Biology subjects

Ning, B.

Publications and source records attributed to Ning, B..

7 recordsLinked to original sources

bioRxiv2026

Continuous Nuclear Export of p62/SQSTM1 Is Essential for Kidney Homeostasis

The selective autophagy receptor p62/SQSTM1 dynamically shuttles between the nucleus and cytoplasm through distinct nuclear localization and export signals, yet the physiological significance of this trafficking has remained unknown. Here, we generated mice carrying a deletion of the p62 nuclear export signal (dNES) to determine the in vivo role of p62 nuclear export. Homozygous dNES mice developed progressive podocyte injury, glomerulosclerosis, and fatal renal failure by 6-7 weeks of age, whereas heterozygous and dNES/- mice did not develop renal dysfunction. Loss of nuclear export caused constitutive nuclear accumulation of p62, accompanied by the formation of insoluble ubiquitin-positive aggregates and widespread alterations in the renal proteome, including activation of energy metabolism-related pathways and suppression of developmental programs. We previously demonstrated that the lipid peroxidation product 4-hydroxy-2-nonenal (4-HNE) inhibits the nuclear export receptor XPO1, resulting in nuclear retention of p62 in cultured cells. The present findings provide in vivo evidence that continuous nuclear export of p62 is indispensable for maintaining kidney homeostasis and reveal that excessive nuclear accumulation, rather than cytoplasmic depletion, underlies p62-mediated toxicity. Collectively, these findings establish continuous nuclear export of p62 as an essential mechanism for maintaining kidney homeostasis. Significance StatementThe adaptor protein p62/SQSTM1 continuously shuttles between the nucleus and cytoplasm, but the physiological significance of this trafficking has remained unknown. Here, we show that disrupting the nuclear export signal of p62 causes progressive podocyte injury, glomerulosclerosis, and fatal kidney failure through excessive nuclear accumulation and aggregate formation. In contrast, dNES/+ and dNES/- mice remain healthy, demonstrating that excessive nuclear accumulation, rather than cytoplasmic depletion, drives disease. These findings identify continuous nuclear export as a fundamental mechanism that prevents toxic nuclear accumulation of p62 and preserves kidney homeostasis.

cell biology↗

bioRxiv2026

3D Cell-Matrix Mechanical Interaction Models for Cancer Invasion and Drug Evaluation

Cancer cells breach the extracellular matrix (ECM) using both protease-driven degradation and force-driven physical remodeling, yet most anti-metastatic drug screens still rely on biochemical assays that overlook cell-matrix mechanical reciprocity. Here, we present a fully synthetic 3D invasion platform based on cellular force-responsive polyisocyanide (PIC) hydrogels that isolates biophysical invasion mechanisms. Cell-generated forces align and densify the PIC fibrous network, reproducing hallmark matrix remodeling seen in the tumor microenvironment. A constitutive model, parameterized by the critical stress for strain stiffening effect, links matrix nonlinear elasticity to pericellular stiffening, long-range mechanotransmission, and intercellular coupling. Using this system, we show that breast cancer cells invade by pulling and pushing the network even when matrix metalloproteinases are inhibited, revealing a physical bypass of protease blockade. Accordingly, broad-spectrum metalloproteinase inhibitors that suppress invasion in Matrigel fail to inhibit invasion here, exposing a limitation of current drug-evaluation pipelines. In co-culture, cancer-associated fibroblasts markedly accelerate invasion by generating aligned fiber tracks through higher contractility, implicating CAF-driven mechanical remodeling as a key route for breaching barriers during metastasis. The platform is thermoresponsive, compatible with standard Transwell formats, enables direct imaging of fiber architecture and invasion fronts, and decouples biophysical from biochemical cues for mechanism-aware, animal-free assessment of anti-metastatic therapies.

cancer biology↗

bioRxiv2025

Epithelial miR-149-5p up-regulation is associated with immune evasion in progressive bronchial premalignant lesions

The molecular drivers bronchial premalignant lesion progression to invasive lung squamous cell carcinoma are not well defined. Prior work profiling longitudinally collected bronchial premalignant lesion biopsies by RNA sequencing defined a proliferative subtype, enriched with bronchial dysplasia. We found that a gene co-expression module associated with interferon gamma signaling and antigen processing/presentation was down-regulated in progressive/persistent versus regressive lesions within the proliferative subtype, suggesting a functional impact of these genes on immune evasion. RNA from these same premalignant lesions was profiled by microRNA (miRNA) sequencing and a miRNA-gene network analysis identified hsa-miR-149-5p as a potential regulator of this antigen presentation gene co-expression module associated with lesion progression. hsa-miR-149-5p was found to be predominantly expressed in the epithelium and up-regulated in progressive/persistent versus regressive proliferative lesions while targets of this miRNA, the transcriptional coactivator of MHC-I gene expression, NLRC5, and the genes it regulates were down-regulated. MicroRNA in situ hybridization of hsa-miR-149-5p in tissue from adjacent fixed biopsies showed that hsa-miR-149-5p was increased in areas of bronchial dysplasia in progressive/persistent versus regressive lesions. Imaging mass cytometry showed that NLRC5 protein expression was decreased in progressive/persistent versus regressive lesions within areas of hyperplasia, metaplasia, and dysplasia. Additionally, basal cells with high versus low levels of NLRC5 were found to be in close spatial proximity to CD8 T cells, suggesting that these cells exhibit increased functional MHC-I gene expression in lesions with low hsa-miR-149-5p expression. Collectively, our data suggests a functional role for hsa-miR-149-5p in bronchial premalignant lesions and may serve as a therapeutic target for PML immunomodulation. STATEMENT OF SIGNIFICANCEIntegrative analysis across bronchial premalignant lesions has identified and localized a potential regulator of immune evasion in progressive/persistent lesions that could be a novel therapeutic target.

cancer biology↗

bioRxiv2023

Zoledronate reduces microdamage accumulation in cortical bone of ovariectomized rats

As a daily physiological mechanism in bone, microdamage accumulation dissipates energy and helps to prevent fractures. However, excessive damage accumulation might bring adverse effects to bone mechanical properties, which is especially problematic among the osteoporotic and osteopenic patients treated by bisphosphonates. Some pre-clinical studies in the literature applied forelimb loading models to produce well-controlled microdamage in cortical bone. Ovariectomized animals were also extensively studied to assimilate human conditions of estrogen-related bone loss. In the present study, we combined both experimental models to investigate microdamage accumulation in the context of osteopenia and zoledronate treatment. Three-month-old normal and ovariectomized rats treated by saline or zoledronate underwent controlled compressive loading on their right forelimb to create in vivo microdamage, which was then quantified by barium sulfate contrast-enhanced micro-CT imaging. Weekly in vivo micro-CT scans were taken to evaluate bone (re)modeling and to capture microstructural changes over time. After sacrifice, three-point-bending tests were performed to assess bone mechanical properties. Results show that the zoledronate treatment can reduce cortical microdamage accumulation in ovariectomized rats, which might be explained by the enhancement of several bone structural properties such as ultimate force, yield force, cortical bone area and volume. The rats showed increased bone formation volume and surface after the generation of microdamage, especially for the normal and the ovariectomized groups. Woven bone formation was also observed in loaded ulnae, which was most significant in ovariectomized rats. Although all the rats showed strong correlations between periosteal bone formation and microdamage accumulation, the correlation levels were lower for the zoledronate-treated groups, potentially because of their lower levels of microdamage. The present study provides insights to further investigations of pharmaceutical treatments for osteoporosis and osteopenia. The same experimental concept can be applied in future studies on microdamage and drug testing.

bioengineering↗

bioRxiv2022

Differential Regulation Analysis Quantifies miRNA Regulatory Roles And Context-Specific Targets

Rewiring of transcriptional regulatory networks has been implicated in many biological and pathological processes. However, most current methods for detecting rewiring events (differential network connectivity) are not optimized for miRNA-mediated gene regulation and fail to systematically examine predicted target genes in study designs with multiple experimental or phenotypic groups. We developed a novel method to address these shortcomings. The method first estimates miRNA-gene expression correlations with Spatial Quantile Normalization to remove the mean-correlation relationship. Then, for each miRNA, genes are ranked by their correlation strength per experimental group. Enrichment patterns of predicted target genes are compared using the Anderson-Darling test and significance levels are estimated via permutation. Finally, context-specific target genes for each miRNA are identified with target prioritization based on the correlation strength between miRNA and predicted target genes within each group. In miR-155 KO RNA-seq data from four mice immune cell types, our method captures the known cell-specific regulatory differences of miR-155, and prioritized targets are involved in functional pathways with cell-type specificity. Moreover, in TCGA BRCA data, our method identified subtype-specific targets that were uniquely altered by miRNA perturbations in cell lines of the same subtype. Our work provides a new approach to characterize miRNA-mediated gene regulatory network rewiring across multiple groups from transcriptomic profiles. The method may offer novel insights into cell-type and cancer subtype-specific miRNA regulatory roles.

bioinformatics↗

bioRxiv2021

DEPDC1/ EEF1A1 complex promotes the progression of human osteosarcoma via downregulation of FOXO3a

There are currently lack of effective therapeutic strategies for osteosarcoma, primarily due to insufficient understanding of the underlying mechanisms of the tumor cells. This study deciphers a potentially critical interplay of DEPDC1-EEF1A1-FOXO3a axis during the osteosarcoma progression. Bioinformatics analysis of documented 25,035 genes for differentially expressed genes were accompanied by transcriptional and translational examinations of clinical osteosarcoma specimens and osteosarcoma cell lines to assess the roles and interactions of DEP domain-containing 1 (DEPDC1), Elongation Factor 1-alpha 1 (EEF1A1), and FOXO3a in the tumor cells proliferation and prognosis. Gene expression profile analysis and clinical tests revealed highly expressed DEPDC1 in human osteosarcoma cells and tumor tissues. Vector-mediated silence of DEPDC1 resulted in halted osteosarcoma cell proliferation, promoted apoptosis, and ceased tumor metastasis. Immunoprecipitation assay confirmed that EEF1A1 directly bind to DEPDC1 protein through three binding regions. Further, DEPDC1/EEF1A1 complex significantly decreased the expression of FOXO3a at transcription and translation levels, which subsequently promoted the proliferation of osteosarcoma cells and tumor metastasis. Correlation studies exhibited that overexpression of DEPDC1/EEF1A1 complex in the clinical specimens negatively correlated with the patient survival rate. In conclusion, DEPDC1-EEF1A1-FOXO3a axis plays as a critical pathway that regulates the progression and prognosis of osteosarcoma.

cell biology↗

bioRxiv2019

Liver X Receptor β Controls Hepatic Stellate Cell Activation via Hedgehog Signaling

Liver X receptors (LXR) and {beta} serve important roles in cholesterol homeostasis, anti-inflammatory processes and the activation of hepatic stellate cells (HSCs). However, the development of therapies for liver fibrosis based on LXR agonists have been hampered due to side-effects such as liver steatosis. In this study, we demonstrated that HSCs expressed high levels of LXR{beta}, but not LXR, and that overexpression of LXR{beta} suppressed fibrosis and HSC activation in a carbon tetrachloride (CCl4)-induced fibrosis mouse model, without resulting in liver steatosis. Furthermore, Hedgehog (Hh)-regulated proteins, markedly increased in the CCl4-affected liver and mainly expressed in activated HSCs, were repressed under conditions of LXR{beta} overexpression. In addition, LXR{beta} knockout led to activation of Hh signaling and triggering of HSC activation, while overexpression of LXR{beta} led to the inhibition of the Hh pathway and suppression of HSC activation. These results suggest that LXR{beta} suppresses the activation mechanism of HSCs by inhibiting Hh signaling. In conclusion, LXR{beta}, by restoring the differentiation of HSCs, may be a promising therapeutic target for liver fibrosis without the adverse side-effects of LXR activation.

cell biology↗