Cell Biology International最新文献

UPF3B encodes a protein that is part of a postsplicing multi-protein complex involved in both mRNA nuclear export and mRNA surveillance. Herein, we demonstrate that UPF3B accelerates the proliferation ability of liver cancer cells in vitro and in vivo. Moreover, UPF3B affects epigenetic regulation in human liver cancer cells. Moreover, ATAC-seq results show that chromatin accessibility is changed between rLV group and rLV-UPF3B group. Therefore, UPF3B alters transcriptome and proteome in liver cancer. In particular, UPF3B affects the heterogeneity of liver cancer and its microenvironment network. Furthermore, UPF3B promotes the modification ability of H3K4me3, H4K16Ac, and RNAPolII on promoter region of CDK12 and then increased the expression of CDK12. Strikingly, UPF3B enhances the interaction between LC3 and DOR, ATG4 and LC3, ATG3 and LC3, ATG3 and ATG12, ATG3 and ATG16L1, ATG3 and ATG7, ATG3 and ATG9A, and the expression of activated LC3, beclin1 dependent on CDK12. Ultimately, UPF3B increases the autophagy via CDK12 and then enhances the expression of ARAF, RRAS, CyclinD1, C-myc, PCNA, PKM2, CDK4, YB-1, H-Ras via CDK12-autophagy pathway. Importantly, our results indicate that CDK12 determines the oncogenic function of UPF3B. In conclusions, these results provide basis for research on liver cancer prevention and treatment.

Patients with diabetic osteoporosis (DOP) face significant challenges in bone defect repair and regeneration. Adipose-derived stem cells (ASCs) have been widely used in bone tissue engineering due to their accessibility and multi-potency. However, DOP-ASCs exhibit lower capacity for osteogenic differentiation compared to control ASCs (CON-ASCs). In this study, we explored the effects of metformin (Met) on the autophagy and osteogenic capacity of DOP-ASCs. DOP mouse model was established with a high-fat and high-glucose diet combined with streptozotocin injection. After treating DOP-ASCs with Met and 3-methyladenine (3-MA), changes in autophagy levels and osteogenic differentiation capacity were observed by western blot analysis, real-time quantitative PCR (qPCR), immunofluorescence, alkaline phosphatase staining, alizarin red staining, and GFP-LC3 fluorescence labeling analysis. DOP-ASCs were cocultured with the Biphasic Calcium Phosphate (BCP), and implanted into the cranial defect area of DOP mice. The mice then received oral Met and intraperitoneal 3-MA injections for 3 months. The implanted BCP was assessed by micro-CT, HE and Masson staining. We observed a significantly reduced autophagic levels and capacity for osteogenic differentiation in DOP-ASCs, as compared to CON-ASCs. Met activated autophagy in DOP-ASCs and improved their osteogenic differentiation capacity. However, in the DOP + Met + 3MA group, both the autophagic level and the osteogenic differentiation capacity were suppressed. The results from the in vitro research and the in vivo outcomes agreed. Moreover, Met dramatically reduced p-PI3K and p-AKT expression. Met improves the osteogenic differentiation capacity by activating autophagy, an effect mediated through the PI3K/AKT signaling pathway.

Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality, is characterized by its aggressive nature and poor prognosis. This study investigates the role of RAD54L, a protein implicated in homologous recombination repair of DNA double-strand breaks, in the progression of HCC and its potential as a prognostic marker. Expression levels of RAD54L were assessed using transcriptomic data from The Cancer Genome Atlas and Gene Expression Omnibus databases. Kaplan-Meier survival curves and multivariate Cox regression analyses were conducted to evaluate the prognostic significance of RAD54L expression. Furthermore, the study explored immune infiltration, protein-protein interaction (PPI) networks, and functional enrichment analyses to elucidate the underlying mechanisms of RAD54L in HCC pathogenesis. Drug sensitivity was measured in the HepG2 cell line and GDSC database. Results showed that RAD54L was significantly upregulated at the mRNA level in HCC tissues (n = 369) compared to adjacent normal liver samples (n = 50), with high expression correlating with a poorer overall survival and disease-free interval. Functional enrichment analysis demonstrated that ATPase activity, helicase activity, and coenzyme binding pathways might be involved in RAD54L's effects on HCC pathogenesis. Additionally, knockdown of RAD54L in HepG2 cells resulted in reduced proliferation and increased sensitivity to gemcitabine treatment. In conclusion, higher expression of RAD54L is associated with poor prognosis in HCC and may enhance gemcitabine efficacy, suggesting its potential as both a prognostic biomarker and a therapeutic target in HCC management.

Pyruvate ferredoxin oxidoreductase (PFOR) is the main enzyme responsible for pyruvate decarboxylation under anaerobic conditions. This enzyme is very well characterized in a wide range of microorganisms, such as anaerobic bacteria and microaerophilic parasites; however, the presence of this enzyme in free-living amoebas (FLAs) has not been demonstrated. Acanthamoeba castellanii (A. castellanii) is an FLA that exhibits trophozoite and cyst forms during its life cycle. The trophozoite form possesses functional mitochondria that are responsible for ATP synthesis. The cyst form possesses a rudimental mitochondrial structure that seems to be not functional and anaerobically synthesizes ATP. In this study, we described the presence of a PFOR in A. castellanii (known as AcPFOR). The structure of this enzyme is very similar to that of PFOR, which has been characterized in other microorganisms, and the main domains responsible for the enzymatic activity of PFOR are present in AcPFOR. The cyst forms exhibited increased expression and enzymatic activity of PFOR. This enzyme is inhibited by nitazoxanide (a PFOR inhibitor), and drug administration was able to inhibit the encystment process by overstimulating autophagy. The inhibition of the enzyme also affects cyst viability, thus resulting in the inhibition of the excystation process. In conclusion, we demonstrated the importance of PFOR in A. castellanii cysts energy homeostasis, thereby indicating that this enzyme may be an interesting therapeutic target.

Our investigation was aimed at deciphering the potential role of copper metabolism MURR1 domain containing 1 (COMMD1) in cervical cancer tumorigenesis and metastasis, along with its underlying molecular mechanism, both in vitro and in vivo. To validate the research objectives, cervical cancer cell lines with stably overexpressed and knockdown COMMD1 were generated. In addition, an orthotopic murine model of cervical cancer with liver metastasis was constructed to elucidate the metastatic impact of COMMD1. Functional assays including CCK-8 assay, colony formation assay, scratch assay, and transwell invasion assay were conducted to evaluate the proliferation, migration, and invasion capabilities of cervical cancer cells. Western blot analysis and immunofluorescence double staining were performed to detect protein expression profiles and visualize actin cytoskeleton remodeling. Hematoxylin-eosin (H&E) staining and immunohistochemistry were utilized to characterize tumor histopathology and protein expression. Key findings revealed that COMMD1 was markedly downregulated in cervical cancer cell lines. Ectopic expression of COMMD1 potently impeded cell proliferation, colony formation, migration, and invasion of cervical cancer cells. Mechanistically, COMMD1, suppressed epithelial–mesenchymal transformation (EMT) by antagonizing the twist family bHLH transcription factor 1 (Twist1)/epithelial (E)-cadherin pathway, as evidenced by reduced expression of EMT-associated markers and restored E-cadherin membrane localization. In the orthotopic mouse model, COMMD1 overexpression significantly attenuated liver metastatic foci formation and blunted EMT progression. In conclusion, COMMD1 acts as a tumor suppressor in cervical cancer, with its antitumor effects primarily mediated by inhibiting Twist1-driven EMT and metastatic cascade.

Zinc (Zn²⁺) is an essential trace element that plays a crucial role in various biological functions. Aberrant Zn²⁺ homeostasis may lead to the occurrence and development of diseases. Zinc transporters, primarily classified into two families in humans: the ZnT (SLC30A) family and the ZIP (SLC39A) family, are critical regulators of Zn²⁺ homeostasis. The roles of ZnT-mediated Zn²⁺ homeostasis in diseases are an active area of research. The ZnT family comprises ten members, belonging to four subfamilies, which are widely distributed in various tissues and subcellular organelles. ZnTs mediate directional Zn²⁺ efflux, transporting cytoplasmic Zn²⁺ into extracellular compartments or sequestering it within intracellular vesicles. Accumulating evidence has shown that ZnT dysregulation or ZnT mutations can disrupt Zn²⁺ homeostasis, leading to the occurrence and development of diseases, such as cancer, cardiovascular disease, and neurodegenerative diseases. In this review, we focus on the distribution and structure of ZnTs. Furthermore, we synthesize recent advances in ZnT-mediated regulation of Zn²⁺ homeostasis in disease pathogenesis to guide the development of novel diagnostic and therapeutic strategies.

The activation of hepatic stellate cells (HSCs) plays a key role in the pathogenesis of liver fibrosis. However, the activation of HSCs requires energy from mitochondria—highly dynamic organelles. In our previous studies, we have confirmed that CCAAT/enhancer binding protein α (C/EBP-α) can inhibit the activation of HSCs, but whether it can affect the activation of HSCs by regulating mitochondrial dynamics is still unclear. In this study, we characterized the roles and mechanisms of C/EBP-α-mediated mitochondrial fission in regulating HSCs activation. We found that C/EBP-α upregulates Drp1 expression through inhibiting YAP expression, thus promoting mitochondrial fission and suppressing the activation of HSCs. In addition, in the HSCs with C/EBP-α overexpression, the epistatic roles of YAP and Drp1 in regulating mitochondrial biology and HSCs activation were interrogated with their respective inhibitors/agonists. Thus, we propose that mitochondrial fission plays an important role in the activation of HSCs and fibrosis that is regulated by a C/EBP-α-YAP-Drp1 axis.

Early intervention for infantile hemangioma (IH) typically involves the use of the first-line drug propranolol, which can be taken orally or applied topically. However, approximately 10% of patients develop resistance, highlighting the need to elucidate the underlying molecular mechanisms. This study found that the expression of glucose transporter 1 (GLUT1) was significantly increased in IH tissues. Knockdown of GLUT1 significantly inhibited the cell viability, colony formation, and angiogenesis of HemEC cells. Moreover, high GLUT1 levels caused insensitivity to propranolol treatment in IH as HemEC cells showed few significant changes to intracellular GLUT1 protein expression and glycolysis level upon treatment with propranolol, while overexpression of GLUT1 promoted colony formation and increased the IC₅₀ value of HemEC cells with propranolol treatment. The YT521-B homology domain family protein 1 (YTHDF1), an m⁶A reader in mRNA, was significantly increased in IH tissues compared with normal adjacent tissues. MeRIP-qPCR results showed that YTHDF1 binds to GLUT1 mRNA and promoted its stability and translation efficiency, resulting in GLUT1 upregulation, thereby inhibiting the sensitivity of IH to propranolol. Additionally, YTHDF1 overexpression promoted the ability of colony formation and increased the IC₅₀ value of HemEC cells with propranolol treatment. However, this promotion was reversed by knockdown of GLUT1. Collectively, our results demonstrated that YTHDF1-mediated m⁶A recognition of GLUT1 is vital in IH development and propranolol insensitivity. The YTHDF1/GLUT1 axis may serve as a potential target for inhibiting IH progression from aggravating and overcoming propranolol resistance in IH.