Biology subjects

Zhi, W.

Publications and source records attributed to Zhi, W..

4 recordsLinked to original sources

bioRxiv2025

Podoplanin-Linked Mesenchymal Shift Synergizes with CCR7 driving Lymphatic Metastasis and Tumor Progression in Breast Cancer

Epithelial-to-mesenchymal-transition (EMT) and upregulation of chemokine receptors are linked to lymphatic metastasis in various types of cancer including breast cancer. However, the underlying molecular mechanisms are not fully understood. Using a triple-negative mammary carcinoma model, conditioned for lymphatic metastasis through expression of the C-C chemokine receptor 7 (CCR7), we identified intrinsic tumor plasticity associated with EMT as a critical determinant for effective metastasis. Specifically, tumor cells upregulate Podoplanin (PDPN) as part of a spontaneous mesenchymal shift that promotes lymphatic dissemination and tumor growth. Intriguingly, the expression of CCR7, or PDPN alone, was not sufficient for these effects. CCR7- and PDPN-positive tumors displayed an immune-cold tumor profile, compared to control, characterized by reduced tumor-infiltrating T-cells. Consistent with this, we found that spontaneous upregulation of PDPN was linked to hypoxia and was associated with the downregulation of homeostatic interferon signaling, and increased expression of collagens. Analysis of single-cell data sets showed that PDPN expression was heterogeneous and correlated significantly with EMT markers, collagen expression, and hypoxia hallmark in human breast cancer cell lines and primary human triple negative (TN) breast cancer, mirroring findings in the mouse model. Further analysis of the human breast cancer METABRIC-microarray datasets supported an association between a high CCR7/PDPN mRNA expression score and aggressive breast cancer subtypes with an independent prognostic value in lymph node-positive tumors. Together, these findings highlight a critical role of tumor microenvironment-driven tumor plasticity and molecular synergy between CCR7 and PDPN-coupled EMT shift in promoting chemokine receptor-mediated tumor dissemination and progression. SummaryCCR7-driven lymphatic metastasis requires a mesenchymal shift with PDPN upregulation. This tumor plasticity, linked to hypoxia and immune evasion, suggests CCR7-PDPN synergy in aggressive breast cancer progression and poor prognosis.

cancer biology↗

bioRxiv2025

The Pro- vs. Anti-Angiogenic Capacity of Short Chain Fatty Acids is Dependent on the Bioavailability of FFAR3 in Peripheral Artery Disease.

BackgroundOur current study builds on our recent report that showed Palmitate aggravates ischemic endothelial (EC) dysfunction in vitro and aims to determine whether Palmitate is a critical determinant of PAD severity. In contrast to Palmitate, we studied the role of short-chain fatty acids (SCFAs) in regulating ischemic revascularization in PAD. MethodsFemoral artery ligation and resection was used as preclinical-PAD model. Hypoxia serum starvation was used as in vitro PAD model. ResultsPalmitate dramatically decreased ischemic-EC survival and angiogenic capacity in vitro, whereas SCFAs significantly induced their angiogenic capacity. LC-MRM MS analysis showed decreased SCFA content in ischemic-muscle. Laser Speckle perfusion imaging showed that intramuscular SCFA treatment significantly induced perfusion recovery, whereas Palmitate showed a modest but significant impairment in perfusion recovery. Immunoblot analysis showed that SCFAs preferentially induce Free fatty acid receptor (FFAR)-3, but not FFAR2. Accordingly, silencing FFAR3 decreased ischemic-EC angiogenic capacity, whereas inhibiting FFAR2 induced ischemic angiogenesis. Pharmacological inhibition of FFAR3 by beta-hydroxybutyrate (BHB) significantly decreased perfusion recovery. SCFA treatment further decreased perfusion recovery in BHB-treated ischemic-muscle. Mechanistically, inhibiting FFAR3-induced FFAR2-levels that inhibited ischemic-EC angiogenic capacity by decreasing NO and inducing ROS levels in SCFA-treated ischemic-ECs. ConclusionsOur data shows that Palmitate alone is not sufficient to drive the PAD severity. Increased FFAR3 levels in ischemic-muscle allow SCFAs to activate the AKT-NO axis to induce ischemic angiogenesis and perfusion recovery. However, loss of FFAR3 in ischemic-muscle promotes FFAR2 activation that blocks SCFA-induced NO-production and redox balance thereby inhibiting perfusion recovery in preclinical-PAD.

pathology↗

bioRxiv2021

Salubrinal induces fetal hemoglobin expression via the stress-signaling pathway in human sickle erythroid progenitors and sickle cell disease mice

Sickle cell disease (SCD) is an inherited blood disorder caused by a mutation in the HBB gene leading to hemoglobin S production and polymerization under hypoxia conditions leading to vaso-occlusion, chronic hemolysis, and progressive organ damage. This disease affects [~]100,000 people in the United States and millions worldwide. An effective therapy for SCD is fetal hemoglobin (HbF) induction by pharmacologic agents such as hydroxyurea, the only Food and Drug Administration-approved drug for this purpose. Therefore, the goal of our study was to determine whether salubrinal (SAL), a selective protein phosphatase 1 inhibitor, induces HbF expression through the stress-signaling pathway by activation of p-eIF2 and ATF4 trans-activation in the {gamma}-globin gene promoter. Sickle erythroid progenitors treated with 24{micro}M SAL increased F-cells levels 1.4-fold (p=0.021) and produced an 80% decrease in reactive oxygen species. Western blot analysis showed SAL enhanced HbF protein by 1.6-fold (p=0.0441), along with dose-dependent increases of p-eIF2 and ATF4 levels. Subsequent treatment of SCD mice by a single intraperitoneal injection of SAL (5mg/kg) produced peak plasma concentrations at 6 hours. Chronic treatments of SCD mice with SAL mediated a 2.3-fold increase in F-cells (p=0.0013) and decreased sickle erythrocytes supporting in vivo HbF induction.

molecular biology↗

bioRxiv2021

Effects of electroacupuncture on the expression of hypothalamic neuropeptide Y and ghrelin in pubertal rats with polycystic ovary syndrome

BackgroundPolycystic ovary syndrome often starts in puberty, and its pathogenesis is not clear. This study aimed to explore the pathogenesis of pubertal polycystic ovary syndrome (PCOS) and assess the therapeutic effect of electroacupuncture on pubertal PCOS. MethodsDihydrotestosterone (DHT) was used to induce rat models of pubertal PCOS. pubertal rats with PCOS were randomly divided into a model group (M), an electroacupuncture group (EA), and a sham acupuncture group (SA). Age-matched normal rats were regarded as normal controls (N). Rats were treated with EA or SA five times a week for 25 minutes during their 6th-7th week. At the end of the experiment, we observed any changes in ovarian morphology; detected levels of metabolic indices in serum, the hypothalamus and pancreas. ResultsEA significantly improved estrous cycle disorders and the ovarian polycystic morphology in pubertal rats with PCOS, but SA only improved disorders of the estrous cycle. The serum levels of insulin, neuropeptide Y(NPY) and fasting blood glucose(FBG) increased significantly, while the serum levels of ghrelin(GHRL) decreased in the model group. After treatment with EA, the levels of NPY and FBG went into decrease, whereas the levels of GHRL and insulin increased. There was few differences in the hypothalamic expression of galanin (GAL), galanin-like peptide (GALP) and ghrelin receptor(GHSR) between the four groups. The upregulation of NPY mRNA and neuropeptide Y2 receptor(NPY2R) mRNA and the downregulation of GHRL protein and mRNA in the hypothalamus, and the increased expression of NPY and NPY2R as well as the decreased expression of GHRL in the arcuate nucleus (ARC) can be rescued by EA. But, surprisingly, SA seem to make no difference to the levels of FBG and insulin, and the protein expression of ghrelin in the hypothalamus and ARC. Co-expression of kisspeptin and GHSR, and co-expression of gonadotrophin releasing hormone(GnRH) and NPY2R were observed in ARC. No differences were found between groups in protein of GAL, GALP and GHRL expression in the pancreas. Neither EA nor SA can attenuate the upregulated kisspeptin protein expression in the pancreas of PCOS model rats. ConclusionsEA and SA improved the symptoms of pubertal PCOS rats, and the mechanism might be associated with regulating hypothalamic NPY and ghrelin levels.

neuroscience↗