Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 3 Loss Activates Purine Metabolism and Promotes Hepatocellular Carcinoma Progression.

Cancer cells metabolize different energy sources to generate biomass rapidly. The purine biosynthetic pathway was recently identified as an important source of metabolic intermediates for these processes. However, very little was known about the regulatory mechanisms of purine metabolism in hepatocellular carcinoma (HCC). We explored the role of dual-specificity tyrosine (Y) phosphorylation-regulated kinase 3 (Dyrk3) in HCC metabolism. Dyrk3 was significantly down-regulated in HCC compared with normal controls. Its introduction in HCC cells markedly suppressed tumor growth and metastasis in xenograft tumor models. Mass spectrometric analysis of metabolites suggests that the effect of Dyrk3 on HCC occurred at least partially through down-regulating purine metabolism, as evidenced by the fact that inhibiting purine synthesis reverted the HCC progression mediated by the loss of Dyrk3. We further provide evidence that this action of Dyrk3 knockdown requires nuclear receptor coactivator 3 (NCOA3), which has been shown to be a coactivator of activating transcription factor 4 (ATF4) to target purine pathway genes for transcriptional activation. Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity. However, the phosphorylation-resistant NCOA3-S1330A mutant has the opposite effect. Interestingly, the promoter activity of Dyrk3 was negatively regulated by ATF4, indicating a double-negative feedback loop. Importantly, levels of Dyrk3 and phospho-NCOA3-S1330 inversely correlate with the expression of ATF4 in human HCC specimens. Conclusion: Our findings not only illustrate a function of Dyrk3 in reprograming HCC metabolism by negatively regulating NCOA3/ATF4 transcription factor complex but also identify NCOA3 as a phosphorylation substrate of Dyrk3, suggesting the Dyrk3/NCOA3/ATF4 axis as a potential candidate for HCC therapy.

Assessing the risk factors associated with nutritional status in patients with liver cirrhosis: A case-control study.

BACKGROUND: Cirrhosis is one of the most common clinical diseases in the world. The patient with cirrhosis has many complications, such as spontaneous peritonitis, hepatic encephalopathy. Malnutrition is one of the most common complications in patients with cirrhosis, and it is also a key factor affecting the prognosis of patients. However, the research on cirrhosis malnutrition is relatively scarce. OBJECTIVE: This study aimed to explore the new factors of the liver cirrhosis with the nutritional status. METHODS: A total of 370 patients with liver cirrhosis were admitted to the Fourth Affiliated Hospital of Harbin Medical University from January 2019 to January 2023 were selected. Patients were assigned to the malnourished group and normal group. The weight, height, mid arm circumference (MAC) and triceps skinfold thickness (TSF) of the two groups were measured. Body mass index (BMI) and mid-arm muscle circumference (MAMC) were calculated. Furthermore, the Health Literacy Management Scale (HeLMS), biochemical indexes, incidence of complications, disease grade were also counted and the Royal Free Hospital-Nutrition Prioritization Tool were used to evaluate the nutritional status of the patient. RESULTS: A total of 370 patients was included in this study, including 177 malnutrition patients, accounting for 45.29%, and the scores and total scores of the patients in the malnutrition group were lower than those in the normal group. The measured values of Na+, Alb, PA, T-Bil, TC, TLC, Hb, and RBC were all lower than those of the normal group, and the difference was statistically significant. The overall complication rate of the patients in the malnourished group was 89.61%, and that of the normal group was 39.78%. Multifactorial logistic regression analysis was performed with nutritional level as the dependent variable (normal = 0, malnutrition = 1), and the above indicators of variability (Na+, Alb, PA, T-Bil, TC, PT, Hb, RBC, HG, and HeLMS scores) as the independent variables. The results showed that Na+, Hb were the influencing factors of nutritional level (P< 0.05). CONCLUSION: The incidence of malnutrition in cirrhotic patients included in this study was at a moderate level, and the nutritional literacy of these patients was low. In addition, the level of serum sodium, Hemoglobin can affect the nutritional level of patients with cirrhosis.

Unraveling the role of tissue colonized microbiome in ovarian cancer progression.

BACKGROUND: Ovarian cancer (OC) is found to be the third most common gynecologic malignancy over the world, having the highest mortality rate among such tumors. Emerging studies underscore the presence of microorganisms within tumor tissues, with certain pathogens intricately linked to disease onset and progression. Disruption of the microbiome frequently precipitates disturbances in host metabolic and immune pathways, thereby fostering the development of cancer. METHODS: In this study, we initiated the investigation by conducting microbial reannotation on the RNA sequencing data derived from ovarian cancer tissues. Subsequently, a comprehensive array of analyses on tissue microbes was executed. These analyses encompassed the assessment of intergroup variations in microbial diversity, differential microbiological analysis, exploration of the association between host gene expression and microbial abundance, as well as an enrichment analysis of functional pathways linked to host genes associated with microbes. RESULTS: The analysis results revealed that Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes were the main components at phylum level in ovarian tissue. Notably, the microbial composition of ovarian cancer tissue significantly diverged from that of normal ovarian tissue e, exhibiting markedly lower alpha diversity and distinct beta diversity. Besides, pathogenic microorganisms Achromobacter xylosoxidans and Enterobacter hormaechei were enriched in cancer tissue. Host genes associated with these pathogens were enriched in key pathways including "JAK-STAT signaling pathway", "Transcriptional misregulation in cancer", and "Th1 and Th2 cell differentiation", suggesting their role in ovarian cancer progression through microbial dysbiosis and immune response interaction. CONCLUSION: Abundance of pathogenic microorganisms in ovarian cancer tissue could modulate the expression of host genes, consequently impacting cancer-related signaling pathways and fostering cancer progression.

The Correlation and Influencing Factors of Crisis Response Ability and Psychological Factors in Patients with Liver Cirrhosis.

BACKGROUND: Illness can provoke a crisis response that affects condition acceptance, treatment and recovery. Patients' sense of coherence can influence this explored across patient cohorts internationally. However, few studies examine these effects in patients with hepatic cirrhosis. This study investigated sense of coherence and social support of patients with hepatic cirrhosis. METHODS: The psychological status of 146 patients admitted to the Digestive System Department, First Affiliated Hospital of Harbin Medical University, Harbin, China from Mar 2016 to Mar 2019 with hepatic cirrhosis was assessed using the Sense of Coherence (SOC-13), Social Support Rating Scale (SSRS) and crisis assessment scales. RESULTS: There was a low level of crisis response in patients with hepatic cirrhosis that was influenced by age, disease course, education level and Child-Pugh grade and negatively correlated with sense of coherence and social support. CONCLUSION: Liver cirrhosis patients had a low level of crisis response. As the level of crisis response in is correlated with patients' sense of coherence, social support and educational level, careful assessment, tailored educational interventions and mobilizing of family support are important to maximize responses to illness and thus improve quality of life.