GDF15 knockdown suppresses cervical cancer cell migration <i>in vitro</i> through the TGF‐β/Smad2/3/Snail1 pathway

Li, Li; Zhang, Ruihong; Yang, Hailei; Zhang, Donghua; Liu, Jiwei; Li, Jinfang; Guo, Bin

doi:10.1002/2211-5463.13013

Cited by 21 publications

(14 citation statements)

References 26 publications

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“…GFs actively act in the pathogenesis of cervical cancer. Notably, these GFs are correlated to proliferation, aggression, and migration [ 23 , 24 , 25 ]. Therefore, these GFs could also be used to monitor metastasis, assess survival, and identify potential drug targets as clinical biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Immunogenomic Identification for Predicting the Prognosis of Cervical Cancer Patients

Wang

Vattai

Vilsmaier

et al. 2021

IJMS

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Cervical cancer is primarily caused by the infection of high-risk human papillomavirus (hrHPV). Moreover, tumor immune microenvironment plays a significant role in the tumorigenesis of cervical cancer. Therefore, it is necessary to comprehensively identify predictive biomarkers from immunogenomics associated with cervical cancer prognosis. The Cancer Genome Atlas (TCGA) public database has stored abundant sequencing or microarray data, and clinical data, offering a feasible and reliable approach for this study. In the present study, gene profile and clinical data were downloaded from TCGA, and the Immunology Database and Analysis Portal (ImmPort) database. Wilcoxon-test was used to compare the difference in gene expression. Univariate analysis was adopted to identify immune-related genes (IRGs) and transcription factors (TFs) correlated with survival. A prognostic prediction model was established by multivariate cox analysis. The regulatory network was constructed and visualized by correlation analysis and Cytoscape, respectively. Gene functional enrichment analysis was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). A total of 204 differentially expressed IRGs were identified, and 22 of them were significantly associated with the survival of cervical cancer. These 22 IRGs were actively involved in the JAK-STAT pathway. A prognostic model based on 10 IRGs (APOD, TFRC, GRN, CSK, HDAC1, NFATC4, BMP6, IL17RD, IL3RA, and LEPR) performed moderately and steadily in squamous cell carcinoma (SCC) patients with FIGO stage I, regardless of the age and grade. Taken together, a risk score model consisting of 10 novel genes capable of predicting survival in SCC patients was identified. Moreover, the regulatory network of IRGs associated with survival (SIRGs) and their TFs provided potential molecular targets.

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Section: Discussionmentioning

confidence: 99%

Immunogenomic Identification for Predicting the Prognosis of Cervical Cancer Patients

Wang

Vattai

Vilsmaier

et al. 2021

IJMS

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“…The expression of GFRAL is brain restricted, and we (data not shown) as well as others failed to show any expression of GFRAL in the lung or other organs, except testis, spleen, and thymus ( 23 , 34 ). Thus, GFRAL-triggered signaling cannot explain all of GDF15-mediated effects reported by us and others in the context of lung fibrosis ( 23 , 34 ), cancer progression ( 69 , 70 ), or cardiac disease ( 65 ), as was also recently reviewed by Wischhusen et al ( 71 ). The crystal structure of GDF15, forming a homodimer stabilized by an interchain disulfide bond, as all other TGF-β family members, suggests that some type of TGF-β receptor signaling could be involved or triggered by this cytokine ( 72 ).…”

Section: Discussionmentioning

confidence: 57%

“…Similar effects were described for TGF-β1, which (after long-term incubation) was inducing colonic lamina propria fibroblasts into myofibroblasts with enhanced αSMA expression and reduced migratory potential ( 74 ). GDF15 was previously associated with increased migration of cancer cells ( 70 , 75 , 76 ) and endothelial cells ( 77 ), but to date, there is no existing evidence of its direct impact on fibroblast migration. It might trigger different effects, depending on the cell type and experimental conditions.…”

Section: Discussionmentioning

confidence: 99%

Increased expression and accumulation of GDF15 in IPF extracellular matrix contribute to fibrosis

Radwańska¹,

Cottage²,

Piras³

et al. 2022

JCI Insight

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Idiopathic pulmonary fibrosis (IPF) is a chronic disease of unmet medical need. It is characterized by formation of scar tissue leading to a progressive and irreversible decline in lung function. IPF is associated with repeated injury, which may alter the composition of the extracellular matrix (ECM). Here, we demonstrate that IPF patient–derived pulmonary ECM drives profibrotic response in normal human lung fibroblasts (NHLF) in a 3D spheroid assay. Next, we reveal distinct alterations in composition of the diseased ECM, identifying potentially novel associations with IPF. Growth differentiation factor 15 (GDF15) was identified among the most significantly upregulated proteins in the IPF lung–derived ECM. In vivo, GDF15 neutralization in a bleomycin-induced lung fibrosis model led to significantly less fibrosis. In vitro, recombinant GDF15 (rGDF15) stimulated α smooth muscle actin (αSMA) expression in NHLF, and this was mediated by the activin receptor-like kinase 5 (ALK5) receptor. Furthermore, in the presence of rGDF15, the migration of NHLF in collagen gel was reduced. In addition, we observed a cell type–dependent effect of GDF15 on the expression of cell senescence markers. Our data suggest that GDF15 mediates lung fibrosis through fibroblast activation and differentiation, implicating a potential direct role of this matrix-associated cytokine in promoting aberrant cell responses in disease.

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“…In present study, our IH staining verified that TGF-β1 signaling pathway was remarkably suppressed not only in BRONJ patients’ gingiva but in BRONJ GMSCs transplantation animal model. TGF-β1 is a pleiotropic cytokine with a crucial role in mediating the differentiation and proliferation of GMSCs and regulating the epithelial-to-mesenchymal transition during wound healing [ 43 , 44 ], and Smad3 was identified as the downstream TGF-β1 effector [ 45 , 46 ]. In addition, TGF-β1 signaling pathway plays an important role in fibrosis, briefly, TGF-β1 binding to TGF-β receptor leads to the phosphorylation of Smad2 and Smad3, and phosphorylated Smad2 and Smad3 subsequently form a complex, which translocates to the nucleus and interacts with nuclear transcription factors, where they regulate the transcription of specific fibrosis-related genes [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Characterization of Mesenchymal Stem Cells Derived from Bisphosphonate-Related Osteonecrosis of the Jaw Patients’ Gingiva

Wang

et al. 2021

Stem Cell Rev and Rep

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Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a clinical condition that specifically occurs in the oral cavity, characterized by retarded wound healing in oral mucosa accelerating the exposure of bone. Moreover, the pathological mechanism remains poorly understood. Gingival mesenchymal stem cells (GMSCs) play a critical role in gingival healing and soft tissue regeneration. Although previous studies have showed that bisphosphonates (BPs) are highly toxic to healthy GMSC, there is overall lack of direct evidence demonstrating the characterization of GMSCs derived from BRONJ patients. In present study, we isolated GMSCs for the first time from the central area of BRONJ patients’ gingiva (center-BRONJ GMSCs) and the peripheral area (peri-BRONJ GMSCs), and found that they exhibited decreased proliferation, adhesion, migration capacities and underwent early apoptosis in vitro compared control GMSCs. Notably, the central and peripheral BRONJ GMSCs transplantation in a mice excisional skin model also displayed lower cell survival rate and poor healing effects than that of controls. Mechanistically, TGF-β1 signaling pathway was suppressed not only in BRONJ patients’ gingival lesions but also in BRONJ GMSCs transplantation animal model. The results above suggested that under the microenvironment of BRONJ patients, the dysfunction of GMSCs and the suppressed TGF-β1 signaling pathway may be the vital factors in impaired gingival healing, thus contributing to persistent exposure of underlying bone and development of BRONJ. This study provides new insights into the prevention for BRONJ by improving the functions of GMSCs and upregulating TGF-β1 in accelerating gingival wound healing. Graphical Abstract Schematic illustration of the dysfunction of BRONJ GMSCs in vitro and BRONJ GMSCs transplantation in a mice skin model delaying cutaneous wound healing mainly via suppressing TGF-β1 signaling pathway.

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GDF15 knockdown suppresses cervical cancer cell migration in vitro through the TGF‐β/Smad2/3/Snail1 pathway

Cited by 21 publications

References 26 publications

Immunogenomic Identification for Predicting the Prognosis of Cervical Cancer Patients

Immunogenomic Identification for Predicting the Prognosis of Cervical Cancer Patients

Increased expression and accumulation of GDF15 in IPF extracellular matrix contribute to fibrosis

Characterization of Mesenchymal Stem Cells Derived from Bisphosphonate-Related Osteonecrosis of the Jaw Patients’ Gingiva

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