FAT10 mediates the sorafenib-resistance of hepatocellular carcinoma cells by stabilizing E3 ligase NEDD4 to enhance PTEN/AKT pathway-induced autophagy.

Although sorafenib is the first-line therapeutic agent for advanced hepatocellular carcinoma (HCC), the development of drug resistance in HCC cells limits its clinical efficacy. However, the key factors involved in mediating the sorafenib resistance of HCC cells and the underlying mechanisms have not been elucidated. In this study, we generated sorafenib-resistant HCC cell lines, and our data demonstrate that HLA-F locus-adjacent transcript 10 (FAT10), a ubiquitin-like protein, is markedly upregulated in sorafenib-resistant HCC cells and that reducing the expression of FAT10 in sorafenib-resistant HCC cells increases sensitivity to sorafenib. Mechanistically, FAT10 stabilizes the expression of the PTEN-specific E3 ubiquitin ligase NEDD4 that causes downregulation of PTEN, thereby inducing AKT-mediated autophagy and promoting the resistance of HCC cells to sorafenib. Moreover, we screened the small molecule Compound 7695-0983, which increases the sensitivity of sorafenib-resistant HCC cells to sorafenib by inhibiting the expression of FAT10 to inhibit NEDD4-PTEN/AKT axis-mediated autophagy. Collectively, our preclinical findings identify FAT10 as a key factor in the sorafenib resistance of HCC cells and elucidate its underlying mechanism. This study provides new mechanistic insight for the exploitation of novel sorafenib-based tyrosine kinase inhibitor (TKI)-targeted drugs for treating advanced HCC.

Cuproptosis-related molecular classification and gene signature of hepatocellular carcinoma and experimental verification.

Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with poor overall prognosis. Cuproptosis, a recently proposed mode of copper-dependent cell death, plays a critical role in the malignant progression of various tumors; however, the expression and prognostic value of cuproptosis-related regulatory genes in HCC remain unclear. Methods: Genomic, genetic, and expression profiles of ten key cuproptosis-related regulatory genes were analyzed using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset and protein expression data from the Human Protein Atlas (HPA) database. Unsupervised clustering of HCC patients based on these ten key cuproptosis-related regulatory genes was used to identify different HCC subtypes and analyze the differences in clinical and immune characteristics among subtypes. Subsequently, univariate Cox and least absolute shrinkage and selection operator (LASSO) Cox analyses were used to establish a cuproptosis-related prognostic signature, and the accuracy of prognostic signature prediction was internally validated by Kaplan-Meier survival analysis and time-dependent receiver operating characteristic curve in TCGA training and testing cohorts. The prognostic signature was externally validated using TCGA-LIHC entire cohort and International Cancer Genome Consortium Liver Cancer (ICGC-LIRI) cohorts. Finally, the expression landscape of cuproptosis-related regulatory genes in prognostic signature was explored by quantitative real-time polymerase chain reaction (qRT-PCR), western blotting and immunohistochemistry (IHC) experiments. Results: Ten cuproptosis-related genes were differentially expressed in normal and HCC tissues. Unsupervised clustering identified two subtypes and HCC patients with these two subtypes had different clinical prognoses and immune characteristics, as well as different degrees of response to immunotherapy. Lipoyltransferase 1 (LIPT1), dihydrolipoamide s-acetyltransferase (DLAT), and cyclin dependent kinase inhibitor 2A (CDKN2A) were selected to construct a prognostic signature, which significantly distinguished HCC patients with different survival periods in the TCGA training and testing cohorts and was well validated in both the TCGA-LIHC entire cohort and ICGC-LIRI cohort. The risk score of the prognostic signature was confirmed to be an independent prognostic factor, and nomograms were generated to effectively predict the probability of HCC patient survival. The qRT-PCR, western blotting and IHC results also revealed a significant imbalance in the expression of these cuproptosis-related genes in HCC. Conclusions: The classification and prognostic signature based on cuproptosis-related regulatory genes helps to explain the heterogeneity of HCC, which may contribute to the individualized treatment of patients with the disease.

The ubiquitin-like protein FAT10 in hepatocellular carcinoma cells limits the efficacy of anti-VEGF therapy by accelerating VEGF-independent angiogenesis.

INTRODUCTION: The efficacy of anti-vascular endothelial growth factor (VEGF) therapy is limited. However, the key factors involved in limiting the efficacy of anti-VEGF therapy and the underlying mechanisms remain unclear. OBJECTIVES: To investigate the effects and mechanisms of human leukocyte antigen F locus-adjacent transcript 10 (FAT10), a ubiquitin-like protein, in limiting the efficacy of anti-VEGF therapy in hepatocellular carcinoma (HCC) cells. METHODS: FAT10 was knocked out in HCC cells using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 technology. Bevacizumab (BV), an anti-VEGF monoclonal antibody, was used to evaluate the efficacy of anti-VEGF therapy in vivo. Mechanisms of FAT10 action were assessed by RNA sequencing, glutathione S-transferase pulldown assays and in vivo ubiquitination assays. RESULTS: FAT10 accelerated VEGF-independent angiogenesis in HCC cells which limited BV efficacy and BV-aggravated hypoxia and inflammation promoted FAT10 expression. FAT10 overexpression increased levels of proteins involved in several signaling pathways in HCC cells, resulting in upregulation of VEGF and multiple non-VEGF proangiogenic factors. Upregulation of multiple FAT10-mediated non-VEGF signals compensated for the inhibition of VEGF signaling by BV, enhancing VEGF-independent angiogenesis and promoting HCC growth. CONCLUSIONS: Our preclinical findings identify FAT10 in HCC cells as a key factor limiting the efficacy of anti-VEGF therapy and elucidate its underlying mechanisms. This study provides new mechanistic insights into the development of antiangiogenic therapies.

Simple cholecystectomy is an adequate treatment for grade I T1bN0M0 gallbladder carcinoma: Evidence from 528 patients.

BACKGROUND: T1b gallbladder carcinoma (GBC) is defined as a tumor that invades the perimuscular connective tissue without extension beyond the serosa or into the liver. However, controversy still exists over whether patients with T1b GBC should undergo cholecystectomy alone or radical GBC resection. AIM: To explore the optimal surgical approach in patients with T1b gallbladder cancer of different pathological grades. METHODS: Patients with T1bN0M0 GBC who underwent surgical treatment between 2000 and 2017 were included in the Surveillance, Epidemiology, and End Results database. The Kaplan-Meier method and log-rank test were used to analyze the overall survival (OS) and disease-specific survival (DSS) of patients with T1b GBC of different pathological grades. Cox regression analysis was used to identify independent predictors of mortality and explore the selection of surgical methods in patients with T1b GBC of different pathological grades and their relationship with prognosis. RESULTS: Of the 528 patients diagnosed with T1bN0M0 GBC, 346 underwent simple cholecystectomy (SC) (65.5%), 131 underwent SC with lymph node resection (SC + LN) (24.8%), and 51 underwent radical cholecystectomy (RC) (9.7%). Without considering the pathological grade, both the OS (P < 0.001) and DSS (P = 0.003) of T1b GBC patients who underwent SC (10-year OS: 27.8%, 10-year DSS: 55.1%) alone were significantly lower than those of patients who underwent SC + LN (10-year OS: 35.5%, 10-year DSS: 66.3%) or RC (10-year OS: 50.3%, 10-year DSS: 75.9%). Analysis of T1b GBC according to pathological classification revealed no significant difference in OS and DSS between different types of procedures in patients with grade I T1b GBC. In patients with grade II T1b GBC, obvious survival improvement was observed in the OS (P = 0.002) and DSS (P = 0.039) of those who underwent SC + LN (10-year OS: 34.6%, 10-year DSS: 61.3%) or RC (10-year OS: 50.5%, 10-year DSS: 78.8%) compared with those who received SC (10-year OS: 28.1%, 10-year DSS: 58.3%). Among patients with grade III or IV T1b GBC, SC + LN (10-year OS: 48.5%, 10-year DSS: 72.2%), and RC (10-year OS: 80%, 10-year DSS: 80%) benefited OS (P = 0.005) and DSS (P = 0.009) far more than SC (10-year OS: 20.1%, 10-year DSS: 38.1%) alone. CONCLUSION: Simple cholecystectomy may be an adequate treatment for grade I T1b GBC, whereas more extensive surgery is optimal for grades II-IV T1b GBC.

Modified median hepatic fissure approach for resection of liver tumours located in the angle between the root of the middle and right hepatic veins.

BACKGROUND: Liver tumours between the root angle of the middle and right hepatic veins are a special type of liver segment VIII tumour. In this study, we designed a modified median hepatic fissure approach to remove these tumours. The safety and effectiveness of the approach were evaluated. MATERIALS AND METHODS: From April 2015 to November 2019, 11 patients with liver tumours between the angle of the middle and right hepatic veins underwent this modified median hepatic fissure approach. We retrospectively analysed data from the perioperative periods of these 11 patients, including general condition, operation time, intraoperative bleeding, and postoperative complications. Disease-free survival and overall survival were assessed. RESULTS: Of the 11 patients, 9 patients had primary hepatocellular carcinoma and 2 had colorectal liver metastases. The average intraoperative blood loss was 285 mL (150-450 mL). Two patients developed postoperative bile leakage, but there were no significant serious complications, such as intraabdominal bleeding and liver failure, in any of the patients. The liver function returned to the normal range on the 5th day after surgery. Of the 11 patients, 5 have survived for more than 3 years (45.5%), and 4 have been disease-free for more than 3 years (36.3%). CONCLUSIONS: For liver tumours between the root angle of the middle and right hepatic veins, the modified median hepatic fissure approach is a safe and feasible method.

Ubiquitin-like protein FAT10 suppresses SIRT1-mediated autophagy to protect against ischemic myocardial injury.

Autophagy plays a deleterious role in ischemic myocardial injury. The deacetylase SIRT1 is a well-established regulator of autophagy that can be modified by the ubiquitin-like protein SUMO1. Our previous work demonstrated that another ubiquitin-like protein, FAT10, exerts cardioprotective effects against myocardial ischemia by stabilizing the caveolin-3 protein; however, the effects of FAT10 on autophagy through SIRT1 are unclear. Here, we constructed a Fat10-knockout rat model to evaluate the role of FAT10 in autophagy. In vivo and in vitro assays confirmed that FAT10 suppressed autophagy to protect the heart from ischemic myocardial injury. Mechanistically, FAT10 was mainly involved in the regulation of the autophagosome formation process. FAT10 affected autophagy through modulating SIRT1 degradation, which resulted in reduced SIRT1 nuclear translocation and inhibited SIRT1 activity via its C-terminal glycine residues. Notably, FAT10 competed with SUMO1 at the K734 modification site of SIRT1, which further reduced LC3 deacetylation and suppressed autophagy. Our findings suggest that FAT10 inhibits autophagy by antagonizing SIRT1 SUMOylation to protect the heart from ischemic myocardial injury. This is a novel mechanism through which FAT10 regulates autophagy as a cardiac protector.

Intrahepatic bile duct exploration lithotomy is a useful adjunctive hepatectomy method for bilateral primary hepatolithiasis: an eight-year experience at a single centre.

BACKGROUND: To evaluate the perioperative and long-term results of intrahepatic bile duct exploration lithotomy (IHBDIL) combined with hepatectomy for patients with complicated bilateral primary hepatolithiasis. METHODS: A study was conducted involving 56 patients with complicated bilateral primary hepatolithiasis who underwent IHBDIL combined with hepatectomy at our hospital from January 2006 to December 2014. The perioperative and long-term outcomes that were retrospectively analysed included the stone clearance rate, operative morbidity and mortality, and stone recurrence rate. Patients with a preoperative diagnosis of cholangiocarcinoma were excluded. RESULTS: In all 56 patients, hepatic duct stones were located in the bilateral IHBD. The surgical method was IHBDIL combined with hepatectomy. Postoperative complications occurred in 15 patients (26.8%), 14 patients responded to conservative management, and there was 1 case of postoperative mortality because of hepatic failure. The overall initial success rate of stone clearance was 85.7%, and the final clearance rate was 92.9% following postoperative choledochoscopic lithotripsy. The stone recurrence rate was 13.5%, and the occurrence of postoperative cholangitis was 10.9% during the follow-up period. CONCLUSION: IHBDIL combined with hepatectomy is a safe, effective, and promising treatment for patients with complicated bilateral primary hepatolithiasis. The perioperative and long-term outcomes are satisfactory for complicated bilateral primary hepatolithiasis.

Bleeding risk in cancer patients treated with sorafenib: A meta-analysis of randomized controlled trials.

OBJECTIVE: Sorafenib, an oral vascular endothelial growth factor receptor tyrosine-kinase inhibitor, has become a cornerstone in the treatment of various malignancies. However, concerns have arisen regarding the risk of hemorrhage with sorafenib use. Nevertheless, the contribution of sorafenib to hemorrhage and the underlying risk factors remains unclear. MATERIALS AND METHODS: We performed a meta-analysis to determine the incidence and risk of hemorrhage associated with sorafenib treatment. Multiple databases were searched to identify relevant studies. The analysis included randomized controlled trials (RCTs) that directly compared cancer patients treated with or without sorafenib. Statistical analyses were conducted to determine the overall incidence, relative risks (RRs), and 95% confidence intervals (CIs) using fixed- or random-effect models. RESULTS: Ten RCTs involving 4720 patients were included in the analysis. Overall, the incidence rates of all- and high-grade hemorrhage in patients receiving sorafenib were 9.89% (95% CI: 8.73-11.18%) and 2.86% (95% CI: 2.25-3.63%), respectively. Sorafenib treatment increased the risk of all-grade hemorrhage in patients compared to control treatment (RR: 1.99; 95% CI: 1.59-2.49; P < 0.00001), but did not increase the incidence of high-grade hemorrhage (RR: 1.42; 95% CI: 0.95-2.12; P = 0.09). Subgroup analysis showed no significant increase in the risk of hemorrhage between patients with various malignancies or concurrent treatment. No evidence of publication bias was observed. CONCLUSION: In patients with malignancy, sorafenib treatment combined with standard treatment significantly increases the risk of low-grade hemorrhagic events.

Human Leukocyte Antigen F Locus Adjacent Transcript 10 Overexpression Disturbs WISP1 Protein and mRNA Expression to Promote Hepatocellular Carcinoma Progression.

Recently, studies on transcriptome-proteome relationships have revealed mRNA/protein expression discordance for certain genes and speculated that protein posttranslational modification (PTM) may be involved. However, there is currently no evidence to support this hypothesis. Wnt-induced secreted protein-1 (WISP1) is the downstream target gene of ß-catenin and plays an important role in tumorigenesis and progression, but the expression and role of WISP1 in different tumor types are controversial. Here, we first confirmed that WISP1 protein expression was significantly down-regulated in hepatocellular carcinoma (HCC) tissue and could be an independent predictor of poor prognosis for patients with HCC. In vivo and in vitro evidence was provided that WISP1 can suppress HCC cell proliferation. Further studies have found that low WISP1 protein expression was related to expression of human leukocyte antigen F locus adjacent transcript 10 (FAT10), a specific ubiquitin-like protein with both degradation and stabilization functions, which plays an important role in PTM. FAT10 overexpression facilitated WISP1 degradation by FAT10ylation to decrease WISP1 protein expression, thus promoting HCC proliferation. Interestingly, we found and demonstrated that FAT10 overexpression could result in WISP1 protein/mRNA expression discordance, with protein expression decreasing while mRNA expression increased. The underlying mechanism is that FAT10 exerts substrate stabilization and degradation functions simultaneously, while FAT10 overexpression promotes WISP1 mRNA expression by stabilizing ß-catenin and directly degrades WISP1 protein. Conclusion: Our study demonstrated that overexpression of FAT10 results in expression discordance between WISP1 protein and mRNA, thereby promoting HCC progression by down-regulating WISP1 protein expression.

Learning curve for performing choledochotomy bile duct exploration with primary closure after laparoscopic cholecystectomy.

BACKGROUND: Primary closure after laparoscopic cholecystectomy (LC) and laparoscopic common bile duct exploration (LCBDE) is a safe and effective approach for treating cholecystolithiasis with choledocholithiasis. The aim of this study was to evaluate the learning curve of performing primary closure after LC+LCBDE. METHODS: We retrospectively identified all patients who underwent primary closure after LC+LCBDE performed by a single surgeon from January 2009 to April 2015 in our institution, and analyzed preoperative, intraoperative, and postoperative data using the cumulative sum (CUSUM) analysis to evaluate the learning curve for this procedure. RESULTS: Overall, there were 390 patients. The total postoperative complications rate was 7.2%, including bile leakage in 9 (2.3%) patients and retained common bile duct stone in 3 (0.8%) patients. The CUSUM operating time (OT) learning curve was best modeled by the equation: CUSUMOT = 312.209 × procedure0.599 × e(-0.011×procedure) + 122.608 (R2 = 0.96). The learning curve was composed of two phases, phase 1 (the initial 54 patients) and phase 2 (the remaining 336 patients). A significant decrease in the OT (116.8 ± 22.4 vs. 93.8 ± 17.8 min; p < 0.001) and complication rate (16.7 vs. 5.7%; p < 0.01) including the rate of bile leakage (7.4 vs. 1.5%; p < 0.01) and retained stone (3.7 vs. 0.3%; p < 0.01) was observed between the two phases. In addition, 20 patients had conversion to open surgery. Impacted stones were independently associated with conversion, as indicated by a multivariable analysis. CONCLUSION: The data suggest that the learning curve of this procedure was achieved in approximately 54 cases. An impacted stone was the only risk factor that affected the conversion rate.

Overexpression of eEF1A1 regulates G1-phase progression to promote HCC proliferation through the STAT1-cyclin D1 pathway.

Hepatocellular carcinoma (HCC) is a common cancer worldwide with an aggressive and highly proliferative activity. Studies had confirmed that HCC cell proliferation is associated with the cell cycle's G1 phase, but the detailed molecular mechanism has not been thoroughly elucidated to date. Eukaryotic translation elongation factor 1A1 (eEF1A1) is an evolutionarily conserved elongation factor protein and is involved in tumor cell proliferation. However, which phase of the cell cycle is regulated by eEF1A1 to influence cell proliferation in HCC and its detailed molecular mechanism remain unclear. In this study, we observed that eEF1A1 influences HCC cell proliferation by regulating the cell cycle's G1 phase. In addition, eEF1A1 influences G1 phase by regulating cyclin D1 expression, promoting HCC cell proliferation both in vitro and in vivo. Moreover, our results indicated that eEF1A1 regulates cyclin D1 expression through STAT1 signaling. STAT1 increases the transcriptional activity of cyclin D1 by binding to the cyclin D1 promoter. Taken together, these findings enabled us to identify a novel mechanism by which eEF1A1 regulates the cell cycle's G1 phase to promote tumor proliferation by regulating cyclin D1 expression through STAT1 signaling in HCC.

Long non-coding RNA00544 serves as a potential novel predictive and prognostic marker for HR+ HER2- subtype breast cancer.

Luminal breast cancers (BC) account for majority of breast cancer. Due to its heterogeneity and the development of treatment resistance, luminal BC patients can vary substantially. Long noncoding RNAs (lncRNAs), as we known, is involved in breast cancer progression. Here, we aim to identify the lncRNAs which are involved in the particular type luminal BC progression. By Gene Chips analysis, we found a novel lncRNA00544, which was highly expressed in the metastatic axillary nodes compared with corresponding luminal BC tissues (fold change = 2.26, P = 0.043). This result was confirmed in luminal BC cell lines (p = 0.0113) and 49 paired breast cancer samples compared with in corresponding controls (p = 0.011). Furthermore, Kaplan-Meier survival curves of 373 breast cancer patients indicated that disease-free survival was significantly poor in breast cancer patients with high lncRNA00544 expression (p < 0.001). Univariate and multivariate Cox regression analyses showed that lncRNA00544 was a significant independent prognostic biomarker in luminal BC patients. Further analysis showed that the prognosis of high lncRNA00544 expression in breast cancer patients was actually related to HR + HER2- subtype. Together, our studies indicate that lncRNA00544 may represent a novel predictive and prognostic indicator in luminal BC patients.

lncRNAs as prognostic molecular biomarkers in hepatocellular carcinoma: a systematic review and meta-analysis.

The latest studies have shown that long non-coding RNAs (lncRNAs) may be considered markers as their expression levels were abnormal in cancer and can be used as a molecular biomarker for the potential assessment of cancer prognosis. In this study, we aimed to assess the prognostic value of lncRNA as marker of patients with hepatocellular carcinoma. We performed a detailed search of the PubMed and Embase databases for articles on the prognostic value of various lncRNAs in HCC. We then carefully extracted the relevant data from the articles, and we used the meta-analysis method to analyze these results; heterogeneity and publication bias were also evaluated. With 40 associative studies included, we found that high expression of 27 types of lncRNA was associated with a poor prognosis in HCC patients, and low expression of 18 types of lncRNAs was associated with a worse prognosis. Patients with higher lncRNA expression had significantly poor overall survival (OS; pooled HR, 1.25; 95% confidence interval [CI], 1.03-1.52) as well as significantly poor recurrence-free survival (RFS; pooled HR, 1.66; 95% CI, 1.26-2.17). Overexpression of lncRNAs may not meaningfully predict disease-free survival (DFS; pooled HR, 1.04; 95% CI, 0.52-2.07; p = 0.91). Our meta-analysis demonstrated that lncRNAs may serve as predictive biomarkers for cancer prognosis.

The diagnostic value of assays for circulating tumor cells in hepatocellular carcinoma: A meta-analysis.

PURPOSE: Circulating tumor cells (CTCs) are considered potential biomarkers for the detection of hepatocellular carcinoma (HCC). Many studies have attempted to explore this role, but the results are variable. We conducted the first comprehensive meta-analysis to evaluate the diagnostic value of CTC assay for HCC patients. Additional prognostic value was also assessed. EXPERIMENTAL DESIGN: All articles included in our study were assessed using QUADAS guidelines after a literature search. Using bivariate generalized linear mixed model and random-effects model, effect measures such as pooled sensitivity/specificity, positive likelihood ratios/negative likelihood ratios (NLRs), diagnostic odds ratios, hazard ratios (HRs), risk ratios, and corresponding 95% confidence intervals (95% CIs) were calculated. We used receiver operating characteristic curves and area under the curve (AUC) to summarize overall test performance. Heterogeneity, publication bias, subgroup, and sensitivity analyses were also performed. RESULTS: A total of 2256 subjects including 998 HCC patients in 20 studies were recruited in this meta-analysis. Although the overall diagnostic accuracy of the CTC assay was high (AUC 0.93, 95% CI: [0.90-0.95]), there was a high probability of error rate (NLR 0.33, 95% CI: [0.23, 0.48]). The results were more robust when nonmagnetic-activated isolation was used, compared with magnetic-activated isolation subgroup (NLR: 0.18 vs. 0.41; z = 2.118, P = .034). CTCs positivity was significantly associated with relapse-free survival (HR 2.417, 95% CI: [1.421-3.250]; P < .001), overall survival (HR 3.59, 95% CI: [1.984-6.495]; P < .001), and some clinical characteristics. CONCLUSION: CTC assay is not recommended as an independent HCC diagnostic tool, but is associated with poor clinicopathologic characteristics of HCC patients and could indicate poor prognosis.

Blockage of glycolysis by targeting PFKFB3 alleviates sepsis-related acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells.

Sepsis-related acute lung injury (ALI) is characterized by excessive lung inflammation and apoptosis of alveolar epithelial cells resulting in acute hypoxemic respiratory failure. Recent studies indicated that anaerobic glycolysis play an important role in sepsis. However, whether inhibition of aerobic glycolysis exhibits beneficial effect on sepsis-induced ALI is not known. In vivo, a cecal ligation and puncture (CLP)-induced ALI mouse model was set up and mice treated with glycolytic inhibitor 3PO after CLP. The mice treated with the 3PO ameliorated the survival rate, histopathological changes, lung inflammation, lactate increased and lung apoptosis of mice with CLP-induced sepsis. In vitro, the exposure of human alveolar epithelial A549 cells to lipopolysaccharide (LPS) resulted in cell apoptosis, inflammatory cytokine production, enhanced glycolytic flux and reactive oxygen species (ROS) increased. While these changes were attenuated by 3PO treatment. Sequentially, treatment of A549 cells with lactate caused cell apoptosis and enhancement of ROS. Pretreatment with N-acetylcysteine (NAC) significantly lowered LPS and lactate-induced the generation of ROS and cell apoptosis in A549 cells. Therefore, these results indicate that anaerobic glycolysis may be an important contributor in cell apoptosis of sepsis-related ALI. Moreover, LPS specifically induces apoptotic insults to A549 cell through lactate-mediated enhancement of ROS.

Comparison of the outcomes of hepatocellular carcinoma after hepatectomy between two regional medical centers in China and Japan.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant disease of the liver in China and Japan. The purpose of this study was to compare the outcomes of HCC patients after hepatectomy between two regional medical centers in China and Japan. METHODS: Data on HCC after hepatectomy were collected from January 2005 to December 2014 from Nagasaki University Hospital in Nagasaki, Japan and the Second Affiliated Hospital of Nanchang University in Nanchang, China. The patient and tumor characteristics, HCC etiology, and overall survival rates after hepatectomy were investigated. RESULTS: Two hundred patients in the Nagasaki group and 238 patients in the Nanchang group were diagnosed with HCC and underwent hepatectomy. The major underlying liver diseases were hepatitis C infection (32%, 64/200) and nonalcoholic steatohepatitis (NASH) (34.5%, 69/200) in the Nagasaki group, while in the Nanchang group, hepatitis B infection (79.4%, 189/238) was the dominant etiology. Large tumors (> 5 cm), the presence of a tumor capsule and a high alpha-fetoprotein value (≥ 400 U/L) were more frequently observed in the Nanchang group as compared with the Nagasaki group (p < 0.05). According to an outcome analysis, the Nanchang patients showed worse survival rates as compared with Nagasaki patients, particularly those with American Joint Committee on Cancer stages I and III due to the aggressive character of HCC in the Nanchang group. CONCLUSION: There are significant differences in the clinicopathologic features and outcomes of HCC patients from Japan and China. These differences may impact the eligibility for potentially curative therapy and the prognosis of patients with HCC.

Doxorubicin-induced mitophagy contributes to drug resistance in cancer stem cells from HCT8 human colorectal cancer cells.

Cancer stem cells (CSCs) are known to be drug resistant. Mitophagy selectively degrades unnecessary or damaged mitochondria by autophagy during cellular stress. To investigate the potential role of mitophagy in drug resistance in CSCs, we purified CD133+/CD44+ CSCs from HCT8 human colorectal cancer cells and then exposed to doxorubicin (DXR). Compared with parental cells, CSCs were more resistant to DXR treatment. Although DXR treatment enhanced autophagy levels in both cell types, the inhibition of autophagy by ATG7 silencing significantly increased the toxicity of DXR only in parental cells, not in CSCs. Interestingly, the level of mitochondrial superoxide was detected to be significantly lower in CSCs than in parental cells after DXR treatment. Furthermore, the mitophagy level and expression of BNIP3L, a mitophagy regulator, were significantly higher in CSCs than in parental cells after DXR treatment. Silencing BNIP3L significantly halted mitophagy and enhanced the sensitivity to DXR in CSCs. Our data suggested that mitophagy, but not non-selective autophagy, likely contributes to drug resistance in CSCs isolated from HCT8 cells. Further studies in other cancer cell lines will be needed to confirm our findings.

TAB3 upregulates Survivin expression to promote colorectal cancer invasion and metastasis by binding to the TAK1-TRAF6 complex.

Transforming growth factor-ß-activated kinase 1 (TAK1)-binding protein 3 (TAB3) is involved in cancer proliferation and metastasis, but its role in colorectal cancer remains unclear. In this study, we demonstrated that TAB3 is upregulated in colorectal cancer tissues and that high TAB3 levels correlated with tumor metastasis and a poor prognosis in colorectal cancer. In addition, TAB3 knockdown decreased Survivin expression and suppressed colorectal cancer cell migration and invasion in vitro, and reduced liver metastasis in vivo. Importantly, we found that TAB3 regulated Survivin expression by activating the NF-κB pathway through the formation of the TAK1-TAB3-TRAF6 complex. These findings suggest TAB3 may be a useful prognostic biomarker in colorectal cancer and a target for treatment of metastatic colorectal cancer.

Ubiquitin-like protein FAT10 promotes bladder cancer progression by stabilizing survivin.

Human HLA-F adjacent transcript 10 (FAT10) is a member of the ubiquitin-like-modifier family of proteins, which have been implicated in cancer development. In addition, the Survivin protein promotes proliferation in bladder cancer (BC). In this study, we explored the link between FAT10 and Survivin. FAT10 expression was dramatically up-regulated in BC tissue samples, and Kaplan-Meier survival analysis revealed that BC patients with high FAT10 expression had shorter overall survival than those with low FAT10 expression. Moreover, RNAi-mediated FAT10 knockdown decreased Survivin protein levels and inhibited BC proliferation both in vitro and in vivo. FAT10 directly bound to and stabilized Survivin protein, thereby promoting cancer cell proliferation by inhibiting ubiquitin-mediated degradation. These results reveal a novel mechanism by which FAT10 promotes tumor proliferation by directly stabilizing Survivin protein in BC.