HNRNPL facilitates ferroptosis in hepatocellular carcinoma cells by promoting S100A9 expression.

OBJECTIVE: This study probed into the effect of HNRNPL on ferroptosis in hepatocellular carcinoma (HCC) cells and related molecular mechanisms. METHODS: Expression patterns of HNRNPL, Recombinant S100 Calcium Binding Protein A9 (S100A9) were analyzed in HCC tissues or cells. Following transfection, HCC cell activity was analyzed, followed by detection of levels of ROS, iron content, LPO, MDA, and GSH as well as the expression of ferroptosis-related proteins. For molecular mechanism, RIP, RNA pull-down assay and actinomycin D assay were implemented to verify the binding relationship between HNRNPL and S100A9. Finally, in vivo nude mouse xenograft tumor experiments were performed for further validate the crucial role of HNENPL expression in HCC. RESULTS: HNRNPL and S100A9 were significantly overexpressed in HCC. sh-HNRNPL treatment led to a significant decrease in cellular activity, GSH content, and expression of GPX4 and SLC7A11, and a significant increase in iron content, LPO level, MDA, ROS content, and expression of ACSL4 and TFR1. In addition, after sh-HNRNPL was combined with oe-S100A9 or Fer-1, a ferroptosis inhibitor, both oe-S100A9 and Fer-1 reversed the promotional effect of sh-HNRNPL on ferroptosis of HCC cells when sh-HNRNPL acted alone. Mechanically, HNRNPL promoted S100A9 mRNA stability and expression through RBP. Furthermore, low expression of HNRNPL in vivo delayed the growth of xenograft tumors and the expression of ferroptosis-related proteins. CONCLUSION: HNRNPL promotes S100A9 mRNA stability and expression through RBP action, thereby promoting ferroptosis in HCC cells.

Prognostic value of neutrophil-to-lymphocyte ratio in colorectal cancer liver metastasis: A meta-analysis of results from multivariate analysis.

We aimed to evaluate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in colorectal cancer liver metastasis (CRLM). A comprehensive search was conducted across PubMed, MedLine, and the Cochrane Library databases for articles published from January 1, 2000 to April 30, 2022 that investigated the long-term prognostic value of NLR in CRLM; only studies with multivariate analyses were enrolled. Hazard ratio (HR) with 95% confidence interval (CI) was used to determine the effect size. A total of 2,522 patients in 12 studies were selected; the meta-analysis demonstrated that elevated NLR correlated with poor overall survival (OS) and disease-free survival (DFS) (HR, 1.95, 95%CI, 1.698-2.223, P < 0.01; HR, 1.80, 95%CI, 1.363-2.363, P < 0.01; respectively). The 5-year OS and disease-free survival rates were higher in the patients with normal NLR than in patients with high NLR (47% vs. 27%, P < 0.01; 37% vs. 6%, P < 0.01, respectively). Further analysis of clinicopathological parameters indicated no significant difference between the patients with and without elevated NLR. Begg's and Egger's tests for publication bias revealed no significant publication bias (P = 0.891 and P = 0.926, respectively). Multivariate analysis revealed that NLR had an excellent prognostic ability in CRLM, which can be used in deciding the treatment and predicting the clinical outcomes. Further multicenter randomized controlled trials are required to verify this conclusion.

Dexamethasone pretreatment attenuates lung and kidney injury in cholestatic rats induced by hepatic ischemia/reperfusion.

Hepatic ischemia followed by reperfusion (IR) results in mild to severe organ injury, in which tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) seem to be involved. Thus, we aim to assess the influence of hepatic ischemia/reperfusion injury on remote organs in addition to cholestasis and consider the possible efficacy of steroid pretreatment in reducing the injury. A common bile duct ligation model was done on 24 male Sprague-Dawley rats. After 7 days, the rats were divided randomly into control group, IR group, and dexamethasone (DEX) group. The IR group showed significant increases in serum alanine aminotransferase, aspartate aminotransferase, and creatinine levels compared with the control and DEX groups. By ELISA techniques, higher levels of TNF-α and IL-1ß in lung and kidney tissues were measured in the IR group than in the control and DEX groups, these were verified by immunohistochemistry. The lung histology of the IR group rats showed neutrophil infiltration, interstitial edema, and alveolar wall thickening. Kidney histology of the IR group rats showed vacuolization of the proximal tubular epithelial cells and tubular dilatation with granular eosinophilic casts. Better morphological aspects were observed in the DEX-pretreated animals. Minimal lesions were observed in the control. The results suggest that hepatic ischemia/reperfusion injury in cholestatic rats induced lung and kidney injuries. Pretreatment with dexamethasone reduced the IR-induced injury in addition to cholestasis.

SNCG gene silencing in gallbladder cancer cells inhibits key tumorigenic activities.

We recently determined that synuclein-gamma (SNCG) is highly expressed in human gallbladder cancer (GBC), and its abnormal expression is associated with tumor aggressiveness. To investigate the effects of SNCG gene silencing on the tumorigenic profiles of the GBC cell line, NOZ, short-hairpin RNA (shRNA) interference was employed. Specifically, the SNCG transcript was targeted by SNCG-shRNA lentiviral particles designed to silence SNCG gene expression. Following selection of NOZ cells stably expressing SNCG-shRNA, SNCG expression was examined by western blot and semi-quantitative RT-PCR analyses. Phenotypic hallmarks of gallbladder carcinogenesis were assayed by CCK-8, soft agar (colony formation), modified Boyden-Chamber (invasion), and flow cytometry (cell-cycle and apoptosis) assays. Our results showed that SNCG gene silencing in NOZ cells inhibited cell growth, colony formation, and invasion. In addition, it directly increased the effectiveness of paclitaxel in inducing G2/M cell-cycle arrest and cell apoptosis. Data from our in vivo study showed a decrease in tumor growth and weight in mice injected with SNCG-silenced NOZ cells. Together, these findings suggest that SNCG plays an important role in the progression of GBC.