Volume 102 Issue 4, April 2022
Inside the USCAP Journals
Advances in neuroendocrine prostate cancer research: From model construction to molecular network analyses
Neuroendocrine prostate cancer (NEPC) is an aggressive prostate cancer (PCa) variant. The exact mechanism underlying PCa development remains unclear due to the limited availability of NEPC models. In this review, the authors summarize strategies for NEPC model development and methods for model evaluation; discuss the origin of NEPC and the neuroendocrine transformation mechanism; and propose the challenges associated with research on NEPC. This study provides valuable insights into NEPC development and reveals potential therapeutic targets for NEPC.
Renal denervation ameliorates cardiac metabolic remodeling in diabetic cardiomyopathy rats by suppressing renal SGLT2 expression
Diabetic cardiomyopathy is a serious diabetes-related cardiovascular complication, which is closely related to myocardial metabolic disorders, but there is no specific therapy currently. Renal denervation (RDN), a novel technique to remove renal sympathetic nerves, can reduce the overexpression of renal SGLT2 in diabetic rats, thereby promoting urinary glucose excretion and maintaining systemic glucose homeostasis. On this basis, RDN ameliorated diabetes-induced cardiac metabolic disorders and mitochondrial damages, ultimately preventing diabetes-induced cardiac dysfunction and pathological remodeling.
Dissection of PD-L1 promoter reveals differential transcriptional regulation of PD-L1 in VHL mutant clear cell renal cell carcinoma
Through analysis of the PD-L1 promoter, the authors describe two clear cell renal cell carcinoma (ccRCC) models that exhibit differential PD-L1 expression levels upon IFNγ and hypoxia stimulation. Mutant-VHL ccRCC cells display higher PD-L1 expression than wild-type-VHL ccRCC cells due to high basal HIF2α expression and a stronger response to IFNγ stimulation. Thus, mutant-VHL ccRCC cells are expected to respond well to immune checkpoint inhibitors.
Commensal microbe effects on alveolar bone homeostasis have been attributed to the oral microbiota, yet the impact of commensal gut microbes is unknown. Studies performed with segmented filamentous bacteria (SFB) monoassociated mice revealed commensal gut microbes modulate osteoimmune responses and skeletal homeostasis in alveolar bone. This work challenges the current paradigm that alveolar bone health is strictly regulated by oral microbes.
Matrix metalloproteinase 11 (MMP11) in macrophages promotes the migration of HER2-positive breast cancer cells and monocyte recruitment through CCL2–CCR2 signaling
The authors demonstrate that matrix metalloproteinase 11 (MMP11) expression in mononuclear inflammatory cells (predominantly macrophages) is an independent negative prognostic factor in breast cancer, whereas tumoral MMP11 expression is not associated with patient survival. This study also shows that MMP11-overexpressing macrophages promote the migration of HER2-positive breast cancer cells and monocyte recruitment through CCL2-CCR2 signaling, suggesting a pro-tumoral role of MMP11 in macrophages in HER2-positive breast cancer through interaction with cancer cells and other cells in the tumor microenvironment.
A murine mesenchymal stem cell model for initiating events in osteosarcomagenesis points to CDK4/CDK6 inhibition as a therapeutic target
Osteosarcoma is a tumour with a highly complex genome, which hampers the identification of driver genes. Using a model of murine mesenchymal stem cells (MSCs) with deficient p15Ink4b, p16Ink4a, or p19Arf that transform earlier compared to wild-type MSCs, the authors demonstrated that loss of p16Ink4a is a driver of osteosarcomagenesis. This can be exploited with a CDK4/CDK6 inhibitor, as osteosarcoma cells showed sensitivity to palbociclib which might be used as a novel therapeutic option.
Smoothened (SMO) regulates insulin-like growth factor 1 receptor (IGF1R) levels and protein kinase B (AKT) localization and signaling
The smoothened (SMO) receptor maintains levels of insulin-like growth factor 1 receptor (IGF1R) in several types of cancer cells, and high protein levels of both receptors correlate with poor survival in diffuse large B-cell lymphoma (DLBCL) patients. Loss of SMO favors IGF1R degradation over recycling, and IGF1R-mediated AKT/PI3K signaling, but MAPK is not significantly impaired. The preferential disruption of AKT signaling correlates with a loss of IGF1R and AKT in raft microdomains.
microRNA-155-5p initiates childhood acute lymphoblastic leukemia by regulating the IRF4/CDK6/CBL axis
The authors explored the role of microRNA-155-5p (miR-155-5p) in childhood acute lymphoblastic leukemia (cALL). They found that miRNA-155-5p targets the E3 ubiquitin ligase CBL and inhibits its expression, reducing the ubiquitination and degradation of interferon regulatory factor 4, thus elevating expression of cyclin-dependent kinase 6. These findings suggest a basis for potential future therapeutic strategies for cALL.
Inhibition of TXNDC5 attenuates lipopolysaccharide-induced septic shock by altering inflammatory responses
Thioredoxin domain containing 5 (TXNDC5) is highly expressed in patients with septic shock. It is also upregulated in mice with lipopolysaccharide (LPS)-induced sepsis and mouse macrophages subjected to LPS stimulation. Txndc5 depletion reduced inflammatory cytokine production and affected recruitment of macrophages and neutrophils in LPS-challenged mice. TXNDC5 inhibition alleviated LPS-induced sepsis by inhibiting the nuclear factor kappa B signaling pathway. These findings suggest that TXNDC5 inhibition may be a therapeutic approach for sepsis.
The role of macrophage–fibroblast interaction in lipopolysaccharide-induced pulmonary fibrosis: an acceleration in lung fibroblast aerobic glycolysis
This study demonstrates that lipopolysaccharide promotes activation of the JNK signaling pathway and endogenous TNF-α secretion in pulmonary macrophages, which facilitates lung fibroblast aerobic glycolysis and lactate production through PFKFB3 activation. These findings suggests that inflammation-metabolism interactions between lung macrophages and fibroblasts might play an essential role in lipopolysaccharide-induced pulmonary fibrosis.
LncRNA GAS5 regulates migration and epithelial-to-mesenchymal transition in lens epithelial cells via the miR-204-3p/TGFBR1 axis
Under high-glucose conditions, LECs obtain characteristics of mesenchymal cells such as high migratory capacity and invasiveness, which is the foundational basis for DC progression. The authors demonstrated that lncRNA GAS5 facilitates high glucose-induced lens epithelial cell migration and epithelial-to-mesenchymal transition by regulating the miR-204-3p/TGFBR1 axis. This study, therefore, provides novel insights into the pathogenesis of DCs.