissues. It promoted cell growth and migration through the Wnt/ß-catenin and TGF-ß/EMT signaling pathways, respectively. The anti-UNC119 treatment inhibited tumor cell proliferation, growth, migration and invasion by inhibiting the Wnt/ß-catenin and GF-ß/ EMT signaling pathways, respectively.

UNC119 promoted cell growth and migration by Wnt/ß-catenin signal and TGF-ß/EMT signal pathway in hepatocellular carcinoma.

PURPOSE: UNC119 was reported to be significantly up-regulated in hepatic cancer cells. However, the clinical significance of target UNC119 to reduce UNC119 expression and mechanisms in hepatocellular carcinoma (HCC) are not well understood. Our purpose was to study how UNC119 is expressed in HCC and its connection with HCC progression. METHODS: UNC119 expression was assessed with quantitative real-time PCR (qRT-PCR), western blot and immunohistochemical analyses in HCC cell lines and in tissues. The biological function of UNC119 for proliferation, growth and cell cycle of tumor cells were also analyzed both in vitro and in vivo. RESULTS: UNC119 expression was up-regulated both in HCC cell lines as well as in tissues through comparison with normal liver cells and tissues. Higher concentration level of UNC119 not only promoted proliferation, but also enhanced migration and invasion of HCC cells. UNC119 promoted the progression of cell cycle and significantly promoted HCC cells growth through Wnt/ß-catenin signal pathway and enhanced tumor migration and invasion via TGF-ß/epithelial-mesenchymal transition (EMT) pathway. Antibody for UNC119 (Anti-UNC119) efficiently inhibited HCC cells proliferation, migration and invasion by blocking Wnt/ß-catenin and TGF-ß/EMT signal pathway, respectively. Anti-UNC119 was not only beneficial for tumor remission, but also contributed to long-term survival of HCC-bearing mice. CONCLUSION: UNC119 is significantly up-regulated and promoted cell growth and migration in hepatic cancer cells and tissues via Wnt/ß-catenin signal pathway and TGF-ß/EMT signal pathway, respectively. Anti-UNC119 treatment inhibited cell proliferation, growth, migration and invasion through inhibition of Wnt/ß-catenin and GF-ß/EMT signal pathway, respectively.

The antifibrotic effects and mechanisms of microRNA-26a action in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high-lethality fibrotic lung disease characterized by excessive fibroblast proliferation, extracellular matrix accumulation, and, ultimately, loss of lung function. Although dysregulation of some microRNAs (miRs) has been shown to play important roles in the pathophysiological processes of IPF, the role of miRs in fibrotic lung diseases is not well understood. In this study, we found downregulation of miR-26a in the lungs of mice with experimental pulmonary fibrosis and in IPF, which resulted in posttranscriptional derepression of connective tissue growth factor (CTGF), and induced collagen production. More importantly, inhibition of miR-26a in the lungs caused pulmonary fibrosis in vivo, whereas overexpression of miR-26a repressed transforming growth factor (TGF)-ß1-induced fibrogenesis in MRC-5 cells and attenuated experimental pulmonary fibrosis in mice. Our study showed that miR-26a was downregulated by TGF-ß1-mediated phosphorylation of Smad3. Moreover, miR-26a inhibited the nuclear translocation of p-Smad3 through directly targeting Smad4, which determines the nuclear translocation of p-Smad2/Smad3. Taken together, our experiments demonstrated the antifibrotic effects of miR-26a in fibrotic lung diseases and suggested a new strategy for the prevention and treatment of IPF using miR-26a. The current study also uncovered a novel positive feedback loop between miR-26a and p-Smad3, which is involved in pulmonary fibrosis.

MicroRNAs contribute to promyelocyte apoptosis in As2O3-treated APL cells.

BACKGROUND: Arsenic trioxide (As2O3), an ancient drug used in traditional Chinese medicine, has substantial anticancer activities, especially in the treatment of patients suffering from acute promyelocytic leukemia (APL); however the underlying mechanisms are not well understood. METHODS: MTT assay was used to detect the cell viability. Flow Cytometry analysis and caspase-3 activity assay were used to measure apoptosis of APL cells. Caspase-3 and Bax levels were analyzed by western blot and let-7d and miR-766 levels were determined by real-time RT-PCR. RESULTS: As2O3 significantly inhibited cell viability and induced apoptosis in APL cells. Several microRNAs, including let-7d and miR-766, were dysregulated in APL cells treated with As2O3. The expression of caspase-3 and Bax, which are targets of let-7d and miR-766, respectively, were up-regulated in As2O3 treated cells. Transfection of let-7d and miR-766 into NB4 cells decreased the expression of caspase-3 and Bax, respectively. Correspondingly, transfection of these microRNAs increased NB4 cell viability. As2O3 induced degradation of promyelocytic leukemia (PML), and then induced the down-regulation of both let-7d and miR-766 in NB4 cells. CONCLUSIONS: We construct a dysregulated microRNA network involved in As2O3-induced apoptosis in APL. Targeting this network may be a new strategy for the prevention of side effects associated with APL treatment with As2O3.