Lysosome plays important roles in cellular homeostasis, and its dysregulation contributes to tumor growth and survival. However, the understanding of regulation and the underlying mechanism of lysosome in cancer survival is incomplete. Here, we reveal a role for a histone acetylation–regulated long noncoding RNA termed lysosome cell death regulator (LCDR) in lung cancer cell survival, in which its knockdown promotes apoptosis. Mechanistically, LCDR binds to heterogenous nuclear ribonucleoprotein K (hnRNP K) to regulate the stability of the lysosomal-associated protein transmembrane 5 (LAPTM5) transcript that maintains the integrity of the lysosomal membrane. Knockdown of LCDR, hnRNP K, or LAPTM5 promotes lysosomal membrane permeabilization and lysosomal cell death, thus consequently resulting in apoptosis. LAPTM5 overexpression or cathepsin B inhibitor partially restores the effects of this axis on lysosomal cell death in vitro and in vivo. Similarly, targeting LCDR significantly decreased tumor growth of patient-derived xenografts of lung adenocarcinoma (LUAD) and had significant cell death using nanoparticles (NPs)-mediated systematic short interfering RNA delivery. Moreover, LCDR/hnRNP K/LAPTM5 are up-regulated in LUAD tissues, and coexpression of this axis shows the increased diagnostic value for LUAD. Collectively, we identified a long noncoding RNA that regulates lysosome function at the posttranscriptional level. These findings shed light on LCDR/hnRNP K/LAPTM5 as potential therapeutic targets, and targeting lysosome is a promising strategy in cancer treatment.
Understanding the complexity of animals' behaviors and intellect relies on decoding the underlying structure and wiring diagram of their brains. Various imaging techniques have been developed to tackle this challenge, yet they still have limitations in mapping all cells in a brain region at mesoscale level. Here we propose an optical multilayer interference tomography (OMLIT) method with serial sectioning capability for mesoscale neuroanatomy. With OMLIT, we can distinguish and reconstruct all cell bodies, large branches of dendrites and myelinated axons, and the vasculature in the region of interest, enabling fast mapping of cell density and classification of certain cell types. Furthermore, using the same form of ultrathin sample section library, our method offers seamless compatibility with tape-based serial scanning electron microscopy, providing a correlative approach to reconstruct both mesoscale and microscale brain atlases in the same tissue.
In this study, we report that tuberoinfundibular peptide of 39 residues (TIP39), a parathyroid hormone ligand family member, increases decorin expression and enhanced wound repair in mice. Fibroblasts show enhances decorin expression when cultured in three-dimensional (3D) collagen gels as measured by qPCR and Western Blot. However, induction of adipocyte differentiation in 3D collagen gels reduced the expression of several proteoglycans, including decorin. TIP39 treatment increased the production of chondroitin sulfate by these differentiated adipocytes. Furthermore, exposure of fibroblasts to TIP39 induced phosphorylation and nuclear translocation of CREB, a known decorin transcription factor. siRNA-mediated silencing of parathyroid hormone 2 receptor (PTH2R), the receptor for TIP39, significantly suppressed the expression of extracellular matrix (ECM)-related genes, including decorin, collagens, fibronectin and matrix metalloproteases. In mice, topical TIP39 treatment accelerated wound repair while TIP39-/-mice had delayed wound repair and abnormal collagen fibrils by electron microscope that were consistent with decorin deficiency. Thus, TIP39 and PTH2R regulate ECM expression and enhance wound repair. These effects may be relevant not only in wound repair, but also in some ECM-related skin diseases.
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