Molecular Medicine最新文献

Background: Low molecular weight protein tyrosine phosphatase (LMWPTP), encoded by the ACP1 gene, has been implicated in tumor progression across multiple malignancies. While its oncogenic functions have been reported in colorectal cancer (CRC), its role in gastric cancer (GC) remains poorly defined. This study investigated the expression patterns, functional relevance, and prognostic impact of LMWPTP in GC, with comparative analyses in CRC.

Methods: Gene expression, immune infiltration, and survival analyses were performed using data from The Cancer Genome Altas (TCGA). LMWPTP protein expression was evaluated in a gastric cancer tissue microarray. Functional assays were conducted in GC and CRC cell lines with CRISPR-Cas9-mediated LMWPTP knockout.

Results: ACP1 mRNA expression was significantly upregulated in both GC and CRC compared with adjacent normal tissues. In GC, high LMWPTP expression was associated with poor differentiation in intestinal-type tumors and reduced survival in diffuse-type cases. ACP1 overexpression correlated with an elevated tumor mutation burden but a decreased cytotoxic lymphocyte infiltration signature in GC, indicating a potential relationship between ACP1 expression, tumor mutational load, and tumor immune microenvironment. Functional assays in vitro showed that LMWPTP knockout reduced migration in both GC and CRC cells, whereas a decrease in invasion was observed only in CRC cells. These findings indicate context-dependent contributions of LMWPTP to gastrointestinal tumor biology.

Conclusion: LMWPTP is consistently upregulated in gastric and colorectal cancers and exhibits tumor-type-specific functional and immune associated features. These findings highlight its distinct oncogenic role and potential as a biomarker and therapeutic target in GC.

Background & aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a multifactorial disease driven by complex molecular mechanisms. Identifying key regulators is critical for developing targeted therapies. Here, we demonstrate the impact of the loss of the apoptosis-antagonizing transcription factor (AATF) on hepatic lipid metabolism and MASH progression.

Methods: A preclinical mouse model recapitulating human MASH was established by feeding C57Bl/6 mice either a chow diet (CD) or a western diet with sugar water (WD). Hepatic AATF silencing was achieved by tail vein injection of siAATF delivered by adeno-associated virus 8 (AAV8) using a liver-specific thyroxine-binding globulin (TBG) promoter. In addition to histological, biochemical, and molecular biology evaluations, mechanistic insights were obtained through whole transcriptomic and untargeted metabolomic analyses.

Results: AAV8-mediated specific knockdown of AATF in hepatocytes significantly reduced body weight, liver weight, and insulin resistance in mice fed a western diet (WD). However, no such effects were observed in mice fed a chow diet (CD). Further analyses showed reduced liver injury, steatosis, and steatohepatitis in WDsiAATF mice. Transcriptomic analysis demonstrated that AATF loss alleviated cellular stress, inflammation, and fibrosis in WD-fed mice. Moreover, AATF silencing altered lipid metabolism, notably by decreasing hepatic lipogenesis in WD mice. Interestingly, untargeted metabolomics revealed increased glycerophospholipid biosynthesis and fatty acid β-oxidation in WDsiAATF mice.

Conclusion: Our findings reveal a previously unrecognized role of AATF as a central regulator of hepatic lipid metabolism in MASH, acting through the AKT-mTORC1 signaling pathway, and establish its inhibition as a promising therapeutic strategy for the treatment of metabolic liver disease.

Post-transcriptional RNA modifications have emerged as critical regulators of stemness, cellular plasticity, adaptation to stress and transformation. Amongst these the N6-methyladenosine (m⁶A) modification orchestrates a wide range of physiological processes; yet its contribution to metabolic regulation remains poorly addressed. In the present study, differential proteomics revealed enrichment of core components of the m⁶A machinery, viz. WTAP (writer) and IGF2BP3 (reader) in stem-like cells of the mesenchymal subtype of High-Grade Serous Ovarian Carcinoma (HGSC). Intriguingly, components of de novo cholesterol biosynthesis were also enriched. In investigating the suggested link between m⁶A regulation and sterol metabolism, we established a m⁶A-dependent stabilization of transcripts encoding rate-limiting de novo cholesterol biosynthetic enzymes by IGF2BP3 towards sustaining cholesterol production. Disruption of this cross-regulation by pharmacological inhibition impaired cell survival, self-renewal, and migration. Analyses of datasets from The Cancer Genome Atlas (TCGA) assigned a clinical significance to this regulatory axis through correlation of elevated expression of de novo cholesterol biosynthetic genes with poor progression-free survival of serous ovarian carcinoma patients. IGF2BP3 knock down, and chemical blockade of de novo cholesterol biosynthesis, both alone or in combination, achieved attenuated disease progression, in vivo. Effectively, our study links RNA modifications with metabolic reprogramming in the HGSC mesenchymal subtype through delineation of a m⁶A-IGF2BP3-cholesterol biosynthesis axis-mediated regulation of tumor cell stemness and aggression.

Background: Maternal fructose intake induces harmful effects in progeny. However, this sugar is not contraindicated during pregnancy. On the other hand, the use of low-calorie sweeteners, such as tagatose, is increasing. Thus, we have studied whether the consumption of tagatose compared to fructose affects lipid metabolism in the offspring of mothers which were supplemented with fructose during their pregnancy.

Methods: Three-month-old male rat offspring from control or fructose mothers received liquid 10% fructose or tagatose for 21 days. A control group (without any additive) was also included. Biochemical and molecular parameters were determined in plasma, tissues and feces.

Results: Both tagatose and fructose consumption caused hypertriglyceridemia in descendants of fructose-fed mothers. Whereas fructose consumption led to a greater hepatic lipogenesis, tagatose supplementation provoked a higher enterohepatic bile acids recirculation, and therefore a higher intestinal lipid absorption and assembly. However, plasma GLP1, a molecule that affects lipid intestinal absorption, was unchanged. Curiously, FGF21, a molecule which regulates lipid and carbohydrate metabolism and is sensitive to GLP1, was augmented in plasma and liver of tagatose-supplemented descendants regardless of their maternal diet. Interestingly, Angiotensin II (Ang II), which can induce FGF21 production, was increased in plasma of all animals supplemented with tagatose. However, the deleterious effects of Ang II were effectively reversed by FGF21 in males from control mothers, but not in descendants of fructose-fed dams.

Conclusions: Maternal fructose consumption determines the response of the offspring to tagatose intake, causing an increased intestinal lipid absorption, and metabolic changes that are characteristic of metabolic syndrome such as dyslipidaemia, steatosis and oxidative stress.

Background: PD-L1 immunotherapy plays a crucial role in cancer treatment, but PD-L1 peptide vaccines have low immunogenicity. A potent peptide derived from the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a significant adjuvant effect, which may increase the immunogenicity of the PD-L1 peptide. This study evaluates whether the PD-L1-SARS peptide enhances PD-L1 immunotherapy and analyzes its potential synergistic effects with anti-PD-L1 antibodies.

Methods: In vivo experiments compared prevention, therapy, and combination therapy using PD-L1 versus PD-L1-SARS peptides in mice. Cytokine multiplex arrays, ELISpot, and IHC were used to evaluate adjuvant effects. Molecular docking (hypothesis-generating), RNA-seq, and LC-MS/MS were used to explore putative mechanisms.

Results: The PD-L1-SARS peptide enhanced the Th1 immune response and increased CD8 and Th17 cell infiltration, effectively inhibiting tumor growth and liver metastasis. Additionally, it promoted M1 macrophage polarization and improved anti-PD-L1 antibody efficacy. Proteomics and bioinformatic analyses were consistent with IFN-γ-linked pathways, and an exploratory docking screen nominated candidate receptors/pathways potentially connecting the adjuvant motif to innate sensing.

Conclusions: Embedding a SARS-derived adjuvant-like motif within a PD-L1 peptide vaccine and delivering it in situ may re-condition the tumor microenvironment toward an immune-activating, Th1/Th17-biased state and complement PD-L1 blockade.