Background Evidence suggests LINC01809 being involved in prostate cancer (PC). We studied LINC01089 functionality, the underlying mechanisms, and translational potential in PC. Methods Multiple PC cohorts (local, TCGA, and others) were utilized. Human (DU145 and LNCaP) and murine (TRAMP-C2) PC cells were used to investigate LINC01089-derived oncogenic potential in vitro and in vivo. Results LINC01089 upregulation occurred in PC, Gleason score 9–10 tumors and metastasis. LINC01089 stratified PC recurrence. Plasma collected from patients (n = 235) prior to treatment contained elevated LINC01089, which was further increased in higher Gleason PCs and modestly correlated with PSA score. LINC01089-positively correlated genes contained a 15-gene panel (Sig15) and were dominantly enriched in RNA splicing in multiple PC datasets, with three genes (DDX17, LUC7L3, and HNRNPH1/Overlap3) conserved. Overlap3 and Sig15 effectively stratified the recurrence risk of PC and poor prognosis across 9 other cancer types, and captured the tumors' RNA splicing property, a major mechanism contributing to androgen receptor (AR) variants. Ectopic LINC01089 enhanced DU145, LNCaP, and TRAMP-C2 PC cell proliferation, colony formation, and migration, and conferred LNCaP and TRAMP-C2 cell proliferation under androgen deprivation, along with AR upregulation in the nucleus. In C57BL/6 mice, TRAMP-C2 LINC01089 allografts grew faster and expressed increased nuclear AR, Ki67, and AKT activation. TRAMP-C2 LINC01089 allografts expressed higher levels of Overlap3 and some Sig15 genes. Conclusion LINC01089 facilitates PC. Overlap3 and Sig15 are novel prognostic biomarkers reflecting cancer-associated RNA splicing. Plasma LINC01089 displays PC diagnostic potential.
Cardiovascular disease remains one of the leading threats to human health. Owing to the limited availability of autologous vessels, the demand for vascular graft substitutes continues to rise. The design of tissue-engineered scaffolds that mimic the composition and architecture of the extracellular matrix (ECM) and facilitate vascular remodeling has become a major research focus in artificial blood vessel development. In this study, we investigated how the surface chemical and physical properties of vascular scaffolds influence cellular behavior. Polycaprolactone/collagen (PCL/Col) composite scaffolds were fabricated via electrospinning. The results demonstrated that the hydrophilic/hydrophobic characteristics of the fiber surface significantly affected cell adhesion and proliferation, with collagen incorporation markedly reducing the inherent hydrophobicity of PCL. In addition to chemical properties, the physical topographical cues were also evaluated. To overcome the small pore size typically associated with electrospun membranes, a three-dimensional PCL/Col fibrous scaffold was successfully constructed using a sodium borohydride gas-foaming method. This gas-foaming technique proved to be a simple and efficient approach to enlarging the pore size, thereby promoting cell infiltration, and holds promise as a practical method for preparing vascular basal layer scaffolds.
DNAJC13 is a member of DNAJ co-chaperone family and its missense mutation causes a rare familial form of Parkinson's disease. DNAJC13 is indispensable for neuronal homeostasis by regulation of autophagy and the regulation of receptor expression on the cell surface. However, the regulatory mechanisms governing DNAJC13 expression remain poorly understood. We previously demonstrated that DNAJC13 binds to RAB40 small GTPase. Unlike other RABs, RAB40 proteins interact with activated Cullin-5 (CUL5) via the SOCS box, forming an Cullin-RING E3 ubiquitin ligase (CRL) complex that regulates ubiquitylation of target proteins. Thus, as a binding partner of RAB40s, DNAJC13 degradation may be regulated by this functional complex. Here, we found that both N-and C-terminal regions of DNAJC13, including IWN1 and IWN3 domains, were essential for its binding to RAB40 A/B/C. Moreover, DNAJC13 degradation of relies predominantly on the ubiquitin-proteasome system rather than on autophagy, and upregulated DNAJC13 ubiquitination in the presence of RAB40A/B/C. Intriguingly, RNAi-mediated silencing of the RAB40 subfamily caused a significant increase in DNAJC13 expression, accompanied by higher autophagic flux. Furthermore, co-immunoprecipitation experiments demonstrated that RAB40C, which is predominantly expressed in midbrain dopaminergic neurons, binds to CUL5 and its activator NEDD8 as well as RBX2 (E2). Finally, DNAJC13 cellular levels were regulated by NEDD8 activity. Taken together, these findings indicate that NEDD8-mediated neddylation plays a key role in RAB40-CUL5-mediated DNAJC13 degradation.
