Ubiquitin ligase TRIM15 promotes the progression of pancreatic cancer via the upregulation of the IGF2BP2-TLR4 axis.

BACKGROUND: The tripartite motif family, predominantly characterized by its E3 ubiquitin ligase activities, is involved in various cellular processes including signal transduction, apoptosis and autophagy, protein quality control, immune regulation, and carcinogenesis. Tripartite Motif Containing 15 (TRIM15) plays an important role in melanoma progression through extracellular signal-regulated kinase activation; however, data on its role in pancreatic tumors remain lacking. We previously demonstrated that TRIM15 targeted lipid synthesis and metabolism in pancreatic cancer; however, other specific regulatory mechanisms remain elusive. METHODS: We used transcriptomics and proteomics, conducted a series of phenotypic experiments, and used a mouse orthotopic transplantation model to study the specific mechanism of TRIM15 in pancreatic cancer in vitro and in vivo. RESULTS: TRIM15 overexpression promoted the progression of pancreatic cancer by upregulating the toll-like receptor 4. The TRIM15 binding protein, IGF2BP2, could combine with TLR4 to inhibit its mRNA degradation. Furthermore, the ubiquitin level of IGF2BP2 was positively correlated with TRIM15. CONCLUSIONS: TRIM15 could ubiquitinate IGF2BP2 to enhance the function of phase separation and the maintenance of mRNA stability of TLR4. TRIM15 is a potential therapeutic target against pancreatic cancer.

PER2 binding to HSP90 enhances immune response against oral squamous cell carcinoma by inhibiting IKK/NF-κB pathway and PD-L1 expression.

BACKGROUND: Programmed death-ligand 1 (PD-L1) contributes to the immune escape of tumor cells and is a critical target for antitumor immunotherapy. However, the molecular mechanisms regulating PD-L1 expression remain unclear, hindering the development of effective therapies. Here we investigate the role and molecular mechanism of the core clock gene Period2 (PER2) in regulating PD-L1 expression and its role in the combination therapy of oral squamous cell carcinoma (OSCC). METHODS: Quantitative real-time PCR, western blotting or immunohistochemistry to detect expression of PER2 and PD-L1 in OSCC tissues and cells. Overexpression and knockdown of PER2 detects the function of PER2. Bioinformatics, immunoprecipitation, GST pull-down, CHX chase assay and western blot and strip to detect the mechanism of PER2 regulation for PD-L1. A humanized immune reconstitution subcutaneous xenograft mouse model was established to investigate the combination therapy efficacy. RESULTS: In OSCC tissues and cells, PER2 expression was reduced and PD-L1 expression was increased, the expression of PER2 was significantly negatively correlated with PD-L1. In vitro and in vivo experiments demonstrated that PER2 inhibited PD-L1 expression and enhanced T-cell-mediated OSCC cell killing by suppressing the IKK/NF-κB pathway. Mechanistically, PER2 binds to heat shock protein 90 (HSP90) through the PAS1 domain and reduces the interaction of HSP90 with inhibitors of kappa B kinase (IKKs), promoting the ubiquitination of IKKα/ß and p65 nuclear translocation to inhibit IKK/NF-κB pathway, thereby suppressing PD-L1 expression. In humanized immune reconstitution subcutaneous xenograft mouse model, it was demonstrated that PER2 targeting combined with anti-PD-L1 treatment improved the inhibition of OSCC growth by promoting CD8+ T-cell infiltration into the tumor. CONCLUSIONS: Our findings reveal the role and mechanism of PD-L1 regulation by PER2 and support the potential clinical application of PER2 targeting in combination with anti-PD-L1 in OSCC immunotherapy.

The biological clock gene PER1 affects the development of oral squamous cell carcinoma by altering the circadian rhythms of cell proliferation and apoptosis.

Circadian rhythms expressed by the biological clock gene PER1 are aberrantly altered in a variety of tumor cells, including oral squamous cell carcinoma (OSCC); however, their functions and mechanisms are unclear. Here, we found that compared with normal oral epithelial HOK cells, OSCC cells showed altered circadian rhythm characteristics of proliferation, apoptosis and PER1 expression, exhibiting abnormal changes in the 3 dimensions of mesor, amplitude and acrophase. It was further found that in OSCC cells overexpressing PER1 (OE-PER1-SCC15), the circadian rhythm characteristics of cell proliferation, apoptosis, p-AKT and p-mTOR expression were abnormally altered. After adding the AKT activator SC79 to OE-PER1-SCC15 cells, the circadian rhythm characteristics of cell proliferation, apoptosis and p-AKT and p-mTOR expression were altered in opposite ways. In vivo tumorigenic assays demonstrated that overexpression of PER1 inhibited OSCC growth. The circadian rhythm characteristics of cell proliferation and apoptosis, PER1, p-AKT and p-mTOR expression were altered similarly to those observed in vitro. Our findings demonstrate for the first time that PER1 regulates the circadian rhythm of OSCC cell proliferation and apoptosis by altering the circadian rhythm characteristics of the AKT/mTOR pathway. The results have the potential to provide a new strategy for circadian rhythm-based treatment of OSCC.

Prevalence of depression symptoms and its influencing factors among pregnant women in late pregnancy in urban areas of Hengyang City, Hunan Province, China: a cross-sectional study.

OBJECTIVES: To evaluate the prevalence of depressive symptoms and its influencing factors in late pregnancy. DESIGN: Cross-sectional study. SETTING: Fourteen community in urban areas of Hengyang City. PARTICIPANTS: The study conducted from July to October 2019, and surveyed 813 women in late pregnancy who lived in urban areas of Hengyang for more than 6 months, signed an informed consent and were without cognitive disorders, severe mental illnesses or other serious diseases. MEASURES: Perinatal depression symptoms were evaluated using the Patient Health Questionnaire-9, and perinatal anxiety symptoms were evaluated using the Generalised Anxiety Disorder-7 Scale. Sociodemographic variables, obstetric characteristics, lifestyle behaviours, family factors, social support, sleep quality and self-efficacy were obtained through structured questionnaires. RESULTS: The prevalence of depression symptoms among pregnant women in late pregnancy was 9.2% (95% CI 7.2%-11.2%). Protective factor: age between 25 and 29 years (OR=0.398; 95% CI 0.16-0.991). RISK FACTORS: a normal relationship with her mother-in-law (OR=5.309; 95% CI 1.122-4.184), artificial insemination (OR=4.339; 95% CI 1.492-12.623), no exercise during pregnancy (OR=2.666; 95% CI 1.177-6.039), low self-efficacy (OR=4.253; 95% CI 1.518-11.916), low social support (OR=2.371; 95% CI 1.206-4.661), poor sleep quality (OR=2.134; 95% CI 1.131-4.027), existence of anxiety symptoms (OR=17.654; 95% CI 8.494-36.689). CONCLUSION: The prevalence of depression symptoms is lower than that in developing countries, but due to the large population base of China, the problem should still be taken seriously. To prevent mental disorders of pregnant women, early screening for mental disorders, promotion of healthy lifestyles, mental healthcare during pregnancy and improved family and social support should be implemented during pregnancy nursing.

Association between family functions and antenatal depression symptoms: a cross-sectional study among pregnant women in urban communities of Hengyang city, China.

OBJECTIVE: To explore the prevalence of depressive symptoms among women in late pregnancy, and assess mediating effect of self-efficacy in the association between family functions and the antenatal depressive symptoms. DESIGN: Community-based, cross-sectional study was conducted among women during the third trimester of pregnancy. SETTING: This study was conducted among pregnant women registered at community health service centres of urban Hengyang City, China from July to October 2019. PARTICIPANTS: 813 people were selected from 14 communities by multi-staged cluster random sampling method. MAIN OUTCOME MEASURES: The Family Adaptation Partnership Growth Affection and Resolve Index, the General Self-efficacy Scale and Patient Health Questionnaire were used to access family functions, self-efficacy and antenatal depression symptoms, respectively. RESULTS: In this study, 9.2% pregnant women reported the symptoms of antenatal depression (95 CI% 7.2% to 11.2%). After adjustment, the results showed that severe family dysfunction (adjusted OR, AOR 3.67; 95% CI 1.88 to 7.14) and low level of self-efficacy (AOR 3.16; 95% CI 1.37 to 7.27) were associated with antenatal depressive symptoms (p<0.05). Furthermore, self-efficacy level partially mediated the association between family functions and antenatal depressive symptoms(ß=-0.05, 95% CI -0.07 to -0.03, p<0.05) and the mediating effect accounted for 17.09% of the total effect. CONCLUSIONS: This study reported 9.2% positive rates of antenatal depression symptoms among women in the third trimester of pregnancy in Hengyang city, China. The mediating effect of self-efficacy on the association between family functions and antenatal depression symptoms among women in the third trimester of pregnancy was found in this study, which provide a theoretical basis to maternal and child health personnel to identify high-risk pregnant women and take targeted intervention for them.

The prevalence of domestic violence and its association with family factors: a cross-sectional study among pregnant women in urban communities of Hengyang City, China.

BACKGROUND: With the increased vulnerability during pregnancy, domestic violence (DV) is a serious threat to the physical and mental health of pregnant women, making it a significant issue in public health initiatives. In China, family is of great significance to pregnant women, but few scholars have focused specifically on the relationship between the family factors of pregnant women and DV. This study aimed to explore the prevalence and association between family factors and DV among women in late pregnancy, to provide evidence for the prevention of domestic violence during pregnancy. METHODS: A cross-sectional survey was conducted from July-October, 2019 among pregnant women in urban communities of Hengyang City, Hunan Province, China. A total of 813 participants were included by a multi-staged cluster random sampling method. DV was assessed by the Abuse Assessment Screen Questionnaire (AAS). A multivariate binary logistic regression model was used to evaluate the relationship between family factors and DV. RESULTS: Ultimately, 127 (15.62%) participants were identified as victims of DV. After adjustment, the potential risk factors of DV were tensions between their mother-in-law and other family members (OR: 2.85; 95% CI: 1.29 to 6.30 and OR: 3.30; 95% CI: 1.57 to 6.93), medium household debt (OR: 2.17; 95% CI: 1.18 to 4.00), middle and low family APGARI (OR: 2.01; 95% CI: 1.30 to 3.13 and OR: 4.01; 95% CI: 2.09 to 7.69). CONCLUSIONS: In summary, women in late pregnancy were at higher risk of DV in the family with tensions, medium household debt and family dysfunction, which may help medical personnel intervene in cases of domestic violence against pregnant women in a reasonable and timely manner.