Comprehensive analyses of transcriptomes induced by Lyme spirochete infection to CNS model system

Abstract Background Lyme disease is a zoonotic disease caused by infection with Borrelia burgdorferi (Bb), the involvement of the nervous system in Lyme disease is usually referred to as Lyme neuroborreliosis (LNB). LNB has diverse clinical manifestations, most commonly including meningitis, Bell’s palsy, and encephalitis. However, the molecular pathogenesis of neuroborreliosis is still poorly understood. Comprehensive transcriptomic analysis following Bb infection could provide new insights into the pathogenesis of LNB and may identify novel biomarkers or therapeutic targets for LNB diagnosis and treatment. Methods In the present study, we pooled transcriptomic datasets (transcriptomic rhesus data from our laboratory and the GSE85143 dataset from the Gene Expression Omnibus database) to screen common differentially expressed genes (DEGs) in the Bb infection group and the control group. Functional and enrichment analyses were conducted using the Database of Annotation Visualization and Integrated Discovery database, Protein-Protein Interaction network, and hub genes were identified using the Search Tool for the Retrieval of Interaction Genes database and the CytoHubba plugin. In addition, in vitro and ex vivo assays were performed to verify the above findings. The mRNA expression levels of these genes were verified by quantitative real-time PCR (qPCR). Results A total of 80 upregulated DEGs and 32 downregulated DEGs were identified. Among them, 11 hub genes were selected. Upregulated genes in the Gene Ontology analysis were significantly enriched in cell adhesion processes. The pathway enrichment analyses revealed that the PI3K-Akt signaling pathway was significantly enriched. The mRNA levels of ANGPT1, TLR6, SREBF1, LDLR, TNC, and ITGA2 in U251 cells and/or rhesus brain explants by exposure to Bb were validated by qPCR. Conclusion Our study suggested that TLR6, ANGPT1, LDLR, SREBF1, TNC, and ITGA were differentially highly expressed in Bb-infected astrocytes compared to normal controls, and overexpression of LDLR might be a favorable prognostic factor of LNB patients. Further study is needed to explore the value of TLR6, ANGPT1, LDLR, SREBF1, TNC, and ITGA in LNB pathogenesis.

Download Full-text

Identification of Hub Genes and Key Pathways of Paraquat Induced Human Embryonic Pulmonary Fibrosis by Bioinformatics Analysis and Vitro Experiments

10.21203/rs.3.rs-73540/v1 ◽

2020 ◽

Author(s):

Yue Fu ◽

Xiang Xia Zeng ◽

Jin Lun Hu ◽

Mei Yan ◽

CHun Ming Xie ◽

...

Keyword(s):

Gene Expression ◽

Pulmonary Fibrosis ◽

Lung Fibrosis ◽

Bioinformatics Analysis ◽

Core Promoter ◽

Interaction Network ◽

Gene Expression Omnibus ◽

Functional Enrichment ◽

Hub Genes

Abstract Background: Paraquat is highly toxic pesticide, which usually led to acute lung injury and subsequently develop pulmonary fibrosis, the exact mechanisms of PQ-induced lung fibrosis remain largely unclear and no specific drugs for this disease have been approved. Methods: Our study aimed to identify its potential mechanism though modeling study in vitro and bioinformatics analysis. Gene expression datasets associated with PQ-induced lung fibrosis were obtained from the Gene Expression Omnibus and differentially expressed genes (DEGs) were identified using GEO2R. Functional enrichment analyses were performed using the Database for Annotation. Results: The DEGs in the two datasets, of which 92 overlapping genes were found in two microarray datasets. Functional analysis demonstrated that the 92 DEGs were enriched in the ‘TNF signaling pathway’, ‘CXCR chemokine receptor binding’, and ‘core promoter binding’. Moreover, nine hub genes were identified from a protein‑protein interaction network. Conclusions: This integrative analysis firstly identified candidate genes and pathways in PQ-induced lung fibrosis, as well as benefit to research novel approaches for treating for control of PQ-induced pulmonary fibrosis.

Download Full-text

BPI and KIR6.1 as significant hub genes for vein graft restenosis

Journal of International Medical Research ◽

10.1177/0300060520969331 ◽

2020 ◽

Vol 48 (11) ◽

pp. 030006052096933

Author(s):

Yun-peng Bai ◽

Bo-chen Yao ◽

Mei Wang ◽

Xian-kun Liu ◽

Xiao-long Zhu ◽

...

Keyword(s):

Vein Graft ◽

Area Under The Curve ◽

Interaction Network ◽

Enrichment Analysis ◽

Gene Expression Omnibus ◽

Differentially Expressed ◽

Control Group ◽

Pathway Enrichment Analysis ◽

Hub Genes ◽

Protein Protein Interaction

Background Vein graft restenosis (VGR), which appears to be caused by dyslipidemia following vascular transplantation, seriously affects the prognosis and long-term quality of life of patients. Methods This study analyzed the genetic data of restenosis (VGR group) and non-stenosis (control group) vessels from patients with coronary heart disease post-vascular transplantation and identified hub genes that might be responsible for its occurrence. GSE110398 was downloaded from the Gene Expression Omnibus database. A repeatability test for the GSE110398 dataset was performed using R language. This included the identification of differentially expressed genes (DEGs), enrichment analysis via Metascape software, pathway enrichment analysis, and construction of a protein–protein interaction network and a hub gene network. Results Twenty-four DEGs were identified between VGR and control groups. The four most important hub genes ( KIR6.1, PCLP1, EDNRB, and BPI) were identified, and Pearson’s correlation coefficient showed that KIR6.1 and BPI were significantly correlated with VGR. KIR6.1 could also sensitively predict VGR (0.9 < area under the curve ≤1). Conclusion BPI and KIR6.1 were differentially expressed in vessels with and without stenosis after vascular transplantation, suggesting that these genes or their encoded proteins may be involved in the occurrence of VGR.

Download Full-text

Decoding Psoriasis: Integrated Bioinformatics Approach to Understand Hub Genes and Involved Pathways

Current Pharmaceutical Design ◽

10.2174/1381612826666200311130133 ◽

2020 ◽

Vol 26 (29) ◽

pp. 3619-3630

Author(s):

Saumya Choudhary ◽

Dibyabhaba Pradhan ◽

Noor S. Khan ◽

Harpreet Singh ◽

George Thomas ◽

...

Keyword(s):

Gene Expression ◽

Differentially Expressed Gene ◽

Therapeutic Targets ◽

Interaction Network ◽

Gene Expression Omnibus ◽

Differentially Expressed ◽

Keratinocyte Differentiation ◽

Hub Genes ◽

Lesional Skin ◽

Ncbi Gene Expression Omnibus

Background: Psoriasis is a chronic immune mediated skin disorder with global prevalence of 0.2- 11.4%. Despite rare mortality, the severity of the disease could be understood by the accompanying comorbidities, that has even led to psychological problems among several patients. The cause and the disease mechanism still remain elusive. Objective: To identify potential therapeutic targets and affecting pathways for better insight of the disease pathogenesis. Method: The gene expression profile GSE13355 and GSE14905 were retrieved from NCBI, Gene Expression Omnibus database. The GEO profiles were integrated and the DEGs of lesional and non-lesional psoriasis skin were identified using the affy package in R software. The Kyoto Encyclopaedia of Genes and Genomes pathways of the DEGs were analyzed using clusterProfiler. Cytoscape, V3.7.1 was utilized to construct protein interaction network and analyze the interactome map of candidate proteins encoded in DEGs. Functionally relevant clusters were detected through Cytohubba and MCODE. Results: A total of 1013 genes were differentially expressed in lesional skin of which 557 were upregulated and 456 were downregulated. Seven dysregulated genes were extracted in non-lesional skin. The disease gene network of these DEGs revealed 75 newly identified differentially expressed gene that might have a role in development and progression of the disease. GO analysis revealed keratinocyte differentiation and positive regulation of cytokine production to be the most enriched biological process and molecular function. Cytokines -cytokine receptor was the most enriched pathways. Among 1013 identified DEGs in lesional group, 36 DEGs were found to have altered genetic signature including IL1B and STAT3 which are also reported as hub genes. CCNB1, CCNA2, CDK1, IL1B, CXCL8, MKI 67, ESR1, UBE2C, STAT1 and STAT3 were top 10 hub gene. Conclusion: The hub genes, genomic altered DEGs and other newly identified differentially dysregulated genes would improve our understanding of psoriasis pathogenesis, moreover, the hub genes could be explored as potential therapeutic targets for psoriasis.

Download Full-text

YAP1 Overexpression Is Associated with Kidney Dysfunction in Lupus Nephritis

Pathobiology ◽

10.1159/000517575 ◽

2021 ◽

pp. 1-12

Author(s):

Ying Xie ◽

Yuanyuan Ruan ◽

Huimei Zou ◽

Yixin Wang ◽

Xin Wu ◽

...

Keyword(s):

Lupus Nephritis ◽

Epithelial Mesenchymal Transition ◽

Kidney Tissue ◽

Mouse Kidney ◽

Experimental Comparison ◽

Control Group ◽

Mrna Levels ◽

Mesenchymal Transition ◽

Protein Levels

Objective: The goal of the present study was to determine the expression of yes-associated protein 1 (YAP1) in renal tissues of mice with lupus nephritis (LN) and elucidate its role in the progression of renal fibrosis. Methods: C57BL/6 mice and MRL/lpr mice were selected for experimental comparison. Mouse kidney tissues were removed and sectioned for hematoxylin and eosin staining, Masson’s trichome staining, Sirius staining, and immunohistochemistry. The mRNA and protein levels of YAP1 in mouse kidney tissues were detected, and the correlation between YAP1 and fibronectin (FN) mRNA levels was analyzed. Mouse renal epithelial cells were used for in vitro experiments. After transfection and stimulation, the cells were divided into 4 groups, namely the C57BL/6 serum group (group 1), the MRL/lpr serum group (group 2), the MRL/lpr serum + siRNA-negative control group (group 3), and the MRL/lpr serum + siRNA-YAP1 group (group 4). Epithelial-mesenchymal transition (EMT) markers in each group were detected by Western blotting and immunofluorescence staining. Serum creatinine, blood urea nitrogen, and urinary protein levels were detected and assessed for their correlation with YAP1 mRNA levels by Spearman’s analysis. Results: Compared to C57BL/6 mice, MRL/lpr mice exhibited obvious changes in fibrosis in renal tissues. In addition, YAP1 expression was significantly higher in the renal tissues of MRL/lpr mice than in those of C57BL/6 mice, and YAP1 mRNA levels were positively correlated with those of FN. YAP1 silencing in lupus serum-stimulated cells could effectively relieve serum-induced EMT. Finally, we observed that YAP1 mRNA levels in mouse kidney tissue were significantly and positively correlated with the degree of renal function injury. Conclusion: YAP1 expression in the kidney tissues of LN mice was higher than that observed in normal mice, indicating that YAP1 may play an important role in the occurrence and development of LN.

Download Full-text

Granulosal and thecal expression of bone morphogenetic protein- and activin-binding protein mRNA transcripts during bovine follicle development and factors modulating their expression in vitro

Reproduction ◽

10.1530/rep-11-0150 ◽

2011 ◽

Vol 142 (4) ◽

pp. 581-591 ◽

Cited By ~ 18

Author(s):

Claire Glister ◽

Leanne Satchell ◽

Phil G Knight

Keyword(s):

Bone Morphogenetic Proteins ◽

Transforming Growth Factor ◽

Ex Vivo ◽

Mrna Level ◽

Transcript Abundance ◽

Transforming Growth Factor Β ◽

Follicle Development ◽

Mrna Levels ◽

Theca Interna

Evidence supports local roles for transforming growth factor β superfamily members including activins and bone morphogenetic proteins (BMP) in follicle development. Access of these ligands to signalling receptors is likely modulated by extracellular binding proteins (BP). In this study, we comparedex vivoexpression of four BPs (chordin, gremlin, noggin and follistatin) in granulosal (GC) and theca interna (TC) compartments of developing bovine antral follicles (1–18 mm). Effects of FSH and IGF on BMP and BP expression by cultured GC, and effects of LH and BMPs on BP expression by cultured TC were also examined. Follicular expression of all four BP transcripts was higher in GC than TC compartments (P<0.001) a finding confirmed by immunohistochemistry. Follicle category affected (P<0.01) gremlin and follistatin mRNA abundance, with a significant cell-type×follicle category interaction for chordin, follistatin and noggin. Noggin transcript abundance was lower (P<0.05) in GC of large ‘E-active’ than ‘E-inactive’ follicles while follistatin mRNA level was higher (P<0.01). FSH enhanced CYP19, FSHR, INHBA and follistatin by GC without affecting BMP or BMP–BP expression. IGF increased CYP19 and follistatin, reduced BMP4, noggin and gremlin but did not affect chordin orFSHRmRNA levels. LH increased TC androgen secretion but had no effect on BMP or BP expression. BMPs uniformly suppressed TC androgen production whilst increasing chordin, noggin and gremlin mRNA levels up to 20-fold (P<0.01). These findings support the hypothesis that extracellular BP, mostly from GC, contribute to the regulation of intrafollicular BMP/activin signalling. Enhancement of thecal BP expression by BMP implies an autoregulatory feedback role to prevent excessive signalling.

Download Full-text

Abstract 5369: Mesenchymal Stem Cells Overexpressing CXCR4 (CXCR4 + -MSCs) Attenuate Remodeling of Post-Myocardial Infarction by Releasing Anti-Fibrotic Enzymes

Circulation ◽

10.1161/circ.118.suppl_18.s_536-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Tao Wang ◽

Yigang Wang ◽

Dongsheng Zhang ◽

Tiemin Zhao ◽

Atif Ashraf ◽

...

Keyword(s):

Basement Membrane ◽

Ventricular Remodeling ◽

Interstitial Fibrosis ◽

Ex Vivo ◽

Genetically Engineered ◽

Control Group ◽

Hypoxic Conditions ◽

Antibody Staining ◽

Adenoviral Transduction

We hypothesize that CXCR4 + -MSCs penetrate and proliferate in infracted heart by releasing collagen degrading enzymes. We genetically engineered male mouse MSCs using ex vivo adenoviral transduction for over-expression of CXCR4/GFP or GFP alone. MSCs (G-I) or CXCR4 + -MSCs (G-II) or CXCR4 + -MSCs treated with epigallocarechin gallate (EGCG, 50μg/ml), a MT1-matrix metalloproteinases (MMPs) inhibitor (G-III) or CXCR4 + -MSCs with AMD3100 (5 μg/mL), a CXCR4-selective antagonist (G-IV). A Trans-Matrigel Chemoinvasion Assay was used to evaluate the ability of MSCs to cross the basement membrane. MMPs were analyzed by Western blot and MMP antibody staining. Sex mismatched MSCs were infused into female mice via a tail vein injection 3 days after MI. Mice in G-III were treated with EGCG (100 mg/kg, oral gavage, daily for 2 weeks) to inhibit MMPs and G-IV was treated with AMD3100 (1 mg/kg, i.p. given continually for 6 days after MI). LV fibrosis was detected by Picrosirius red staining. Echocardiography was performed at 4 weeks after MI and hearts were harvested for histological analysis. In vitro, cell migration was significantly higher in G-II in the presence of SDF-1α as compared with other groups, ( p <0.01). EGCG or AMD3100 markedly prevented this response. MMP-9 and MT1-MMP were upregulated significantly only in G-II (p<0.01) exposed to hypoxia. Infiltration of GFP and Y chromosome positive cells in the peri- or infarct area was increased significantly in G-II. CXCR4 + -MSCs penetrated more effectively into the infarcted region and survived in the ischemic environment as compared to control group. These effects were reduced with EGCG or AMD3100. The ventricular remodeling and interstitial fibrosis were also reduced in G-II but not in other groups. G-II also had less LV dilation (diastolic dimension 4.9±0.2 vs. 6.2±0.3 mm, p<0.05), EF (62±3 vs. 44±4%, p<0.05). Infarct size (31±3.8 vs 43±4.7% of LV, p<0.05) and collagen area fraction (16±2 vs. 28±4 %, p<0.05) were significantly reduced in G-2 compared to G-I. Under hypoxic conditions MMPs were upregulated in CXCR4 + -MSCs which crossed the basement membrane by releasing enzymes leading to breakdown or reduction of scar formation thus facilitating cell homing and proliferation.

Download Full-text

Effect of the proinflammatory cytokine TNF-α on intestinal riboflavin uptake: inhibition mediated via transcriptional mechanism(s)

AJP Cell Physiology ◽

10.1152/ajpcell.00295.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. C653-C663 ◽

Cited By ~ 5

Author(s):

Kasin Yadunandam Anandam ◽

Omar A. Alwan ◽

Veedamali S. Subramanian ◽

Padmanabhan Srinivasan ◽

Rubina Kapadia ◽

...

Keyword(s):

Ex Vivo ◽

Significant Inhibition ◽

Mrna Levels ◽

In Vivo Models ◽

Uptake Inhibition ◽

Tnf Α ◽

Vitro Model ◽

Factor Α

Riboflavin (RF), is essential for normal cellular metabolism/function. Intestinal RF absorption occurs via a specific carrier-mediated process that involves the apical transporter RFVT-3 ( SLC52A3) and the basolateral RFVT-1 (SLC52A1). Previously, we characterized different cellular/molecular aspects of the intestinal RF uptake process, but nothing is known about the effect of proinflammatory cytokines on the uptake event. We addressed this issue using in vitro, ex vivo, and in vivo models. First, we determined the level of mRNA expression of the human (h)RFVT-3 and hRFVT-1 in intestinal tissue of patients with inflammatory bowel disease (IBD) and observed a markedly lower level compared with controls. In the in vitro model, exposing Caco-2 cells to tumor necrosis factor-α (TNF-α) led to a significant inhibition in RF uptake, an effect that was abrogated upon knocking down TNF receptor 1 (TNFR1). The inhibition in RF uptake was associated with a significant reduction in the expression of hRFVT-3 and -1 protein and mRNA levels, as well as in the activity of the SLC52A3 and SLC52A1 promoters. The latter effects appear to involve Sp1 and NF-κB sites in these promoters. Similarly, exposure of mouse small intestinal enteroids and wild-type mice to TNF-α led to a significant inhibition in physiological and molecular parameters of intestinal RF uptake. Collectively, these findings demonstrate that exposure of intestinal epithelial cells to TNF-α leads to inhibition in RF uptake and that this effect is mediated, at least in part, via transcriptional mechanism(s). These findings may explain the significantly low RF levels observed in patients with IBD.

Download Full-text

P163 Biosamples from at risk SSc patients show classic pathological signs of scleroderma: opportunity for a diagnosis of pre-clinical SSc

Rheumatology ◽

10.1093/rheumatology/keaa111.158 ◽

2020 ◽

Vol 59 (Supplement_2) ◽

Author(s):

Rebecca L Ross ◽

Ioanna Georgiou ◽

Antonio Carriero ◽

Giuseppina Abignano ◽

Chris Wasson ◽

...

Keyword(s):

At Risk ◽

Clinical Signs ◽

Clinical Manifestations ◽

Clinical Intervention ◽

Bimodal Distribution ◽

Mrna Levels ◽

Window Of Opportunity ◽

Risk Patients ◽

Skin Biopsies

Abstract Background The VEDOSS study has recently indicated that more than 80% of patients affected by Raynaud’s phenomenon (RP) and specific SSc auto-antibodies + capillaroscopy changes satisfied ACR/EULAR 2013 criteria within 5 years.These data suggest that there is a window of opportunity for early detection of SSc in these patients. Here we aimed to determine whether sera, skin biopsies and skin fibroblasts cultured from these patients showed any biomarker sign of SSc. Methods Fifty-nine at risk patients identified by having RP and SSc auto-antibodies or capillaroscopy pattern (or both) were enrolled in the national inception cohort (Kennedy Cohort). Sera were tested for IFN inducible chemokines (CXCL-9,10 and 11 and CCL2, 8 and 19) and biomarker of extracellular matrix turnover (ELF test), all previously shown to be increased in SSc. Further, two 3mm skin biopsies were taken from the forearms from 3 ACA+ve (anti-centromere antibodies), 3 SCL70+ve patients. One biopsy was subjected to histology analysis, including haematoxylin and eosin staining and immunohistological staining for Collagen Type 1, alpha-SMA, Caveolin 1 and CD31 as endothelial marker. The other biopsy was used to explant fibroblasts cultures. mRNA and protein were isolated from primary fibroblasts and processed for RT-qPCR and western blotting analyses. Results Sera from at risk patients showed overall higher IFN inducible chemokines and ELF test (P < 0.05) with bimodal distribution among patients. Skin biopsies from both ACA or SCL70+ve patients showed decreased number of CD31+ cells, increased number of myofibroblasts and increased collagen bundles within the dermis, as usually seen in SSc, compared to healthy controls. In vitro, fibroblasts from both ACA or SCL70+ve patients showed average 10-fold higher collagen mRNA levels and 31-fold increased collagen protein levels compared to healthy control fibroblasts. Furthermore, fibroblasts from ACA or SCL70+ve patients showed limited TGF-beta induced increase in collagen and SMA expression, similar to SSc fibroblasts. Conclusion Although pilot in nature, this study suggests that patients “at risk” already show biomarker signs of SSc both in their sera and at skin biopsy and fibroblast level. Longitudinal studies on patients at this stage of pre-clinical disease may inform on the stratification strategies for imminent progression to clinical manifestations and offer both insights on pathogenesis of clinical signs and a window of opportunity for delaying the onset clinical intervention trials. Disclosures R.L. Ross None. I. Georgiou None. A. Carriero None. G. Abignano None. C. Wasson None. G. Migneco None. A. Herrick None. C. Denton None. F. Del Galdo None.

Download Full-text

The Diverse Potential of Gluten from Different Durum Wheat Varieties in Triggering Celiac Disease: A Multilevel In Vitro, Ex Vivo and In Vivo Approach

Nutrients ◽

10.3390/nu12113566 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3566

Author(s):

Federica Gaiani ◽

Sara Graziano ◽

Fatma Boukid ◽

Barbara Prandi ◽

Lorena Bottarelli ◽

...

Keyword(s):

Immune Response ◽

Celiac Disease ◽

Durum Wheat ◽

Ex Vivo ◽

Diet Group ◽

Control Group ◽

Wheat Varieties ◽

Before And After

The reasons behind the increasing prevalence of celiac disease (CD) worldwide are still not fully understood. This study adopted a multilevel approach (in vitro, ex vivo, in vivo) to assess the potential of gluten from different wheat varieties in triggering CD. Peptides triggering CD were identified and quantified in mixtures generated from simulated gastrointestinal digestion of wheat varieties (n = 82). Multivariate statistics enabled the discrimination of varieties generating low impact on CD (e.g., Saragolla) and high impact (e.g., Cappelli). Enrolled subjects (n = 46) were: 19 healthy subjects included in the control group; 27 celiac patients enrolled for the in vivo phase. Celiacs were divided into a gluten-free diet group (CD-GFD), and a GFD with Saragolla-based pasta group (CD-Sar). The diet was followed for 3 months. Data were compared between CD-Sar and CD-GFD before and after the experimental diet, demonstrating a limited ability of Saragolla to trigger immunity, although not comparable to a GFD. Ex vivo studies showed that Saragolla and Cappelli activated immune responses, although with great variability among patients. The diverse potential of durum wheat varieties in triggering CD immune response was demonstrated. Saragolla is not indicated for celiacs, yet it has a limited potential to trigger adverse immune response.

Download Full-text

Proteoglycan-4 is correlated with longer survival in HCC patients and enhances sorafenib and regorafenib effectiveness via CD44 in vitro

Cell Death and Disease ◽

10.1038/s41419-020-03180-8 ◽

2020 ◽

Vol 11 (11) ◽

Author(s):

Francesco Dituri ◽

Rosanna Scialpi ◽

Tannin A. Schmidt ◽

Martina Frusciante ◽

Serena Mancarella ◽

...

Keyword(s):

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Ex Vivo ◽

Mrna Levels ◽

Drug Effectiveness ◽

Proteoglycan 4 ◽

Tumor Expression ◽

A Prospective Study ◽

Hcc Cells

AbstractSorafenib and regorafenib administration is among the preferential approaches to treat hepatocellular carcinoma (HCC), but does not provide satisfactory benefits. Intensive crosstalk occurring between cancer cells and other multiple non-cancerous cell subsets present in the surrounding microenvironment is assumed to affect tumor progression. This interplay is mediated by a number of soluble and structural extracellular matrix (ECM) proteins enriching the stromal milieu. Here we assess the HCC tumor expression of the ECM protein proteoglycan 4 (PRG4) and its potential pharmacologic activity either alone, or in combination with sorafenib and regorafenib. PRG4 mRNA levels resulted strongly correlated with increased survival rate of HCC patients (p = 0.000) in a prospective study involving 78 HCC subjects. We next showed that transforming growth factor beta stimulates PRG4 expression and secretion by primary human HCC cancer-associated fibroblasts, non-invasive HCC cell lines, and ex vivo specimens. By functional tests we found that recombinant human PRG4 (rhPRG4) impairs HCC cell migration. More importantly, the treatment of HCC cells expressing CD44 (the main PRG4 receptor) with rhPRG4 dramatically enhances the growth-limiting capacity of sorafenib and regorafenib, whereas not significantly affecting cell proliferation per se. Conversely, rhPRG4 only poorly potentiates drug effectiveness on low CD44-expressing or stably CD44-silenced HCC cells. Overall, these data suggest that the physiologically-produced compound PRG4 may function as a novel tumor-suppressive agent by strengthening sorafenib and regorafenib effects in the treatment of HCC.

Download Full-text