Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma.

Transposable elements (TEs) contribute to gene expression regulation by acting as cis-regulatory elements that attract transcription factors and epigenetic regulators. This research aims to explore the functional and clinical implications of transposable element-related molecular events in hepatocellular carcinoma, focusing on the mechanism through which liver-specific accessible TEs (liver-TEs) regulate adjacent gene expression. Our findings reveal that the expression of HNF4A is inversely regulated by proximate liver-TEs, which facilitates liver cancer cell proliferation. Mechanistically, liver-TEs are predominantly occupied by the histone demethylase, KDM1A. KDM1A negatively influences the methylation of histone H3 Lys4 (H3K4) of liver-TEs, resulting in the epigenetic silencing of HNF4A expression. The suppression of HNF4A mediated by KDM1A promotes liver cancer cell proliferation. In conclusion, this study uncovers a liver-TE/KDM1A/HNF4A regulatory axis that promotes liver cancer growth and highlights KDM1A as a promising therapeutic target. Our findings provide insight into the transposable element-related molecular mechanisms underlying liver cancer progression.

POH1 facilitates pancreatic carcinogenesis through MYC-driven acinar-to-ductal metaplasia and is a potential therapeutic target.

Pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), a necessary process for pancreatic ductal adenocarcinoma (PDAC) initiation. However, the regulatory role of POH1, a deubiquitinase linked to several types of cancer, in ADM and PDAC is unclear. In this study, we investigated the role of POH1 in ADM and PDAC using murine models. Our findings suggest that pancreatic-specific deletion of Poh1 alleles attenuates ADM and impairs pancreatic carcinogenesis, improving murine survival. Mechanistically, POH1 deubiquitinates and stabilizes the MYC protein, which potentiates ADM and PDAC. Furthermore, POH1 is highly expressed in PDAC samples, and clinical evidence establishes a positive correlation between aberrantly expressed POH1 and poor prognosis in PDAC patients. Targeting POH1 with a specific small-molecule inhibitor significantly reduces pancreatic tumor formation, highlighting POH1 as a promising therapeutic target for PDAC treatment. Overall, POH1-mediated MYC deubiquitination is crucial for ADM and PDAC onset, and targeting POH1 could be an effective strategy for PDAC treatment, offering new avenues for PDAC targeted therapy.

Gene Coexpression Network Characterizing Microenvironmental Heterogeneity and Intercellular Communication in Pancreatic Ductal Adenocarcinoma: Implications of Prognostic Significance and Therapeutic Target.

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by intensive stromal involvement and heterogeneity. Pancreatic cancer cells interact with the surrounding tumor microenvironment (TME), leading to tumor development, unfavorable prognosis, and therapy resistance. Herein, we aim to clarify a gene network indicative of TME features and find a vulnerability for combating pancreatic cancer. Methods: Single-cell RNA sequencing data processed by the Seurat package were used to retrieve cell component marker genes (CCMGs). The correlation networks/modules of CCMGs were determined by WGCNA. Neural network and risk score models were constructed for prognosis prediction. Cell-cell communication analysis was achieved by NATMI software. The effect of the ITGA2 inhibitor was evaluated in vivo by using a KrasG12D -driven murine pancreatic cancer model. Results: WGCNA categorized CCMGs into eight gene coexpression networks. TME genes derived from the significant networks were able to stratify PDAC samples into two main TME subclasses with diverse prognoses. Furthermore, we generated a neural network model and risk score model that robustly predicted the prognosis and therapeutic outcomes. A functional enrichment analysis of hub genes governing gene networks revealed a crucial role of cell junction molecule-mediated intercellular communication in PDAC malignancy. The pharmacological inhibition of ITGA2 counteracts the cancer-promoting microenvironment and ameliorates pancreatic lesions in vivo. Conclusion: By utilizing single-cell data and WGCNA to deconvolute the bulk transcriptome, we exploited novel PDAC prognosis-predicting strategies. Targeting the hub gene ITGA2 attenuated tumor development in a PDAC mouse model. These findings may provide novel insights into PDAC therapy.

The association between serum uric acid level and the risk of cognitive impairment after ischemic stroke.

Post-stroke cognitive impairment (PSCI) is a severe complication of stroke. Predicting PSCI is difficult because some risk factors for stroke, such as blood glucose level and blood pressure, are affected by many other elements. Although recent studies have shown that high serum uric acid (UA) levels are associated with cognitive dysfunction and may be a risk factor for PSCI, its impact remains unclear. Accordingly, the present study aimed to explore the association between serum UA level and PSCI. In total, 274 patients who experienced acute cerebral infarction, confirmed between January 2016 and December 2018, were enrolled. Baseline data and biological indicators were recorded. According to the Montreal Cognitive Assessment (MoCA) scores, patients were divided into two groups: PSCI and non-PSCI. Logistic regression analysis was used to determine possible risk factors for PSCI. Results demonstrated that serum UA levels were significantly higher in the PSCI group than in the non-PSCI group. Multivariable logistic analysis revealed that age, years of education, and UA level were independent risk factors for PSCI. PSCI patients were subdivided according to serum UA level: high and low. Hypertension history and homocysteine (Hcy) levels differed significantly between the high and low UA level groups. Further analysis revealed that a history of hypertension and Hcy demonstrated a certain correlation (r = 0.163, 0.162; P < 0.05), suggesting that serum UA level was an independent risk factor for PSCI. These findings indicate that serum UA level was correlated with PSCI in post-stroke patients and is anticipated to be used in clinical practice to reduce the incidence of PSCI.

Fecal microbiota transplantation alleviated Alzheimer's disease-like pathogenesis in APP/PS1 transgenic mice.

Alzheimer's disease (AD) is the most common dementia in the elderly. Treatment for AD is still a difficult task in clinic. AD is associated with abnormal gut microbiota. However, little is known about the role of fecal microbiota transplantation (FMT) in AD. Here, we evaluated the efficacy of FMT for the treatment of AD. We used an APPswe/PS1dE9 transgenic (Tg) mouse model. Cognitive deficits, brain deposits of amyloid-ß (Aß) and phosphorylation of tau, synaptic plasticity as well as neuroinflammation were assessed. Gut microbiota and its metabolites short-chain fatty acids (SCFAs) were analyzed by 16S rRNA sequencing and 1H nuclear magnetic resonance (NMR). Our results showed that FMT treatment could improve cognitive deficits and reduce the brain deposition of amyloid-ß (Aß) in APPswe/PS1dE9 transgenic (Tg) mice. These improvements were accompanied by decreased phosphorylation of tau protein and the levels of Aß40 and Aß42. We observed an increases in synaptic plasticity in the Tg mice, showing that postsynaptic density protein 95 (PSD-95) and synapsin I expression were increased after FMT. We also observed the decrease of COX-2 and CD11b levels in Tg mice after FMT. We also found that FMT treatment reversed the changes of gut microbiota and SCFAs. Thus, FMT may be a potential therapeutic strategy for AD.