A bidirectional two-sample Mendelian randomization study to evaluate the relationship between psoriasis and interstitial lung diseases.

BACKGROUND: Prior observational studies have suggested a potential direct link between psoriasis (PSO) and interstitial lung disease (ILD). Consequently, we applied Mendelian randomization (MR) to further evaluate the bidirectional causal relationships between PSO and its different phenotypes [psoriatic arthritis (PSA)/psoriasis vulgaris (PSV)] and ILD. METHODS: Data regarding PSO/PSA/PSV and ILD were sourced from publicly accessible genome-wide association studies (GWAS) databases, focusing on European populations. We used five algorithms- MR Egger, weighted median, inverse-variance weighted (IVW), simple mode, and weighted mode- to evaluate the causal relationships between PSO/PSA/PSV and ILD, with a primary emphasis on the IVW method. RESULTS: The analysis indicated a potential association between PSA and an elevated risk of ILD [IVW odds ratio (OR): 1.035 (95% CI 1.008, 1.064; P = 0.012)], with no evidence of a direct relationship between total PSO and PSV with ILD. Conversely, no substantial evidence emerged from the reverse MR analysis to suggest that ILD significantly affects total PSO or the specific PSA/PSV phenotypes. CONCLUSION: Our findings provide genetic evidence supporting the notion that PSA may be a contributory risk factor for ILD. Further investigations are warranted to explore the underlying mechanisms of this potential causal relationship between PSA and ILD.

Risk factors analyses associated with postoperative infection in choledochoscopy for intrahepatic bile duct stones (IHDs): a single-center retrospective study in real-world setting.

BACKGROUND: Choledochoscopy is a highly effective approach for managing intrahepatic bile duct stones (IHDs). However, postoperative infection is a common complication that significantly impacts treatment outcomes. Despite its clinical relevance, the risk factors associated with this procedure remain largely unexplored. METHODS: This study focused on a consecutive cohort of patients who underwent choledochoscopy for IHDs at our institution between January 2016 and December 2022. The primary objective was to analyze the relationship between various clinical factors and postoperative infection, and to compare the postoperative infection of different choledochoscopic procedures. RESULTS: The study cohort consisted of 126 patients, with 60 individuals (47.6%) experiencing postoperative infection. Notably, preoperative biliary obstruction (odds ratio [OR] 1.861; 95% confidence interval [CI] 1.314-8.699; p = 0.010) and operation time (OR 4.414; 95% CI 1.635-12.376; p = 0.004) were identified as risk factors for postoperative infection. Additionally, biliary tract infections (60.00%) were primarily responsible for postoperative infection, with Escherichia coli (47.22%) being the predominant bacterial strain identified in bile cultures. Furthermore, biliary tract obstruction (OR 4.563; 95% CI 1.554-13.401; p = 0.006) and body mass index (BMI) (OR 1.186; 95% CI 1.015-1.386; p = 0.031) were determined to be independent risk factors for postoperative biliary tract infection. CONCLUSIONS: The occurrence of postoperative infection in patients undergoing choledochoscopy was primarily associated with the duration of the operation and the presence of preoperative biliary obstruction.

MICA+ Tumor Cell Upregulated Macrophage-Secreted MMP9 via PROS1-AXL Axis to Induce Tumor Immune Escape in Advanced Hepatocellular Carcinoma (HCC).

BACKGROUND: tumor-associated macrophages (TAMs) constitute a significant proportion of non-cancerous cells within the intricate tumor microenvironment (TME) of hepatocellular carcinoma (HCC). Understanding the communication between macrophages and tumor cells, as well as investigating potential signaling pathways, holds promise for enhancing therapeutic responses in HCC. METHODS: single-cell RNA-sequencing data and bulk RNA-sequencing data were derived from open source databases Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Through this analysis, we elucidated the interactions between MICA+ tumor cells and MMP9+ macrophages, primarily mediated via the PROS1-AXL axis in advanced HCC. Subsequently, we employed a range of experimental techniques including lentivirus infection, recombinant protein stimulation, and AXL inhibition experiments to validate these interactions and unravel the underlying mechanisms. RESULTS: we presented a single-cell atlas of advanced HCC, highlighting the expression patterns of MICA and MMP9 in tumor cells and macrophages, respectively. Activation of the interferon gamma (IFN-γ) signaling pathway was observed in MICA+ tumor cells and MMP9+ macrophages. We identified the existence of an interaction between MICA+ tumor cells and MMP9+ macrophages mediated via the PROS1-AXL axis. Additionally, we found MMP9+ macrophages had a positive correlation with M2-like macrophages. Subsequently, experiments validated that DNA damage not only induced MICA expression in tumor cells via IRF1, but also upregulated PROS1 levels in HCC cells, stimulating macrophages to secrete MMP9. Consequently, MMP9 led to the proteolysis of MICA. CONCLUSION: MICA+ HCC cells secreted PROS1, which upregulated MMP9 expression in macrophages through AXL receptors. The increased MMP9 activity resulted in the proteolytic shedding of MICA, leading to the release of soluble MICA (sMICA) and the subsequent facilitation of tumor immune escape.

Macrophage metabolism, phenotype, function, and therapy in hepatocellular carcinoma (HCC).

The pivotal role of the tumor microenvironment (TME) in the initiation and advancement of hepatocellular carcinoma (HCC) is widely acknowledged, as it fosters the proliferation and metastasis of HCC cells. Within the intricate TME of HCC, tumor-associated macrophages (TAMs) represent a significant constituent of non-malignant cells. TAMs engage in direct communication with cancer cells in HCC, while also exerting influence on other immune cells to adopt a tumor-supportive phenotype that facilitates tumor progression. Among the multifaceted mechanisms at play, the metabolic reprogramming of both tumor cells and macrophages leads to phenotypic alterations and functional modifications in macrophages. This comprehensive review elucidates the intricate interplay between cellular metabolism and macrophage phenotype/polarization, while also providing an overview of the associated signaling molecules and potential therapeutic strategies for HCC.

Risk Factors and Long-Term Implications of Unplanned Conversion During Laparoscopic Liver Resection for Hepatocellular Carcinoma.

Background: Laparoscopic liver resection (LLR) has become a widely used standardized operation for patients with hepatocellular carcinoma (HCC) in the field of hepatic surgery. However, the risk factors and long-term implications associated with unplanned conversion to an open procedure during the LLR have not been adequately studied. Methods: The study incorporated 96 patients with HCC. Risk factors of conversion and their prognosis were analyzed by comparing patients who successfully underwent LLR with those who required unplanned conversion. Results: In this study, the unplanned conversion rate for laparoscopic hepatectomy was 42.7%. Patients who underwent conversion had longer length of stay (8 versus 7 days, P < .001), longer operation time (297.73 versus 194.03 minutes, P = .000), a higher transfusion rate (29.3% versus 5.5%, P < .001), and more postoperative complications compared with patients who successfully underwent LLR. The two surgical maneuvers did not show substantial disparities in terms of total survival and disease-free survival rates. Risk factors of unplanned conversion contained tumor location (odds ratio [OR], 3.129; 95% confidence interval [CI]: 1.214-8.066; P = 0.018) and tumor size (OR, 2.652; 95% CI: 1.039-6.767; P = 0.041). Conclusions: The unplanned conversion during LLR for HCC was linked to unfavorable short-term prognosis, yet it did not influence long-term oncologic outcomes. Moreover, preoperative evaluation of tumor size and location may effectively reduce the probability of unplanned conversion during LLR.

SCNN1B regulates the proliferation, migration, and collagen deposition of human lung fibroblasts.

The aim of this study was to investigate the role of amiloride-sensitive sodium channel protein 1B (SCNN1B) on the proliferation and migration of human lung fibroblasts and the possible mechanism that promote the development of acute respiratory distress syndrome (ARDS). Cultivate human embryonic lung fibroblasts (MRC-5) in vitro and screen out the most effective small interfering RNA to silence the expression of SCNN1B. Then, quantitative real-time PCR (qRT-PCR), CCK-8, Transwell, and Western blot detections were performed separately. The results of qRT-PCR showed that all three SCNN1B siRNAs were able to significantly decrease the mRNA expression level of SCNN1B compared with the si-NC group (P < 0.01), with the most significant decrease in the SCNN1B siRNA-83 group. Additionally, compared with the si-NC group, the proliferation ability of MRC-5 cells in the si-SCNN1B group was significantly enhanced, and the migration rate was significantly decreased (P < 0.01). Western blot results showed that low expression of SCNN1B significantly inhibited the protein expression levels of collagen deposition related proteins Collagen I and Heat shock proteins 47 (P < 0.01). In summary, SCNN1B can inhibit cell proliferation and promote cell migration and extracellular matrix deposition of human lung fibroblasts, and may be involved in the occurrence and development of ARDS.

Hepatocellular carcinoma-derived FOXO1 inhibits tumor progression by suppressing IL-6 secretion from macrophages.

Tumor heterogeneity dominates tumor biological behavior and shapes the tumor microenvironment. However, the mechanisms of tumor genetic features modulate immunity response were not clearly clarified. Tumor associated macrophages (TAMs) exert distinct immune functions in the progression of hepatocellular carcinoma (HCC) based on the inducible phenotype. FOXO family members sense changes in the extracellular or intracellular environment by activating a series of signaling pathways. FOXO1, a transcription factor that a common suppressor in hepatocellular carcinoma, correlated with a better tumor biological behavior in HCC through shaping macrophages anti-tumour response. Here, we found that human HCC tissue microarray (TMA) slides were employed to showed tumor derived FOXO1 negatively related with distribution of protumour macrophages. This phenomenon was confirmed in mouse xenograft model and in vitro. HCC-derived FOXO1 inhibits tumorigenesis not only by targeting tumor cells but also by synchronizing with re-educated macrophages. These effects may be partially dependent on FOXO1 transcriptionally modulates IRF-1/nitrio oxide (NO) axis in exerting effects in macrophages and decreasing IL-6 releasing from macrophages in tumor microenvironment indirectly. This feedback suppressed the progression of HCC by inactivation of IL-6/STAT3 in HCC. It implicates the potential role of FOXO1 in the therapeutic effects for modulating immune response by targeting macrophages.

Delimiting Low Level of Difficulty Scoring System Based on the Extent of Resection Difficulty Scoring System for Laparoscopic Liver Resection.

Background: The difficulty scoring system based on the extent of resection (DSS-ER) is a common tool for assessing the difficulty and risk of laparoscopic liver resection (LLR), but DSS-ER fails to comprehensively and accurately assess low level for beginners. Methods: The 93 cases of LLRs for primary liver cancer in the general surgery department of the Second Affiliated Hospital of Guangxi Medical University from 2017 to 2021 were retrospectively analyzed. The low level of DSS-ER difficulty scoring system was reclassified into three grades. The intraoperative and postoperative complications were compared among different groups. Results: There were significant differences in the operative time, blood loss, intraoperative allogeneic blood transfusion, conversion to laparotomy, and allogeneic blood transfusion among the different groups. Meanwhile, the postoperative complications were mainly pleural effusion and pneumonia, and the incidence of grade III was higher compared with other two grades. No significant difference existed in the postoperative biliary leakage and liver failure among three grades. Conclusions: This reclassified low level of DSS-ER difficulty scoring system has certain clinical value for LLR beginners to complete the corresponding learning curve.

Inhibition of Checkpoint Kinase 1 (CHK1) Upregulates Interferon Regulatory Factor 1 (IRF1) to Promote Apoptosis and Activate Anti-Tumor Immunity via MICA in Hepatocellular Carcinoma (HCC).

BACKGROUND: CHK1 is considered a key cell cycle checkpoint kinase in DNA damage response (DDR) pathway to communicate with several signaling pathways involved in the tumor microenvironment (TME) in numerous cancers. However, the mechanism of CHK1 signaling regulating TME in hepatocellular carcinoma (HCC) remains unclear. METHODS: CHK1 expression in HCC tissue was determined by IHC staining assay. DNA damage and apoptosis in HCC cells induced by cisplatin or CHK1 inhibition were detected by WB and flow cytometry. The interaction of CHK1 and IRF1 was analyzed by single-cell RNA-sequence, WB, and immunoprecipitation assay. The mechanism of IRF1 regulating MICA was investigated by ChIP-qPCR. RESULTS: CHK1 expression is upregulated in human HCC tumors compared to the background liver. High CHK1 mRNA level predicts advanced tumor stage and worse prognosis. Cisplatin and CHK1 inhibition augment cellular DNA damage and apoptosis. Overexpressed CHK1 suppresses IRF1 expression through proteolysis. Furthermore, single-cell RNA-sequence analyses confirmed that MICA expression positively correlated with IRF1 in HCC cells. Immunoprecipitation assay showed the binding between CHK1 and IRF1. Cisplatin and CHK1 inhibition upregulate MICA expression through IRF1-mediated transcriptional effects. A novel specific cis-acting IRF response element was identified at -1756 bp in the MICA promoter region that bound IRF1 to induce MICA gene transcription. MICA may increase NK cell and CD8+T cell infiltration in HCC. CONCLUSIONS: DNA damage regulates the interaction of CHK1 and IRF1 to activate anti-tumor immunity via the IRF1-MICA pathway in HCC.

Effects of methylprednisolone combined with advanced antibiotics and antiviral drugs on serum immunoglobulin and inflammatory factor levels in patients with viral pneumonia.

Viral pneumonia (VP) is known for its wide transmission and severe pathological damage. ninety cases of VP patients were rolled into an experimental group (group E, methylprednisolone + advanced antibiotics + antiviral drugs) and a control group (group C, methylprednisolone), with 45 cases in each group. General information about the patients, inflammatory factors, serum immunoglobulins, T lymphocyte subsets, and treatment outcomes (efficiency rate, conversion rate to negative) were compared. In group E, interleukin-6 (IL-6) (0.18±0.07) ng/L was inferior to in group C (0.33±0.09) ng/L, p<0.05; tumor necrosis factor-alpha (TNF-α) (17.22±4.13) ng/L was inferior to group C (26.07±4.08) ng/L, p<0.05; lgA (0.81±0.22) g/L was superior to in group C (0.68±0.17) g/L, P<0.05; lgM (1.62±0.13) g/L was superior to group C (1.09±0.03) g/L, p<0.05; lgE (0.19±0.02) g/L was inferior to group C (0.23±0.03) g/L, p<0.05; CD4+/CD8+ ratio (1.71±0.33) was superior to group C (1.24±0.43), p<0.05; the total efficiency rate in group C (77.78%) was inferior to group E (97.78%), p<0.05; the conversion rate to negative of viral antigens in group E (91.11%) was superior to in group C (64.44%), p<0.05. methylprednisolone in combination with advanced antibiotics and antiviral drugs is an effective treatment approach for VP.

Interferon regulatory factor 1 (IRF-1) downregulates Checkpoint kinase 1 (CHK1) through miR-195 to upregulate apoptosis and PD-L1 expression in Hepatocellular carcinoma (HCC) cells.

BACKGROUND: CHK1 is considered an oncogene with overexpression in numerous cancers. However, CHK1 signalling regulation in hepatocellular carcinoma (HCC) remains unclear. METHODS: CHEK1 mRNA, protein, pri-miR-195 and miR-195 expression in HCC tissue was determined by qPCR, WB and IF staining assay. Survival analyses in HCC with high- and low-CHEK1 mRNA expression was performed using TCGA database. Relative luciferase activity was investigated in HCC cells transfected with p-CHEK1 3'UTR. Apoptosis was detected by TUNEL assay. NK and CD8+ T cells were analysed by flow cytometry. RESULTS: CHK1 is increased in human HCC tumours compared with non-cancerous liver. High CHK1 predicts worse prognosis. IFN-γ suppresses CHK1 via IRF-1 in HCC cells. The molecular mechanism of IRF-1 suppressing CHK1 is post-transcriptional by promoting miR-195 binding to CHEK1 mRNA 3'UTR, which exerts a translational blockade. Upregulated IRF-1 inhibits CHK1, which induces apoptosis of HCC cells. Likewise, CHK1 inhibition augments cellular apoptosis in HCC tumours. This effect may be a result of increased tumour NK cell infiltration. However, IRF-1 expression or CHK1 inhibition also upregulates PD-L1 expression via increased STAT3 phosphorylation. CONCLUSIONS: IRF-1 induces miR-195 to suppress CHK1 protein expression. Both increased IRF-1 and decreased CHK1 upregulate cellular apoptosis and PD-L1 expression in HCC.

IRF2 regulates cellular survival and Lenvatinib-sensitivity of hepatocellular carcinoma (HCC) through regulating ß-catenin.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Lenvatinib oral chemotherapy is approved as a first-line treatment of patients with unresectable HCC. The efficacy and therapeutic duration of lenvatinib are limited by drug resistance, and the mechanism is unclear. IRF2 is a constitutive transcription factor associated with the development of various cancers by regulating cancer cell growth, apoptosis, and drug resistance. However, the potential role of IRF2 in lenvatinib resistance in HCC has not been explored. In this study, we found that IRF2 promoted proliferation, inhibited apoptosis, and increased lenvatinib resistance of HCC cells by regulating ß-catenin expression. Silencing IRF2 downregulated the expression of ß-catenin, while overexpressing IRF2 upregulated ß-catenin. Moreover, the expression of ß-catenin and IRF2 was positively correlated in HCC tissues. Inhibiting ß-catenin with XAV-939 effectively abrogated ß-catenin expression caused by lenvatinib treatment. These findings identify an important function of IRF2 in HCC and demonstrate a mechanism of lenvatinib resistance of HCC cells. Targeting IRF2 may be a potential strategy to improve the therapeutic effect of lenvatinib on HCC.

Interferon regulatory factor 1(IRF-1) activates anti-tumor immunity via CXCL10/CXCR3 axis in hepatocellular carcinoma (HCC).

Interferon regulatory factor 1 (IRF-1) is a tumor suppressor gene in cancer biology with anti-proliferative and pro-apoptotic effect on cancer cells, however mechanisms of IRF-1 regulating tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remain only partially characterized. Here, we investigated that IRF-1 regulates C-X-C motif chemokine 10 (CXCL10) and chemokine receptor 3 (CXCR3) to activate anti-tumor immunity in HCC. We found that IRF-1 mRNA expression was positively correlated with CXCL10 and CXCR3 through qRT-PCR assay in HCC tumors and in analysis of the TCGA database. IRF-1 response elements were identified in the CXCL10 promoter region, and ChIP-qPCR confirmed IRF-1 binding to promote CXCL10 transcription. IRF-2 is a competitive antagonist for IRF-1 mediated transcriptional effects, and overexpression of IRF-2 decreased basal and IFN-γ induced CXCL10 expression. Although IRF-1 upregulated CXCR3 expression in HCC cells, it inhibited proliferation and exerted pro-apoptotic effects, which overcome proliferation partly mediated by activating the CXCL10/CXCR3 autocrine axis. In vitro and in vivo studies showed that IRF-1 increased CD8+ T cells, NK and NKT cells migration, and activated IFN-γ secretion in NK and NKT cells to induce tumor apoptosis through the CXCL10/CXCR3 paracrine axis. Conversely, this effect was markedly abrogated in HCC tumor bearing mice deficient in CXCR3. Therefore, the IRF-1/CXCL10/CXCR3 axis contributes to the anti-tumor microenvironment in HCC.

Interferon Regulatory Factor-1 (IRF1) activates autophagy to promote liver ischemia/reperfusion injury by inhibiting ß-catenin in mice.

Autophagy is an important factor in liver ischemia-reperfusion injury. In the current study we investigate the function of interferon regulatory factor-1 (IRF1) in regulating autophagy to promote hepatic ischemia reperfusion injury (IR). The high expression of IRF1 during hepatic IR exhibited increased liver damage and was associated with activation of autophagy shown by Western blot markers, as well as immunofluorescent staining for autophagosomes. These effects were diminished by IRF1 deficiency in IRF1 knock out (KO) mice. Moreover, the autophagy inhibitor 3-MA decreased IR-induced liver necrosis and markedly abrogated the rise in liver injury tests (AST/ALT). ß-catenin expression decreased during liver IR and was increased in the IRF1 KO mice. Immunoprecipitation assay showed the binding between IRF1 and ß-catenin. Overexpression of IRF1 induced autophagy and also inhibited the expression of ß-catenin. ß-catenin inhibitor increased autophagy while ß-catenin agonist suppressed autophagy in primary mouse hepatocytes. These results indicate that IRF1 induced autophagy aggravates hepatic IR injury in part by inhibiting ß-catenin and suggests that targeting IRF1 may be an effective strategy in reducing hepatic IR injury.

iNOS/NO is required for IRF1 activation in response to liver ischemia-reperfusion in mice.

BACKGROUND: Ischemia and reperfusion (I/R) induces cytokines, and up-regulates inducible nitric oxide synthase (iNOS), interferon regulatory factor-1(IRF1) and p53 up-regulated modulator of apoptosis (PUMA), which contribute to cell death and tissue injury. However, the mechanisms that I/R induces IRF1-PUMA through iNOS/NO is still unknown. METHODS: Ischemia was induced by occluding structures in the portal triad (hepatic artery, portal vein, and bile duct) to the left and median liver lobes for 60 min, and reperfusion was initiated by removal of the clamp. Induction of iNOS, IRF1 and PUMA in response to I/R were analyzed. I/R induced IRF1 and PUMA expression were compared between iNOS wild-type and iNOS knockout (KO) mice. Human iNOS gene transfected-cells were used to determine iNOS/NO signals targeting IRF1. To test whether HDAC2 was involved in the mediation of iNOS/NO-induced IRF1 transcriptional activities and its target gene (PUMA and p21) expression, NO donors were used in vitro and in vivo. RESULTS: IRF1 nuclear translocation and PUMA transcription elevation were markedly induced following I/R in the liver of iNOS wild-type mice compared with that in knock-out mice. Furthermore, I/R induced hepatic HDAC2 expression and activation, and decreased H3AcK9 expression in iNOS wild-type mice, but not in the knock-out mice. Mechanistically, over-expression of human iNOS gene increased IRF1 transcriptional activity and PUMA expression, while iNOS inhibitor L-NIL reversed these effects. Cytokine-induced PUMA through IRF1 was p53 dependent. IRF1 and p53 synergistically up-regulated PUMA expression. iNOS/NO-induced HDAC2 mediated histone H3 deacetylation and promoted IRF1 transcriptional activity. Moreover, treating the cells with romidepsin, an HDAC1/2 inhibitor decreased NO-induced IRF1 and PUMA expression. CONCLUSIONS: This study demonstrates a novel mechanism that iNOS/NO is required for IRF1/PUMA signaling through a positive-feedback loop between iNOS and IRF1, in which HDAC2-mediated histone modification is involved to up-regulate IRF1 in response to I/R in mice.

Interferon regulatory factor 1 (IRF-1) and IRF-2 regulate PD-L1 expression in hepatocellular carcinoma (HCC) cells.

The objective response rate of immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC) with anti PD-L1/PD-1 therapy is low. Discovering the signaling pathways regulating PD-L1 might help to improve ICB response rates. Here, we investigate transcription factors IRF-1 and IRF-2 signaling pathways regulating PD-L1 in HCC cells. In vivo studies show that IRF-1 and PD-L1 mRNA expression in human HCC tumors are significantly repressed compared with noncancerous background liver. IRF-1, IRF-2, and PD-L1 mRNA expression correlated positively in HCC tumors. Increased IRF-1 mRNA expression was observed in patients with well-differentiated or early stage HCC tumors. In vitro studies show that IFN-γ induces PD-L1 mRNA and protein expression through upregulation of IRF-1 in mouse and human HCC cells. IRF-1, IRF-2, and PD-L1 mRNA expression is upregulated in murine HCC by co-culture with effector T cells from spleen cells incubated with anti-CD3/CD28 antibodies. IRF-2 over-expression down-regulates IFN-γ induced PD-L1 promoter activity and protein levels in a dose-dependent manner. We identify two IRF-1 response elements (IRE1/IRE2) in the upstream 5'-flanking region of the CD274 (PD-L1) gene promoter. Site-directed mutagenesis shows both IRE1 and IRE2 are functional in transfection promoter assays. IRF-1 traditionally functions as tumor suppressor gene. However, these novel findings show a complex role for IRF-1 which upregulates PD-L1 in the inflammatory tumor microenvironment. IRF-1 antagonizes IRF-2 for binding to the IRE promoter element in PD-L1 which gives new insight to the regulation of PD-L1/PD-1 pathways in HCC ICB therapy.

MicroRNA-301a (miR-301a) is induced in hepatocellular carcinoma (HCC) and down- regulates the expression of interferon regulatory factor-1.

Hepatocellular carcinoma (HCC) tumors evade death in part by downregulating expression of the tumor suppressor gene Interferon regulatory factor-1 (IRF-1). However, the molecular mechanisms accounting for IRF-1 suppression in HCC have not been well described. In this study, we identified a novel microRNA-301a (miR-301a) binding site in the 3'-untranslated region (3'- UTR) of the human IRF-1 gene and hypothesized a functional role for miR-301a in regulating HCC growth. We show that miR-301a is markedly upregulated in primary HCC tumors and HCC cell lines, while IRF-1 is down-regulated in a post-transcriptional manner. MiR-301a regulates basal and inducible IRF-1 expression in HCC cells with an inverse relationship between miR-301a and IRF-1 expression in HCC cells. Chronic hypoxia induces miR-301a in HCC in vitro and decreases IRF-1 expression. Finally, miR-301a inhibition increases apoptosis and decreases HCC cell proliferation. These findings suggest that targeting of IRF-1 by miR-301a contributes to the molecular basis for IRF-1 downregulation in HCC and provides new insight into the regulation of HCC by miRNAs.

Laparoscopic Liver Resection: A Review of Current Status.

BACKGROUND: Laparoscopic liver resection (LLR) has been increasing since it was first reported in 1991. Two international expert consensus conferences on LLR surgery were held in Louisville, KY, USA, in 2008 and in Morioka, Japan, in 2014, respectively. While most initial minimally invasive liver resections were typically done for benign lesions in anterior or left lateral segments, LLR is currently being applied for major anatomic resections, malignancy, cirrhosis, and live donor hepatectomy. METHODS: A systematic search of PubMed, MEDLINE, and Ovid databases was performed and English language articles published between January 2001 and May 2016 were reviewed. The titles and abstracts were screened and those studies related to following several topics were further retrieved. RESULTS: This review provides a comprehensive insight into the current status of LLR, including hot topics such as laparoscopic major hepatectomy, robotic liver resection, laparoscopic live donor hepatectomy, and laparoscopic ALPPS. LLR has gained greater acceptance in recent years and the acceptance will likely increase with patient benefits. CONCLUSIONS: This field is anxiously awaiting the results of randomized clinical trials comparing LLR to open liver resection for malignancy. Learning curve and scoring systems for degree of difficulty will continue to evolve.

MicroRNA-23a downregulates the expression of interferon regulatory factor-1 in hepatocellular carcinoma cells.

Interferon regulatory factor-1 (IRF-1) is a tumor-suppressor gene induced by interferon-γ (IFNγ) and plays an important role in the cell death of hepatocellular carcinoma (HCC). HCC tumors evade death in part by downregulating IRF-1 expression, yet the molecular mechanisms accounting for IRF-1 suppression in HCC have not yet been characterized. Previous studies have shown that microRNA-23a (miR-23a) can suppress apoptosis by targeting IRF-1. Therefore, we hypothesized that miR-23a promotes HCC growth by downregulating IRF-1. For the in vivo studies, 7 cases of resected HCC and adjacent liver samples were analyzed. For the in vitro studies, IRF-1 mRNA and protein were examined in HepG2 and Huh-7 HCC cells after IFNγ stimulation by real-time PCR and western blotting, respectively. To determine the role of miR-23a in regulating IRF-1, HepG2 cells were transfected with an miR-23a mimic or inhibitor, and IRF-1 expression was examined. Binding of miR-23a was assessed by cloning the 528-bp human IRF-1 3'-untranslated region (3'UTR) into luciferase reporter plasmid pMIR-IRF-1-3'UTR. The results showed that IRF-1 mRNA expression was downregulated in the human HCC tumor tissues compared to that in the adjacent background liver tissues. IFNγ-induced IRF-1 protein was less in the HepG2 tumor cells compared to that in the primary human hepatocytes. miR-23a expression was inversely correlated with IRF-1, and addition of the miR-23a inhibitor increased basal IRF-1 mRNA and protein. Likewise, the miR-23a mimic downregulated IFNγ-induced IRF-1 protein expression, while the miR-23a inhibitor increased IRF-1. Furthermore, the miR-23a mimic repressed IRF-1-3'UTR reporter activity, while the miR-23a inhibitor increased the reporter activity. These results demonstrated that IRF-1 expression is downregulated in human HCC tumors compared to that noted in the background liver. miR-23a downregulates the expression of IRF-1 in HCC cells, and the IRF-1 3'UTR has an miR­23a binding site that binds miR-23a and decreases reporter activity. These findings suggest that the targeting of IRF-1 by miR-23a may be the molecular basis for IRF-1 downregulation in HCC and provide new insight into the regulation of HCC by miRNAs.