Thioredoxin reductase 1 (TXNRD1) which is a selenocysteine-containing protein is overexpressed in many malignancies. Its role in the hepatocellular carcinoma (HCC) prognosis has not been investigated. In this study, we investigated whether TXNRD1 functions as an independent prognostic factor for HCC patients. We found TXNRD1 was overexpressed in HCC tissues and cells, immunohistochemical analysis suggested TXNRD1 was elevated in 57 of 120 (47.5%) clinical samples, and its level was increased with the increasing clinical stage. In addition, TXNRD1 expression was positively correlated with clinical stage (p=3.5e-5), N classification (p=4.4e-4), and M classification (p=0.037) of HCC patients. Kaplan-Meier analysis revealed that patients with high TXNRD1 expression had significantly shorter survival time than patients with low TXNRD1 expression. Multivariate analysis found TXNRD1 was an independent prognostic factor for HCC patients. In conclusion, our data suggested that TXNRD1 was a biomarker for the prognosis of patients with HCC.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Many microRNAs (miRNAs), small non-coding RNAs, are involved in regulating cancer cell proliferation, metastasis, migration, invasion and apoptosis. We investigated the expression of miR-135a in HCC cell lines and clinical tissues. The effect of miR-135a on migration and invasion of HepG2 and MHCC-97L were examined using wound healing and Transwell assay. We determined the expression of miR-135a, forkhead box O1 (FOXO1), matrix metalloproteinase-2 (MMP-2) and Snail using real-time PCR and western blotting. We found miR-135a was upregulated in HCC cell lines and tissues. miR-135a overexpression promoted HCC cells migration and invasion, whereas miR-135a inhibition suppressed HCC cells migration and invasion. miR-135a overexpression could upregulate the expression of MMP2, Snail and the phosphorylation of AKT, but decreased FOXO3a phosporylation. Tumor suppressor FOXO1 was the direct target for miR-135a. Our results suggested that miR-135a might play an important role in promoting migration and invasion in HCC and presents a novel mechanism of miRNA-mediated direct suppression of FOXO1 in HCC cells.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer related death worldwide; however, the molecular mechanisms regulating HCC progression remain largely unknown. In this study, we determined the role of DDX39 which a DEAD-box RNA helicase in HCC progression, and found DDX39 was upregulated in HCC tissues and cells, DDX39 expression was positive correlated with advanced clinical stage, survival analysis showed patients with high-DDX39 levels had poor outcome, it was an independent prognostic factor. Functional analysis revealed that DDX39 overexpression promoted HCC cell migration, invasion, growth, and metastasis, DDX39 knockdown inhibited HCC cell migration, invasion, growth, and metastasis. Mechanism analysis suggested DDX39 overexpression increased β-catenin expression in nucleus and increased Wnt/β-catenin pathway target genes levels, while DDX39 knockdown reduced this effect. Knockdown of Wnt/β-catenin pathway co-activators TCF4 and LEF1 in DDX39 overexpressing HCC cells inhibited Wnt/β-catenin pathway target genes. The invasion ability was also reduced, confirming DDX39 regulates HCC progression by activating Wnt/β-catenin pathway. In conclusion, we found DDX39 is a target and prognostic factor for HCC, and promotes HCC migration, invasion, growth, and metastasis by activating Wnt/β-catenin pathway.

Wnt/β-catenin signaling pathway plays important roles in human cancer progression. Better understanding the mechanism underlying regulation of Wnt/β-catenin signaling pathway might provide novel therapeutic targets for cancer treatment. miR-610 expression levels in hepatocellular carcinoma (HCC) cell lines, HCC tissues and 76 archived HCC specimens were determined using real-time PCR. Cell viability was measured by 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay. The level of DNA synthesis was determined by BrdU incorporation assay. Flow cytometry analysis was used to analyze cell cycle progression. The cells proliferation and tumorigenesis were determined by colony formation and anchorage-independent growth assays in vitro, and by xenograft tumors in vivo. Luciferase assay and micro-ribonucleoprotein complex immunoprecipitation assay were used to confirm the association of the targeted mRNAs with miR-610. miR-610 was downregulated in human HCC cells and tissues, and correlated with HCC progression and patient survival. Inhibition of miR-610 promoted, but overexpression of miR-610 reduced, HCC cell proliferation and tumorigenicity both in vitro and in vivo. Furthermore, we found that inhibiting miR-610 activated, but overexpressing miR-610 decreased, the Wnt/β-catenin activity through directly suppressing lipoprotein receptor-related protein 6 (LRP6) and transducin β–like protein 1 (TBL1X). The in vitro analysis was consistent with the inverse correlation detected between miR-610 levels with expression of LRP6 and TBL1X in a cohort of human HCC samples. Our results indicate that miR-610 downregulation plays essential roles in HCC progression and reduced miR-610 is correlated with Wnt/β-catenin signaling pathway.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to cardiometabolic disorders, and cardiovascular disease is the leading cause of death among affected individuals. Identifying simple biomarkers that capture metabolic-inflammatory burden and predict long-term mortality in MASLD remains a clinical priority. The C-reactive protein-triglyceride-glucose index (CTI) integrates inflammation, dyslipidaemia, and glycaemic status, but its relevance to MASLD and long-term mortality has not been fully elucidated. We conducted a multi-stage investigation using two nationally representative cohorts from the United States and China. Cross-sectional associations between CTI and MASLD were assessed in the National Health and Nutrition Examination Survey (NHANES) and the China Health and Retirement Longitudinal Study (CHARLS). Prospective associations of CTI with cardiovascular and all-cause mortality among participants with MASLD were examined utilising multivariable Cox proportional hazards models, restricted cubic splines, threshold analyses, and competing risk models. Causal mediation analyses were performed to measure the mediating functions of diabetes, hypertension, and body mass index. Extensive sensitivity analyses using alternative MASLD definitions and analytic strategies were conducted to assess robustness. Results from NHANES were externally validated in CHARLS. Higher CTI levels were strongly and nonlinearly associated with the presence of MASLD in both cohorts. Among individuals with MASLD, elevated CTI was associated with significantly increased risks of all-cause and cardiovascular mortality. Each unit increase in CTI in NHANES was linked to a 57% increased risk of cardiovascular death (HR 1.57, 95% CI 1.24-1.99) and a 47% increased risk of all-cause death (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.28-1.69) in fully adjusted models. A pronounced threshold effect was observed, with mortality risk rising sharply once CTI exceeded approximately 5.6. Consistent associations with all-cause mortality were observed in CHARLS. Mediation analyses indicated that diabetes accounted for a substantial proportion of the association between CTI and mortality, whereas body mass index played a minimal mediating role. CTI is a robust metabolic-inflammatory marker associated with MASLD and long-term all-cause and cardiovascular mortality across diverse populations. The strong mediating role of diabetes underscores the central importance of glycaemic dysfunction in cardiometabolic risk. As a readily obtainable index, CTI may aid in cardiometabolic risk stratification among individuals with MASLD.