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Cancer-associated fibroblast-derived SDF-1 induces epithelial-mesenchymal transition of lung adenocarcinoma via CXCR4/?-catenin/PPAR? signalling.

ABSTRACT: Cancer-associated fibroblasts (CAFs) contribute to tumour epithelial-mesenchymal transition (EMT) via interaction with cancer cells. However, the molecular mechanisms underlying tumour-promoting EMT of CAFs in lung adenocarcinoma (ADC) remain unclear. Here, we observed that CAFs isolated from lung ADC promoted EMT via production of stromal cell-derived factor-1 (SDF-1) in conditioned medium (CM). CAF-derived SDF-1 enhanced invasiveness and EMT by upregulating CXCR4, ?-catenin, and PPAR?, while downregulating these proteins reversed the effect. Furthermore, RNAi-mediated CXCR4 knockdown suppressed ?-catenin and PPAR? expression, while ?-catenin inhibition effectively downregulated PPAR? without affecting CXCR4; however, treatment with a PPAR? inhibitor did not inhibit CXCR4 or ?-catenin expression. Additionally, pairwise analysis revealed that high expression of CXCR4, ?-catenin, and PPAR? correlated positively with 75 human lung adenocarcinoma tissues, which was predictive of poor prognosis. Thus, targeting the CAF-derived, SDF-1-mediated CXCR4 ?-catenin/ PPAR? cascade may serve as an effective targeted approach for lung cancer treatment.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7910618 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Cancer-associated fibroblast-derived SDF-1 induces epithelial-mesenchymal transition of lung adenocarcinoma via CXCR4/β-catenin/PPARδ signalling.

Wang Yingyan Y Lan Wen W Xu Mingxin M Song Jing J Mao Jun J Li Chunyan C Du Xiaohui X Jiang Yunling Y Li Encheng E Zhang Rui R Wang Qi Q

Cell death & disease 20210226 2

Cancer-associated fibroblasts (CAFs) contribute to tumour epithelial-mesenchymal transition (EMT) via interaction with cancer cells. However, the molecular mechanisms underlying tumour-promoting EMT of CAFs in lung adenocarcinoma (ADC) remain unclear. Here, we observed that CAFs isolated from lung ADC promoted EMT via production of stromal cell-derived factor-1 (SDF-1) in conditioned medium (CM). CAF-derived SDF-1 enhanced invasiveness and EMT by upregulating CXCR4, β-catenin, and PPARδ, while d ...[more]

PMID: 33637678

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Project description:Epithelial‑mesenchymal transition (EMT) has been demonstrated to serve a crucial role in the progression of interstitial fibrosis, which is one of the principal pathological features of chronic allograft nephropathy (CAN). However, to the best of our knowledge, the mechanisms of EMT in CAN have not been investigated. In the present study, the effect of stromal cell‑derived factor 1 (SDF‑1) and the Wnt signaling pathway on the progression of EMT following kidney transplantation was investigated. The CAN model was established using Fisher 344 and Lewis rats, treated with low‑dose cyclosporine with or without AMD3100. CAN was confirmed by the pathological alterations and chronic allograft damage index scoring, and EMT was confirmed by western blotting and reverse transcription‑quantitative polymerase chain reaction. In the AMD3100 group, there were lower expression levels of α‑SMA and higher expression levels of E‑cadherin, which indicated that CAN and EMT were ameliorated by AMD3100. The kidney tissue was analyzed using an mRNA + long noncoding (lnc)RNA microarray. A total of 506 mRNAs and 404 lncRNAs were demonstrated to be significantly differentially expressed between the two groups, which revealed the involvement of SDF‑1/CXC chemokine receptor 4 (CXCR4) and the Wnt pathway. SDF‑1 was demonstrated to induce EMT in vitro through the upregulation of α‑SMA, downregulation of E‑cadherin and the wound healing assay, and in the rat renal tubular epithelial cells via the nuclear accumulation of β‑catenin, which were all inhibited by either AMD3100 or DKK‑1. CXXC finger protein 5 (CXXC5), a negative regulator of the Wnt pathway, was downregulated following treatment with SDF‑1, which was inhibited by AMD3100 but not by DKK‑1. Thus, CXXC5 may be a regulator downstream of SDF‑1/CXCR4 in EMT. In conclusion, SDF‑1/CXCR4 induces EMT of renal tubular epithelial cells with the involvement of the Wnt pathway, which may be a novel mechanism and therapeutic target in kidney allograft fibrosis of rats.

Project description:BackgroundLung cancer is the most common and lethal malignancy worldwide. TCTP is highly expressed in various cancers including lung cancer. Epithelial-mesenchymal transition (EMT) could increase cancer cell invasion. Whether TCTP's expression is associated with EMT in lung adenocarcinoma is largely unknown.MethodsSeveral Gene Expression Omnibus datasets were used to analyze the correlation between TCTP expression and overall survival of lung adenocarcinoma patients by Kaplan-Meier survival analysis. Then, 24 surgically removed fresh lung adenocarcinoma tissue samples and paired paracancer tissue samples were used to analyze the correlation between TCTP expression and tumor stage by immunohistochemical analysis. Furthermore, stable cell lines were generated using lentiviral transduction systems to knock down or overexpress TCTP in A549 cells. Cell migration and invasion were measured by scratch and transwell assays, and EMT marker proteins such as α-SMA, ZEB1, and E-cadherin were quantitated by Western blot. The expression levels of miR-200a, miR-141, and miR-429 were determined by real-time quantitative PCR, and their target genes were predicted by an online database miRTarBase. The interaction between TCTP and these genes was analyzed by String database and visualized by Cytoscape.ResultsTCTP was highly expressed in tumor tissues compared to paracancer tissues. The expression of TCTP was associated with shorter overall survival. TCTP knockdown experiment in A549 cells suggested that TCTP knockdown could decrease the migration and invasion of lung cancer cells, and the expression level of ZEB1 and α-SMA, but increase the expression of E-cadherin and p53. Vice versa, overexpression of TCTP could increase the migration and invasion of cancer cells, and the expression level of ZEB1 and α-SMA, but decrease the expression of E-cadherin and p53. Furthermore, we found the expression of miR-200a, miR-141, and miR-429 was associated with TCTP expression.ConclusionTCTP promotes EMT in lung adenocarcinoma, and this effect may be associated with miR-200 family members like miR-200a, miR-141, and miR-429.

Project description:Lung cancer is a malignant tumor responsible for the highest mortality rate in humans. The identification of novel functional genes is of great importance in the treatment of lung cancer. The reported roles of replication factor C subunit 3 (RFC3) in tumorigenesis are contradictory. The present study aimed to explore the role and mechanism of RFC3 in lung cancer cells. An immunohistochemical study of 165 lung cancer and adjacent tissues was conducted (123 lung adenocarcinoma tissues and 42 lung squamous cell carcinoma tissues). Kaplan‑Meier analysis and Cox multivariate analysis were employed to explore the relationship between RFC3 and patient prognosis. In addition, the proliferation, cell cycle distribution and apoptosis of A549 and H1299 cells were determined by MTT assay and flow cytometry, respectively, following cell transfection to induce overexpression and knockdown of RFC3. A Boyden chamber assay and wound‑healing assay were conducted to determine the invasive and migratory abilities of A549 and H1299 cells. Western blotting was used to analyze the effects of RFC3 overexpression and RFC3 small interfering RNA‑induced knockdown, and to explore the potential mechanism and pathway underlying the effects of RFC3. Positive expression of RFC3 was detected in lung adenocarcinoma, and overexpression of RFC3 shortened the survival time of patients with lung adenocarcinoma. Furthermore, overexpression of RFC3 increased the invasion and migration of A549 cells, whereas knockdown of RFC3 significantly reduced the invasion and migration of H1299 cells. Ectopic expression of RFC3 induced epithelial‑mesenchymal transition (EMT), as determined by downregulation of E‑cadherin, and upregulation of N‑cadherin, vimentin and Wnt signaling target genes, including c‑MYC, Wnt1 and β‑catenin, and the ratio of phosphorylated‑glycogen synthase kinase 3 (GSK3)‑β (Ser9)/GSK3‑β. In conclusion, RFC3 may be considered a coactivator that promotes the Wnt/β‑catenin signaling pathway, and induces EMT and metastasis in lung adenocarcinoma.

Dataset Information

Cancer-associated fibroblast-derived SDF-1 induces epithelial-mesenchymal transition of lung adenocarcinoma via CXCR4/?-catenin/PPAR? signalling.

Publications

Cancer-associated fibroblast-derived SDF-1 induces epithelial-mesenchymal transition of lung adenocarcinoma via CXCR4/β-catenin/PPARδ signalling.

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