Platelet-derived Growth factor-D Research Articles

Genomic analysis of worldwide sheep breeds reveals PDGFD as a major target of fat-tail selection in sheep

BackgroundFat tail is a unique trait in sheep acquired during domestication. Several genomic analyses have been conducted in sheep breeds from limited geographic origins to identify the genetic factors underlying this trait. Nevertheless, these studies obtained different candidates. The results of these regional studies were easily biased by the breed structures.ResultsTo minimize the bias and distinguish the true candidates, we used an extended data set of 968 sheep representing 18 fat-tailed breeds and 14 thin-tailed breeds from around the world, and integrated two statistical tests to detect selection signatures, including Genetic Fixation Index (FST) and difference of derived allele frequency (ΔDAF). The results showed that platelet derived growth factor D (PDGFD) exhibited the highest genetic differentiation between fat- and thin-tailed sheep breeds. Analysis of sequence variation identified that a 6.8-kb region within the first intron of PDGFD is likely the target of positive selection and contains regulatory mutation(s) in fat-tailed sheep. Histological and gene expression analyses demonstrated that PDGFD expression is associated with maturation and hemostasis of adipocytes. Further retrospective analysis of public transcriptomic datasets revealed that PDGFD expression is down-regulated during adipogenesis in both human and mouse, and is higher in fat tissues of obese individuals than that in lean individuals.ConclusionsThese results reveal that PDGFD is the predominant factor for the fat tail phenotype in sheep by contributing to adiopogenesis and maintaining the hemostasis of mature adipocytes. This study provides insights into the selection of fat-tailed sheep and has important application to animal breeding, as well as obesity-related human diseases.

PDGFD induces ibrutinib resistance of diffuse large B‑cell lymphoma through activation of EGFR.

Ibrutinib, an FDA approved, orally administered BTK inhibitor, has demonstrated high response rates to diffuse large B-cell lymphoma (DLBCL), however, complete responses are infrequent and acquired resistance to BTK inhibition can emerge. The present study investigated the role of the platelet-derived growth factor D (PDGFD) gene and the ibrutinib resistance of DLBCL in relation to epidermal growth factor receptor (EGFR). Bioinformatics was used to screen and analyze differentially expressed genes (DEGs) in complete response (CR), partial response (PR) and stable disease (SD) in DLBCL treatment with ibrutinib, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to analyze enriched the signaling pathways increasing DEGs. The Search Tool for Interactions of Chemicals database was used to analyze the target genes of ibrutinib. An interaction network of DEGs, disease-related genes and ibrutinib was constructed. The expression of PDGFD in tissues that were resistant or susceptible to DLBCL/ibrutinib was detected via immunohistochemistry (IHC), and the expression of PDGFD in DLBCL/ibrutinib-resistant strains and their parental counterparts were examined via reverse transcription-quantitative PCR and western blot analyses. Subsequently, a drug-resistant cell model of DLBCL/ibrutinib in which PDGFD was silenced was constructed. The apoptosis of the DLBCL/ibrutinib-resistant strains was examined using MTT and flow cytometry assays. EGFR gene expression was then assessed. At the same time, a PDGFD-interfering plasmid and an EGFR overexpression plasmid were transfected into the DLBCL drug-resistant cells (TMD8-ibrutinib, HBL1-ibrutinib) separately or together. MTT was used to measure cell proliferation and changes in the IC50 of ibrutinib. A total of 86 DEGs that increased in the CR, PR and SD tissues were screened, and then evaluated with GO and KEGG. The interaction network diagram showed that there was a regulatory relationship between PDGFD and disease-related genes, and that PDGFD could indirectly target the ibrutinib target gene EGFR, indicating that PDGFD could regulate DLBCL via EGFR. IHC results showed high expression of PDGFD in diffuse large B-cell lymphoma tissues with ibrutinib tolerance. PDGFD expression in ibrutinib-resistant DLBCL cells was higher compared with in parental cells. Following interference with PDGFD expression in ibrutinib-resistant DLBCL cells, the IC50 value of ibrutinib decreased, the rate of apoptosis increased and EGFR expression decreased. In brief, EGFR overexpression can reverse the resistance of DLBCL to ibrutinib via PDGFD interference, and PDGFD induces the resistance of DLBCL to ibrutinib via EGFR.

Verification and Analysis of Sheep Tail Type-Associated PDGF-D Gene Polymorphisms.

Simple SummaryPDGF-D can be considered a candidate gene for selection for sheep tail type. This study investigated genetic variation of the PDGF-D gene in sheep with different tail types verified at a cellular level and revealed the molecular mechanism of PDGF-D in sheep tail fat deposition. We detected a total of two SNPs among 533 sheep. g.4122606 C > G site was significantly correlated with tail length, and g.3852134 C > T site was significantly correlated with tail width. In addition, overexpression of PDGF-D in sheep preadipocytes can promote adipogenic differentiation. The PDGF-D gene may participate in sheep tail fat deposition and could be used for molecular marker-assisted selection of sheep tail type.The aim of this study was to examine the correlation between the platelet-derived growth factor-D (PDGF-D) gene and sheep tail type character and explore the potential underlying mechanism. A total of 533 sheep were included in this study. Polymorphic sites were examined by Pool-seq, and individual genotype identification and correlation analysis between tail type data were conducted using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF-MS) method. JASPART website was used to predict transcription factor binding sites in the promoter region with and without PDGF-D gene mutation. The effect of PDGF-D on adipogenic differentiation of sheep preadipocytes was investigated. Two single nucleotide polymorphism sites were identified: g.4122606 C > G site was significantly correlated with tail length, and g.3852134 C > T site was significantly correlated with tail width. g.3852134 C > T was located in the promoter region. Six transcription factor binding sites were eliminated after promoter mutation, and three new transcription factor binding sites appeared. Expression levels of peroxisome proliferator-activated receptor gamma (PPARγ) and lipoproteinlipase (LPL) were significantly up-regulated upon PDGF-D overexpression. Oil red O staining showed increased small and large oil drops in the PDGF-D overexpression group. Together these results indicate the PDGF-D gene is an important gene controlling sheep tail shape and regulating sheep tail fat deposition to a certain degree.

Dynamic Expression of Platelet-Derived Growth Factor-D and Phosphorylated Platelet-Derived Growth Factor Receptor-Β after Traumatic Brain Injury in Rats.

We explored the dynamic expression of platelet-derived growth factor-D (PDGF-D) and phosphorylated platelet-derived growth factor receptor-β (p-PDGFR-β) after traumatic brain injury in rats to provide theoretical basis for selecting therapeutic target and intervention time after traumatic brain injury. This study prepared the weight drop/impact acceleration-induced traumatic brain injury (TBI) model in rats, including sham group and TBI groups at different observation time points (6 hours, 12 hours, 24 hours, 3 days, and 7 days after TBI). The dynamic expression of PDGF-D and p-PDGFR-β after TBI were detected by western blot and immunofluorescence staining. The expression level of PDGF-D and p-PDGFR-β after TBI was detected by western blot. The PDGF-D level was increased (p < 0.05) 6 hours after TBI and remained at the high level until 3 days after TBI (p < 0.05). The p-PDGFR-β level was increased (p < 0.05) 12 hours after TBI and remained at the high level until 3 days after TBI (p < 0.05). PDGF-D and p-PDGFR-β in brain tissues were found by immunofluorescence in the perihematoma area 24 hours after TBI. This study revealed the expression phenomenon of PDGF-D and p-PDGFR-β after TBI in rats, suggesting that PDGF-D participates in the process of secondary brain injury after TBI through specific binding with PDGFR-β, which provides a theoretical basis for further research on selecting therapeutic targets and intervention times after TBI.

428 Itraconazole inhibits the PDGF-D/PI3K/Akt/mTOR pathway in vitro and down-regulates serum PDGF-A of infantile hemangioma via oral administration

The incidence of infantile hemangiomas (IHs) is 8-10% in children. We found that itraconazole, a common anti-fungal agent, can improve or cure IH for the first time. However, the underlying molecular mechanisms are still unclear. Our research showed that itraconazole treatment significantly inhibits the proliferation and promotes apoptosis of the endothelial cells of mouse hemangioma (EOMA) cell line and infantile primary hemangioma endothelial cell (HemEC). Itraconazole also remarkably reduce angiogenesis of HemEC in vitro. We performed transcriptome profiling via mRNA microarrays in HemEC cells upon itraconazole treatment, and identified cytokine-cytokine receptor interaction as the top significantly enriched pathway. Importantly, itraconazole significantly reduced platelet-derived growth factor D (PDGF-D) level, resulting in suppression of PDGFR-β activation and inhibition of its downstream effectors, such as PI3K, Akt, 4E-BP1, p70S6K and mTOR signaling pathway, which are important for cellular growth and survival of IH. Oral itraconazole solution with 5mg/kg/d was administrated in 17 children, aging from 1 to 12 months (average 5.4 months), weighing from 5 to 10.5 kg. The blood samples collected were used to detect the concentration of serum vascular endothelial growth factor (VEGF) and PDGF-A by ELISA kits. The treatment period varied from 13 to 63 days, with total dose of itraconazole 390-2250 mg. Serum PDGF-A concentration was 52879.92 ± 31435.65 pg/mL before treatment and 26289.34 ± 26095.77 pg/mL after treatment (p<0.05), whereas VEGF showed no statistical difference (p>0.05). Both in vitro and in vivo data suggest that PDGF (at least A and D) is a novel target of itraconazole in IH, which need further investigations.

From the Editor’s desk…: April 2019

From the Editor’s desk…: April 2019

Possible Role and Therapeutic Target of PDGF-D Signalling in Colorectal Cancer

Platelet-derived growth factor D (PDGF-D) has been shown to mediate cellular processes of importance in cancer progression. This study aimed to investigate the expression and putative involvement of PDGF-D signaling in colorectal carcinogenesis. PDGF-D was expressed in vascular endothelial cells in tumor and normal tissues. PDGF-D stimulation of cells altered genes of importance in carcinogenic processes. In addition, PDGF-D increased the proliferation rate while imatinib inhibited these effects. PDGF-D and its PDGF receptor beta (PDGFR-β) are expressed in colorectal cancer and blockage of PDGF-D/PDGFR-β signaling using tyrosine kinase inhibitors, such as imatinib, might be important in inhibiting tumor-promoting actions.

Overexpression of matriptase in tumor stroma is a poor prognostic indicator of extrahepatic bile duct cancer.

Bile duct cancer is known to contain numerous fibroblasts, and reported to recruit cancer- associated fibroblasts by secreting platelet-derived growth factor-D (PDGF-D) which needs serine proteases, such as matriptase, to behave as a ligand. However, their expression pattern, and prognostic value have not been clarified. In this study, we investigated the clinicopathological significance of PDGF-D and matriptase expression in patients with extrahepatic bile duct cancer. The samples were obtained from 256 patients who underwent the surgical resection between 1991 and 2015, and the expression levels of PDGF-D and matriptase were evaluated immunohistochemically. Staining intensities and distribution were scored, and finally classified into low and high expression groups in cancer cells and stroma respectively. High expression of matriptase in the cancer stroma was detected in 91 tumors (40%). The high stromal matriptase expression was significantly associated with shorter recurrence-free survival (RFS) and overall survival (OS) (P = 0.0027 and 0.0023, respectively). Multivariate analyses also demonstrated that the stromal matriptase expression level was an independent influential factor in RFS (P = 0.0050) and OS (P = 0.0093). Our findings suggest that the high stromal matriptase expression was strongly associated with tumor progression, recurrence and poor outcomes in patients with extrahepatic bile duct cancer.

Molecular and Cellular Effect of Angiotensin 1-7 on Hypertensive Kidney Disease.

Studies implicate that angiotensin 1-7 (Ang1-7) imparts protective effects in the kidney. However, its relevance in hypertensive kidney disease is not fully understood. The purpose of this study was to explore the role of Ang1-7 on renal damage/remodeling during hypertension and its potential underlying molecular-cellular mechanisms. Hypertension was induced in adult Sprague-Dawley rats by infusion of aldosterone (ALDO; 0.75 μg/hour) for 4 weeks with or without co-treatment of Ang1-7 (1 mg/kg/day). Untreated rats served as controls. Systolic blood pressure was monitored by tail-cuff technique. Renal fibrosis was evaluated by picrosirius red staining and renal collagen volume fraction was quantitated using imaging analyzing system. The expression of profibrotic factors [transforming growth factor-β1 (TGF-β1), platelet-derived growth factor-D (PDGF-D), fibroblast growth factor-1 (FGF-1), vascular endothelial growth factor-D (VEGF-D), and tissue inhibitors of metalloproteinases (TIMPs)] and free radical producing enzymes (inducible nitric oxide synthase and nicotinamide adenine dinucleotide phosphate [NADPH] oxidase) in the kidney were examined by reverse transcription-polymerase chain reaction and western blot. Renal oxidative stress was assessed by malondialdehyde (MDA) measurement. Chronic ALDO infusion caused hypertension and hypertensive renal disease represented as glomerular damage/sclerosis. Ang1-7 co-treatment did not affect blood pressure in ALDO-treated rats, but significantly attenuated the glomerular damage/fibrosis. ALDO treatment significantly elevated renal expression of profibrogenic factors, including TGF-β1, TIMP-1/TIMP-2, FGF-1, PDGF-D, and VEGF-D, whereas Ang1-7 co-treatment significantly reduced renal TGF-β1, TIMP-1/TIMP-2, and FGF-1, but not PDGF-D and VEGF-D. Furthermore, ALDO infusion elevated NADPH oxidase (gp91phox) and MDA in the kidney, which was attenuated by Ang1-7 co-treatment. Ang1-7 plays a protective role in the hypertensive kidney disease independent of blood pressure. The beneficial effects of Ang1-7 are likely mediated via suppressing TGF-β/FGF-1 pathways and oxidative stress.

Itraconazole Induces Regression of Infantile Hemangioma via Downregulation of the Platelet-Derived Growth Factor–D/PI3K/Akt/mTOR Pathway

Infantile hemangioma is the most common benign vascular tumor of infancy. We have previously reported that itraconazole, a common antifungal agent, can clinically improve or cure infantile hemangioma; however, the underlying molecular mechanisms are still unclear. Here, we show that itraconazole treatment significantly inhibits proliferation and promotes apoptosis of the endothelial cells of mouse hemangioma cell line and infantile primary hemangioma endothelial cell. Itraconazole also remarkably reduced angiogenesis of hemangioma endothelial cell invitro. We further performed transcriptome profiling via mRNA microarrays in hemangioma endothelial cell upon itraconazole treatment, and identified cytokine-cytokine receptor interaction as the top significantly enriched pathway. Importantly, itraconazole significantly reduced platelet-derived growth factor-D level, resulting in suppression of platelet-derived growth factor-β activation and inhibition of its downstream effectors, such as PI3K, Akt, 4E-BP1, and p70S6K, which are important for cellular growth and survival of infantile hemangioma. In conclusion, our results suggest that platelet-derived growth factor-D is a target of itraconazole in infantile hemangioma.

Platelet-derived growth factor-D expression mediates the effect of differentiated degree on prognosis in epithelial ovarian cancer.

Platelet-derived growth factor-D (PDGF-D) can enhance invasion and metastasis in several human malignancies. Although several studies have been performed to investigate the association between clinicopathological characteristics and prognosis in epithelial ovarian cancer (EOC), the mediation effect of PDGF-D on above-mentioned association have been seldom assessed. In this study, we detected the PDGF-D expression from the tissues of patients with EOC and further collected clinicopathological characteristics and prognostic information to identify whether PDGF-D mediated the effect of differentiated degree on prognosis in patients with EOC. A total of 190 paraffin-embedded tissue samples from patients with EOC between July 2005 and December 2010 were collected. We performed a Kaplan-Meier analysis for the association between differentiated degree and prognosis followed by a causal mediation analysis. The analysis results indicated that differentiated degree was associated with prognosis and PDGF-D mediated the effect of differentiated degree on prognosis in patients with EOC, which might be a potential target for ovarian cancer treatment.

Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma

In cholangiocarcinoma, early metastatic spread via lymphatic vessels often precludes curative therapies. Cholangiocarcinoma invasiveness is fostered by an extensive stromal reaction, enriched in cancer-associated fibroblasts (CAFs) and lymphatic endothelial cells (LECs). Cholangiocarcinoma cells recruit and activate CAFs by secreting PDGF-D. Herein, we investigated the role of PDGF-D and liver myofibroblasts in promoting lymphangiogenesis in cholangiocarcinoma. Human cholangiocarcinoma specimens were immunostained for podoplanin (LEC marker), α-SMA (CAF marker), VEGF-A, VEGF-C, and their cognate receptors (VEGFR2, VEGFR3). VEGF-A and VEGF-C secretion was evaluated in human fibroblasts obtained from primary sclerosing cholangitis explants. Using human LECs incubated with conditioned medium from PDGF-D-stimulated fibroblasts we assessed migration, 3D vascular assembly, transendothelial electric resistance and transendothelial migration of cholangiocarcinoma cells (EGI-1). We then studied the effects of selective CAF depletion induced by the BH3 mimetic navitoclax on LEC density and lymph node metastases in vivo. In cholangiocarcinoma specimens, CAFs and LECs were closely adjacent. CAFs expressed VEGF-A and VEGF-C, while LECs expressed VEGFR2 and VEGFR3. Upon PDGF-D stimulation, fibroblasts secreted increased levels of VEGF-C and VEGF-A. Fibroblasts, stimulated by PDGF-D induced LEC recruitment and 3D assembly, increased LEC monolayer permeability, and promoted transendothelial EGI-1 migration. These effects were all suppressed by the PDGFRβ inhibitor, imatinib. In the rat model of cholangiocarcinoma, navitoclax-induced CAF depletion, markedly reduced lymphatic vascularization and reduced lymph node metastases. PDGF-D stimulates VEGF-C and VEGF-A production by fibroblasts, resulting in expansion of the lymphatic vasculature and tumor cell intravasation. This critical process in the early metastasis of cholangiocarcinoma may be blocked by inducing CAF apoptosis or by inhibiting the PDGF-D-induced axis. Cholangiocarcinoma is a highly malignant cancer affecting the biliary tree, which is characterized by a rich stromal reaction involving a dense population of cancer-associated fibroblasts that promote early metastatic spread. Herein, we show that cholangiocarcinoma-derived PDGF-D stimulates fibroblasts to secrete vascular growth factors. Thus, targeting fibroblasts or PDGF-D-induced signals may represent an effective tool to block tumor-associated lymphangiogenesis and reduce the invasiveness of cholangiocarcinoma.

Platelet‑derived growth factorD promotes the angiogenic capacity of endothelial progenitor cells.

Neovascularization and re-endothelialization rely on endothelial progenitor cells (EPCs). However, the recruitment and angiogenic roles of EPCs are subject to regulation through the vascular microenvironment, which remains largely unknown. Platelet-derived growth factor D (PDGF-D) is a new member of the PDGF family that binds the PDGFR-β homodimer. However, it remains unknown whether and how it affects the angiogenic capacity of EPCs and participates in tube-like formation. EPCs were derived from rat bone marrow cells, and the gain-of-function approach was used to study the effects of PDGF-D on the biological activities of EPCs. EPCs that stably express PDGF-D were generated by lentiviral-mediated transduction, and the expression levels were evaluated by western blotting and reverse transcription, followed by real-time quantitative polymerase chain reaction (RT-qPCR). The biological activities of EPCs evaluated in the present study included proliferation, adhesion, migration, tube formation and senescence. Furthermore, the downstream signaling of PDGF-D was explored by western blot analysis. The results revealed that the lentiviral-mediated expression of PDGF-D in the microenvironment promoted the migration, proliferation, adhesion and tube formation of EPCs. In addition, PDGF-D suppressed the senescence of EPCs. Mechanistically, PDGF-D induced the phosphorylation of several signaling molecules, including STAT3, AKT, ERK1/2, mTOR and GSK-3β, suggesting that PDGF-D enhanced the angiogenic function of EPCs through PDGF receptor-dependent and -independent signaling pathways. In conclusion, PDGF-D promotes the angiogenic capacity of EPCs, including proliferation, migration, adhesion and tube formation, and thereby contributes to angiogenesis.

Retraction: Down-regulation of Platelet-Derived Growth Factor-D Inhibits Cell Growth and Angiogenesis through Inactivation of Notch-1 and Nuclear Factor-κB Signaling.

Retraction: Down-regulation of Platelet-Derived Growth Factor-D Inhibits Cell Growth and Angiogenesis through Inactivation of Notch-1 and Nuclear Factor-κB Signaling.

Effects of 3-Tetrazolyl Methyl-3-Hydroxy-Oxindole Hybrid (THOH) on Cell Proliferation, Apoptosis, and G2/M Cell Cycle Arrest Occurs by Targeting Platelet-Derived Growth Factor D (PDGF-D) and the MEK/ERK Signaling Pathway in Human Lung Cell Lines SK-LU-1, A549, and A-427.

BackgroundThe aim of this study was to evaluate the effects of 3-tetrazolyl methyl-3-hydroxy-oxindole hybrid (THOH) on cell proliferation, apoptosis, and the cell cycle in human lung cancer cell lines SK-LU-1, A549, and A-427, and the normal lung fibroblast cell line, MRC-5, in vitro.Material/MethodsHuman lung adenocarcinoma cells SK-LU-1, A549, and A-427, and the normal lung fibroblast cells, MRC-5 were cultured and treated with increasing concentrations of 10 mM of a stock solution of THOH in dimethyl sulfoxide (DMSO). An MTT cell proliferation assay was used. Cell apoptosis and the cell cycle were studied using fluorescence-activated cell sorting (FACs) with fluorescein isothiocyanate (FITC), Annexin-V, propidium iodide (PI), and nuclear staining with 4′,6-diamidino-2-phenylindole (DAPI). DNA damage was measured using the comet (single-cell gel electrophoresis) assay. Cell migration was evaluated using a wound healing assay, and Western blotting was used to measure protein expression levels.ResultsTreatment of SK-LU-1 cells with THOH inhibited cell migration. Treatment of lung cancer cells, SK-LU-1, A549, and A-427, with THOH inhibited cell proliferation, with the most marked inhibition found in the SK-LU-1 lung cancer cells (IC50, 12 μM). Treatment of lung cancer cells, SK-LU-1, A549, and A-427, with THOH increased cell apoptosis, resulted in G2/M cell cycle arrest, and inhibited both the platelet-derived growth factor D (PDGF-D) and MEK/ERK signaling pathways.ConclusionsTreatment of adenocarcinoma cells, SK-LU-1, A549, and A-427, with THOH inhibited cell proliferation, apoptosis, and resulted in G2/M cell cycle arrest by targeting PDGF-D and the MEK/ERK signaling pathway.

The roles and mechanism of platelets with podoplanin over-expressing human mammary fibroblasts in the in situ growth of breast cancer

Objective To confirm the role of podoplanin (PDPN) over-expressing human mammary fibroblasts (HMF) in tumorigenesis of breast cancer cell line MDA-MB-231, and study the effect and mechanism of reducing the peripheral platelet count in the progress of PDPN over-expressing HMF (HMF-P)-induced tumor growth. Methods We firstly constructed PDPN eukaryotic expression plasmid PDPN-pEGFP-LV5 and established HMF-P by lentivirus transfection. Then we investigated the effect of HMF-P on tumorigenesis in nude mice. We constructed a mouse model of thrombocytopenia by antibodies for mouse platelet depletion polyconal purified R300 and investigated the effect of HMF-P again in these special mice. Lastly, the expression of some tumor growth factors was detected by Western blotting. Results MDA-MB-231 cells commixed with HMF-P generated tumors of greatest volume 3.16 cm3; while the volume of HMF+ MDA-MB-231 and MDA-MB-231 groups was 1.93 cm3 and 0.52 cm3 respectively. The tumors volume in HMF-P + MDA-MB-231 group decreased to 1.03 cm3 in mice with thrombocytopenia, while the change in HMF+ MDA-MB-231 groups was not obvious. Western blotting analysis showed that the expression of platelet-derived growth factor-D (PDGF-D) in HMF-P + MDA-MB-231 group was significantly increased, and that in thrombocytopenia group was significantly decreased. Conclusion HMF-P can promote the tumorigenesis of MDA-MB-231. Its mechanism may be related to the interaction of PDPN with infiltrating platelets to promote its activation and release of PDGF-D. Reducing the peripheral blood platelet count to reduce platelet infiltration can inhibit the effect of HMF-P promoting tumor growth. Key words: Breast cancer; Platelets; Podoplanin; Mammary fibroblasts

Perivascular Adipose Tissue-Derived PDGF-D Contributes to Aortic Aneurysm Formation During Obesity.

Obesity increases the risk of vascular diseases, including aortic aneurysm (AA). Perivascular adipose tissue (PVAT) surrounding arteries are altered during obesity. However, the underlying mechanism of adipose tissue, especially PVAT, in the pathogenesis of AA is still unclear. Here we showed that angiotensin II (AngII) infusion increases the incidence of AA in leptin-deficient obese mice (ob/ob) and high-fat diet-induced obese mice with adventitial inflammation. Furthermore, transcriptome analysis revealed that platelet-derived growth factor-D (PDGF-D) was highly expressed in the PVAT of ob/ob mice. Therefore, we hypothesized that PDGF-D mediates adventitial inflammation, which provides a direct link between PVAT dysfunction and AA formation in AngII-infused obese mice. We found that PDGF-D promotes the proliferation, migration, and inflammatory factors expression in cultured adventitial fibroblasts. In addition, the inhibition of PDGF-D function significantly reduced the incidence of AA in AngII-infused obese mice. More importantly, adipocyte-specific PDGF-D transgenic mice are more susceptible to AA formation after AngII infusion accompanied by exaggerated adventitial inflammatory and fibrotic responses. Collectively, our findings reveal a notable role of PDGF-D in the AA formation during obesity, and modulation of this cytokine might be an exploitable treatment strategy for the condition.

Platelet-Derived Growth Factor D Is a Prognostic Biomarker and Is Associated With Platinum Resistance in Epithelial Ovarian Cancer.

This study aimed to investigate whether platelet-derived growth factor D (PDGF-D) is a prognostic biomarker and is associated with platinum resistance in epithelial ovarian cancer, which has not been studied by others previously. In this study, we detected expression of PDGF-D in ovarian cancer tissues through immunohistochemistry and Western blotting. Furthermore, we analyzed the association between PDGF-D expression and clinicopathological features including prognosis in epithelial ovarian cancer. Statistical analyses were performed by using χ test, log-rank test, Cox regression test, and Kaplan-Meier method. High PDGF-D expression is positively correlated with International Federation of Gynecology and Obstetrics stage (P < 0.001), histologic grade (P < 0.001), lymph node metastasis (P = 0.022), and poor prognosis (P < 0.001). Platelet-derived growth factor D in platinum-resistant cases is overexpressed compared with that in platinum-sensitive cases (P < 0.001). Obstetrics stage (P = 0.029) and PDGF-D overexpression (P < 0.001) are independently correlated with platinum resistance. Our study indicates that PDGF-D overexpression is an independent predictor of platinum-based chemotherapy resistance and that it may also be a potential biomarker for targeted therapy and poor prognosis.

Platelet-derived growth factor-D promotes colorectal cancer cell migration, invasion and proliferation by regulating Notch1 and matrix metalloproteinase-9.

Colorectal cancer (CRC) has been one of the most common types of cancer for decades worldwide. The pathogenesis of CRC is associated with the processes of activating oncogenes and inactivating anti-oncogenes. Platelet-derived growth factor-D (PDGF-D) was confirmed to regulate migration, invasion, proliferation, apoptosis and metastasis in various cancer cells. Overexpression of PDGF-D exists in a number of human malignancies, including pancreatic, prostate and breast cancer. However, the expression and function of PDGF-D and its associated molecular mechanism in CRC remain unclear. Thus, the expression of PDGF-D was detected in CRC tissues and human colon cancer lines. Subsequently, the effects of PDGF-D on the invasion, migration and proliferation of cancer cells were investigated. The corresponding molecular mechanism had also been explored. The present study revealed that PDGF-D was upregulated not only in CRC tissues but also in CRC cell lines, and simultaneously, facilitated the processes of migration, invasion and proliferation. Silencing PDGF-D in the SW480 cell line inhibited migration, invasion and proliferation distinctly, with reduced expression of Notch1 and matrix metalloproteinase-9. Furthermore, upregulating PDGF-D in HCT116 cells led to the opposite results. These findings indicate that PDGF-D may be developed into a potential therapeutic target for CRC treatment.

Identification of zinc finger protein of the cerebellum 5 as a survival factor of prostate and colorectal cancer cells.

Identification of specific drug targets is very important for cancer therapy. We recently identified zinc finger protein of the cerebellum 5 (ZIC5) as a factor that promotes melanoma aggressiveness by platelet‐derived growth factor D (PDGFD) expression. However, its roles in other cancer types remain largely unknown. Here we determined the roles of ZIC5 in prostate cancer (PCa) and colorectal cancer (CRC) cells. Results showed that ZIC5 was highly expressed in CRC and dedifferentiated PCa tissues, whereas little expression was observed in relevant normal tissues. Knockdown of ZIC5 decreased proliferation of several PCa and CRC cell lines with induction of cell death. ZIC5 knockdown significantly suppressed PDGFD expression transcriptionally, and PDGFD suppression also decreased proliferation of PCa and CRC cell lines. In addition, suppression of ZIC5 or PDGFD expression decreased levels of phosphorylated focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3) which are associated with PCa and CRC aggressiveness. Furthermore, knockdown of ZIC5 or PDGFD enhanced death of PCa and CRC cells induced by the anti‐cancer drugs docetaxel or oxaliplatin, respectively. These results suggest that ZIC5 and PDGFD promote survival of PCa and CRC cells by enhancing FAK and STAT3 activity, and that the roles of ZIC5 are consistent across several cancer types.