scholarly journals Microglia-Derived Olfactomedin-like 3 Promotes Pro-Tumorigenic Microglial Function and Malignant Features of Glioma Cells

2021 ◽  
Vol 22 (23) ◽  
pp. 13052
Author(s):  
Ryan G. Toedebusch ◽  
Christopher A. Lucchesi ◽  
Eshetu T. Debebe ◽  
Luke A. Wittenburg ◽  
Xinbin Chen ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Glioma Cell ◽  
Target Gene ◽  
Transforming Growth Factor ◽  
Migration And Invasion ◽  
Microglial Cell Line ◽  
Direct Target Gene ◽  
Murine Microglia ◽  
Glioma Growth ◽  
Cell Malignancy

Under the influence of transforming growth factor-beta (TGFβ), glioma-associated microglia produce molecules that promote glioma growth and invasion. Olfactomedin-like 3 (Olfml3), a novel, secreted glycoprotein, is known to promote several non-CNS cancers. While it is a direct TGFβ1 target gene in microglia, the role of microglia-derived OLFML3 in glioma progression is unknown. Here, we tested the hypotheses that microglial Olfml3 is integral to the pro-tumorigenic glioma-associated microglia phenotype and promotes glioma cell malignancy. Using an Olfml3 knockout microglial cell line (N9), we demonstrated that Olfml3 is a direct target gene of all TGFβ isoforms in murine microglia. Moreover, loss of Olfml3 attenuated TGFβ-induced restraint on microglial immune function and production of cytokines that are critical in promoting glioma cell malignancy. Importantly, microglia-derived OLFML3 directly contributes to glioma cell malignancy through increased migration and invasion. While exposure to conditioned medium (CM) from isogenic control microglia pre-treated with TGFβ increased mouse glioma cell (GL261) migration and invasion, this effect was abolished with exposure to CM from TGFβ-treated Olfml3-/- microglia. Taken together, our data suggest that Olfml3 may serve as a gatekeeper for TGFβ-induced microglial gene expression, thereby promoting the pro-tumorigenic microglia phenotype and glioma cell malignancy.

Ectopic RASGRP2 (CalDAG-GEFI) expression in rheumatoid synovium contributes to the development of destructive arthritis

2018 ◽  
Vol 77 (12) ◽  
pp. 1765-1772 ◽  
Author(s):  
Hiroyuki Nakamura ◽  
Sanae Shimamura ◽  
Shinsuke Yasuda ◽  
Michihito Kono ◽  
Michihiro Kono ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Therapeutic Target ◽  
Transforming Growth Factor ◽  
Remission Rate ◽  
Bone Destruction ◽  
Type Ii Collagen ◽  
Small Gtpase ◽  
Actin Dynamics ◽  
Migration And Invasion ◽  
Tissue Samples

ObjectivesRheumatoid arthritis (RA) is an autoimmune polyarthritis, in which fibroblast-like synoviocytes (FLS) play a key role in cartilage and bone destruction through tumour-like proliferation and invasiveness. Considering still unsatisfactory remission rate in RA even under treatment with biological disease-modifying antirheumatic drugs, novel therapeutic strategy for treatment-resistant RA is still awaited. In this study, we analysed the expression and function of Ras guanine nucleotide-releasing proteins (RASGRPs), guanine exchange factors for small GTPase Ras, in FLS as a potential therapeutic target for RA.MethodsThe expression of RASGRPs mRNA was quantified by a real-time PCR assay in FLS isolated from synovial tissue samples. RASGRP2 protein was also evaluated immunohistochemically. Then, we transiently transfected FLS with RASGRP2 expression vector and assessed their proliferation, adhesion, migration and invasion by cellular functional assays and downstream signalling activation using immunoblot. Finally, the therapeutic effect of RASGRP2 silencing was evaluated in type-II collagen-induced arthritis rats.ResultsRASGRP2 was abundantly expressed in FLS from RA synovium, whereas scarcely found in those from osteoarthritis. Expression of RASGRP2 in RA-FLS was enhanced by transforming growth factor-beta. RASGRP2 activated RAP-1, subsequently affecting nuclear factor kappa-light-chain-enhancer of activated B cells pathway and actin dynamics in FLS. RASGRP2-overexpressed FLS had increased abilities of adhesion, migration and interleukin (IL)-6 production. Silencing of RASGRP2 using the intra-articular injection of Rasgrp2-specific siRNAs dampened experimental arthritis in rats by inhibiting pannus formation.ConclusionsRASGRP2 was identified to be involved in the pathogenesis of RA by promoting adhesion, migration and IL-6 production from FLS, proposed as a potential novel non-immunosuppressive therapeutic target for RA.

scholarly journals LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer

Cancers ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 260 ◽  
Author(s):  
Qing Zhang ◽  
Xiaonan Hou ◽  
Bradley Evans ◽  
Jamison VanBlaricom ◽  
Saravut Weroha ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Cell Lines ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Migration And Invasion ◽  
Ascites Formation ◽  
Tgf Β1

Transforming growth factor beta (TGF-β) signaling has pleiotropic functions regulating cancer initiation, development, and metastasis, and also plays important roles in the interaction between stromal and cancer cells, making the pathway a potential therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-β receptor I (TGFBRI), was examined for its ability to inhibit ovarian cancer (OC) growth both in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to study the effect of LY treatment on expression of cancer- and fibroblast-derived genes. Results showed that exposure to TGF-β1 induced phosphorylation of SMAD2 and SMAD3 in all tested OC cell lines, but this induction was suppressed by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-β1-induced fibroblast activation was blocked by LY. LY also delayed tumor growth and suppressed ascites formation in vivo. In addition, independent of tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft specimens we confirmed the inhibitory effect of LY on TGF-β signaling and tumor stromal expression of collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations suggest a role for anti-TGF-β signaling-directed therapy in ovarian cancer.

scholarly journals TGFβ1-induced cell motility is mediated through Cten in colorectal cancer

2018 ◽  
Author(s):  
Abdulaziz Asiri ◽  
Teresa Pereira Raposo ◽  
Abdulaziz Alfahed ◽  
Mohammad Ilyas
Keyword(s):  
Colorectal Cancer ◽  
Cell Motility ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Growth Factor Beta ◽  
Emt Markers ◽  
Tgf Β1

ABSTRACTCten is a tensin which promotes epithelial-mesenchymal transition (EMT) and cell motility. The precise mechanisms regulating Cten are unknown, although Cten could be regulated by several cytokines and growth factors. Since Transforming growth factor beta 1 (TGF-β1) regulates integrin function and promotes EMT / cell motility, we investigated whether this happens through Cten signalling in colorectal cancer (CRC).TGF-β1 signalling was modulated by either stimulation or knockdown in the CRC cell lines SW620 and HCT116. The effect of this modulation on expression of Cten, EMT markers and cellular function was tested. Cten role as a direct mediator of TGF-β1 signalling was investigated in a CRC cell line with a deleted Cten gene (SW620ΔCten).When TGF-β1 was stimulated or inhibited, this resulted in, respectively, upregulation and downregulation of Cten expression and EMT markers. Cell migration and invasion were significantly increased following TGF-β1 stimulation and lost by TGF-β1 knockdown. TGF-β1 stimulation in SW620ΔCten resulted in selective loss of the effect of TGF-β1 signalling on EMT and cell motility whilst the stimulatory effect on cell proliferation was retained.These data suggested Cten may play an essential role in mediating TGF-β1-induced EMT and cell motility and may play a role in metastasis in CRC.

scholarly journals Suppression of ANT2 by miR-137 Inhibits Prostate Tumorigenesis

2021 ◽  
Vol 12 ◽  
Author(s):  
Heyuan Zhang ◽  
Nanhui Chen ◽  
Zhihai Deng ◽  
Yang Mai ◽  
Limin Deng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Target Gene ◽  
Inhibitory Effect ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Prostate Tumorigenesis ◽  
Direct Target Gene ◽  
Reporter Assays ◽  
Serious Disease ◽  
Cancer Tissues

Prostate cancer (PCa) is a serious disease that affects men’s health. To date, no effective and long-lasting treatment option for this condition is available in clinical practice. ANT2 is highly expressed in a variety of hormone-related cancers, but its relationship and regulatory mechanism with PCa are unclear. In this study, we found that ANT2 expression was significantly upregulated in PCa tissues relative to control samples. Genetic knockdown of ANT2 effectively inhibited, while overexpression promoted, proliferation, migration, and invasion of PCa cells. In addition, miR-137 expression was reduced in prostate cancer tissues relative to control tissues. We identified a regulatory site for miR-137 in the 3′-UTR of ANT2 mRNA; luciferase reporter assays indicated that ANT2 is a direct target gene for miR-137. Transfecting cells with miR-137 mimics and/or an ANT2-encoding plasmid revealed that ANT2 promotes proliferation, migration, and invasion of PCa, whereas co-expression of miR-137 mimics inhibited these behaviors. These observations suggest that miR-137 mimics inhibit development of PCa by antagonizing expression of ANT2. Furthermore, tumorigenic assays in nude mice showed that miR-137 inhibitors abolished the inhibitory effect of ANT2 knockdown on PCa tumor growth. Collectively, our findings suggest that ANT2, a target gene of miR-137, is intimately involved in development of PCa, providing new evidence for the mechanism underlying pathogenesis of PCa as well as new options for targeted therapy.

Fucoidan suppresses the gastric cancer cell malignant phenotype and production of TGF-β1 via CLEC-2

Glycobiology ◽  
2019 ◽  
Vol 30 (5) ◽  
pp. 301-311 ◽  
Author(s):  
Ling Xu ◽  
Fenglin Liu ◽  
Can Li ◽  
Shuxuan Li ◽  
Hao Wu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Transcription Factor ◽  
Gastric Carcinoma ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Inhibitory Effect ◽  
Sulfated Polysaccharide ◽  
Migration And Invasion ◽  
Malignant Phenotype ◽  
Tgf Β1

Abstract The sulfated polysaccharide fucoidan displays excellent anticancer properties with low toxicity in many kinds of cancers. However, its detailed pharmacological effect and mechanism of action in gastric carcinoma remains unclear. In this study, we found that fucoidan could suppress gastric cancer (GC) cell growth, as well as cell migration and invasion. A cytokine expression screen demonstrated that transforming growth factor beta 1 (TGF-β1) secretion was decreased in fucoidan-treated cells. Fucoidan has been reported to be a platelet agonist for the C-type lectin-like receptor 2 (CLEC-2), and our previous research found that upregulation of CLEC-2 inhibited GC progression. Here, we confirmed that fucoidan, combined with CLEC-2, significantly increased CLEC-2 expression in GC cells via the transcription factor caudal type homeobox transcription factor 2, an important regulator of gut homeostasis. In addition, the inhibitory effect of fucoidan on the GC cell malignant phenotype and TGF-β1 secretion could be restored by knocking down CLEC-2. Thus, our data suggest that fucoidan targets CLEC-2 to exert antitumorigenesis and antimetastatic activity, suggesting that fucoidan is a promising treatment for gastric carcinoma.

scholarly journals ppGalNAc-T4-catalyzed O-Glycosylation of TGF-β type Ⅱ receptor regulates breast cancer cells metastasis

2020 ◽  
pp. jbc.RA120.016345
Author(s):  
Qiong Wu ◽  
Cheng Zhang ◽  
Keren Zhang ◽  
Qiushi Chen ◽  
Sijin Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Transforming Growth Factor Beta ◽  
Breast Cancer Cells ◽  
Transforming Growth Factor ◽  
Migration And Invasion ◽  
Breast Cancer Cell Lines ◽  
Mesenchymal Transition

GalNAc-type O-glycosylation, initially catalyzed by polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts), is one of the most abundant and complex post-translational modifications of proteins. Emerging evidence has proven that aberrant ppGalNAc-Ts are involved in malignant tumor transformation. However, the exact molecular functions of ppGalNAc-Ts are still unclear. Here, the role of one isoform, ppGalNAc-T4, in breast cancer cell lines was investigated. The expression of ppGalNAc-T4 was found to be negatively associated with migration of breast cancer cells. Loss-of function studies revealed that ppGalNAc-T4 attenuated the migration and invasion of breast cancer cells by inhibiting the epithelial-mesenchymal transition (EMT) process. Correspondingly, transforming growth factor beta (TGF-β) signaling, which is the upstream pathway of EMT, was impaired by ppGalNAc-T4 expression. ppGalNAc-T4 knock-out decreased O-GalNAc modification of TGF-β type Ⅰ and Ⅱ receptor (TβR Ⅰ and Ⅱ) and led to the elevation of TGF-β receptor dimerization and activity. Importantly, a peptide from TβR Ⅱ was first identified as the naked peptide substrate of ppGalNAc-T4 with a higher affinity than ppGalNAc-T2. Further, Ser31, corresponding to the extracellular domain of TβR Ⅱ, was identified as the O-GalNAcylation site upon in vitro glycosylation by ppGalNAc-T4. The O-GalNAc-deficient S31A mutation enhanced TGF-β signaling activity and EMT in breast cancer cells. Together, these results identified a novel mechanism of ppGalNAc-T4-catalyzed TGF-β receptors O-GalNAcylation that suppresses breast cancer cell migration and invasion via the EMT process. Targeting ppGalNAc-T4 may be a potential therapeutic strategy for breast cancer treatment.

scholarly journals Long non-coding RNA linc00645 promotes TGF-β-induced epithelial–mesenchymal transition by regulating miR-205-3p-ZEB1 axis in glioma

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Chenlong Li ◽  
Hongshan Zheng ◽  
Weiliang Hou ◽  
Hongbo Bao ◽  
Jinsheng Xiong ◽  
...  
Keyword(s):  
Cell Lines ◽  
Glioma Cell ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Glioma Cells ◽  
Vital Role ◽  
Migration And Invasion ◽  
Poor Overall Survival ◽  
Mesenchymal Transition

Abstract Accumulating evidence indicates long noncoding RNAs (lncRNA) play a vital role in tumor progression. However, the role of linc00645-induced accelerated malignant behavior in glioblastoma (GBM) remains unknown. In the present study, linc00645 expression was significantly upregulated in GBM tissues and cell lines. High level of linc00645 was associated with poor overall survival in GBM patients. Knockdown of linc00645 suppressed the proliferation, stemness, migration, invasion, and reversed transforming growth factor (TGF)-β-induced motility of glioma cell lines. Furthermore, linc00645 directly interacted with miR-205-3p and upregulated of miR-205-3p impeded efficiently the increase of ZEB1 induced by linc00645 overexpression. Moreover, knockdown of linc00645 significantly suppressed the progression of glioma cells in vivo. miR-205-3p was a target of linc00645 and linc00645 modulates TGF-β-induced glioma cell migration and invasion via miR-205-3p. Taken together, our findings identified the linc00645/miR-205-3p/ZEB1 signaling axis as a key player in EMT of glioma cells triggered by TGF-β. These data elucidated that linc00645 plays an oncogenic role in glioma and it may serve as a prognostic biomarker and a potential therapeutic target for the treatment of glioma in humans.

scholarly journals BORIS/CTCFL promotes a switch from a proliferative towards an invasive phenotype in melanoma cells

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Sanne Marlijn Janssen ◽  
Roy Moscona ◽  
Mounib Elchebly ◽  
Andreas Ioannis Papadakis ◽  
Margaret Redpath ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Melanoma Cells ◽  
Migration And Invasion ◽  
State Transitions ◽  
Transcriptional Reprogramming ◽  
Binding Factor ◽  
Transcriptional Switch ◽  
Phenotype Switching ◽  
Whole Transcriptome Analysis

AbstractMelanoma is among the most aggressive cancers due to its tendency to metastasize early. Phenotype switching between a proliferative and an invasive state has been suggested as a critical process for metastasis, though the mechanisms that regulate state transitions are complex and remain poorly understood. Brother of Regulator of Imprinted Sites (BORIS), also known as CCCTC binding factor-Like (CTCFL), is a transcriptional modulator that becomes aberrantly expressed in melanoma. Yet, the role of BORIS in melanoma remains elusive. Here, we show that BORIS is involved in melanoma phenotype switching. Genetic modification of BORIS expression in melanoma cells combined with whole-transcriptome analysis indicated that BORIS expression contributes to an invasion-associated transcriptome. In line with these findings, inducible BORIS overexpression in melanoma cells reduced proliferation and increased migration and invasion, demonstrating that the transcriptional switch is accompanied by a phenotypic switch. Mechanistically, we reveal that BORIS binds near the promoter of transforming growth factor-beta 1 (TFGB1), a well-recognized factor involved in the transition towards an invasive state, which coincided with increased expression of TGFB1. Overall, our study indicates a pro-invasive role for BORIS in melanoma via transcriptional reprogramming.

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