scholarly journals Snail/FOXK1/Cyr61 Signaling Axis Regulates the Epithelial–Mesenchymal Transition and Metastasis in Colorectal Cancer

2018 ◽  
Vol 47 (2) ◽  
pp. 590-603 ◽  
Author(s):  
Xiaoting Huang ◽  
Li Xiang ◽  
Yueqiao Li ◽  
Yingying Zhao ◽  
Huiqiong Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Expression Patterns ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Signaling Axis

Background/Aims: Metastasis is the primary cause of colorectal cancer (CRC)-related death. However, the molecular mechanisms underlying metastasis in CRC remain unclear. Methods: We evaluated mRNA and protein expression levels by quantitative real-time reverse transcription PCR, western blotting, immunofluorescence, tissue microarrays, and immunohistochemistry assays. We also assessed the migration and invasion abilities of CRC cells in vitro by wound healing assays, invasion and migration assays, western blot analysis, and immunofluorescence. Tumor metastasis was evaluated in nude mice in vivo. Results: A positive correlation was observed between the expression patterns of Forkhead box k1 (FOXK1) and Snail in CRC. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that Snail directly bound to and activated the human FOXK1 gene promoter. Moreover, the Snail-FOXK1 axis promote epithelial mesenchymal transition (EMT)-mediated CRC cell invasion and metastasis. FOXK1 and Snail expression levels were correlated with tumor progression and served as significant predictors of overall survival in patients with CRC. Furthermore, overexpression of FOXK1 induced the EMT by upregulating the expression of cysteine-rich angiogenic inducer 61 (Cyr61). Luciferase assays showed that Cyr61 was a direct transcriptional target of FOXK1. Down regulation of Cyr61 decreased FOXK1-enhanced “CRC cell” migration, invasion, and metastasis. Additionally, FOXK1 expression was positively correlated with Cyr61 expression and was associated with poor prognosis. Conclusions: The Snail/FOXK1/Cyr61 signaling axis regulates the EMT and metastasis of CRC.

scholarly journals Circular RNA hsa_circ_0000277 sequesters miR-4766-5p to upregulate LAMA1 and promote esophageal carcinoma progression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Peng Li Zhou ◽  
Zhengyang Wu ◽  
Wenguang Zhang ◽  
Miao Xu ◽  
Jianzhuang Ren ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Bioinformatics Analysis ◽  
Epithelial Mesenchymal Transition ◽  
Expression Profiles ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Mesenchymal Transition ◽  
Dismal Prognosis ◽  
Advanced Tumor

AbstractGrowing evidence has indicated that circular RNAs (circRNAs) play a pivotal role as functional RNAs in diverse cancers. However, most circRNAs involved in esophageal squamous cell carcinoma (ESCC) remain undefined, and the underlying molecular mechanisms mediated by circRNAs are largely unclear. Here, we screened human circRNA expression profiles in ESCC tissues and found significantly increased expression of hsa_circ_0000277 (termed circPDE3B) in ESCC tissues and cell lines compared to the normal controls. Moreover, higher circPDE3B expression in patients with ESCC was correlated with advanced tumor-node-metastasis (TNM) stage and dismal prognosis. Functional experiments demonstrated that circPDE3B promoted the tumorigenesis and metastasis of ESCC cells in vitro and in vivo. Mechanistically, bioinformatics analysis, a dual-luciferase reporter assay, and anti-AGO2 RNA immunoprecipitation showed that circPDE3B could act as a competing endogenous RNA (ceRNA) by harboring miR-4766-5p to eliminate the inhibitory effect on the target gene laminin α1 (LAMA1). In addition, LAMA1 was significantly upregulated in ESCC tissues and was positively associated with the aggressive oncogenic phenotype. More importantly, rescue experiments revealed that the oncogenic role of circPDE3B in ESCC is partly dependent on the miR-4766-5p/LAMA1 axis. Furthermore, bioinformatics analysis combined with validation experiments showed that epithelial-mesenchymal transition (EMT) activation was involved in the oncogenic functions of the circPDE3B–miR-4766-5p/LAMA1 axis in ESCC. Taken together, we demonstrate for the first time that the circPDE3B/miR-4766-5p/LAMA1 axis functions as an oncogenic factor in promoting ESCC cell proliferation, migration, and invasion by inducing EMT, implying its potential prognostic and therapeutic significance in ESCC.

scholarly journals SPNS2 Downregulation Induces EMT and Promotes Colorectal Cancer Metastasis via Activating AKT Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Lei Lv ◽  
Qiyi Yi ◽  
Ying Yan ◽  
Fengmei Chao ◽  
Ming Li
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
Akt Inhibitor ◽  
Colon Adenoma ◽  
Mesenchymal Transition

Spinster homologue 2 (SPNS2), a transporter of S1P (sphingosine-1-phosphate), has been reported to mediate immune response, vascular development, and pathologic processes of diseases such as cancer via S1P signaling pathways. However, its biological functions and expression profile in colorectal cancer (CRC) is elusive. In this study, we disclosed that SPNS2 expression, which was regulated by copy number variation and DNA methylation of its promoter, was dramatically upregulated in colon adenoma and CRC compared to normal tissues. However, its expression was lower in CRC than in colon adenoma, and low expression of SPN2 correlated with advanced T/M/N stage and poor prognosis in CRC. Ectopic expression of SPNS2 inhibited cell proliferation, migration, epithelial–mesenchymal transition (EMT), invasion, and metastasis in CRC cell lines, while silencing SPNS2 had the opposite effects. Meanwhile, measuring the intracellular and extracellular level of S1P after overexpression of SPNS2 pinpointed a S1P-independent model of SPNS2. Mechanically, SPNS2 led to PTEN upregulation and inactivation of Akt. Moreover, AKT inhibitor (MK2206) abrogated SPNS2 knockdown-induced promoting effects on the migration and invasion, while AKT activator (SC79) reversed the repression of migration and invasion by SPNS2 overexpression in CRC cells, confirming the pivotal role of AKT for SPNS2’s function. Collectively, our study demonstrated the suppressor role of SPNS2 during CRC metastasis, providing new insights into the pathology and molecular mechanisms of CRC progression.

SETD1A to induce epithelial-mesenchymal transition to promote invasion and metastasis through epigenetic reprogramming of snail in gastric cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 241-241
Author(s):  
Jugang Wu ◽  
Jiwei Yu ◽  
Yan Gu
Keyword(s):  
Gastric Cancer ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Epigenetic Modification ◽  
Epigenetic Reprogramming ◽  
Migration And Invasion ◽  
Mrna Levels ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
E Cadherin

241 Background: Aberrant epigenetic modification induces oncogenes expression and promotes cancer development. The histone lysine methyltransferase SETD1A, which specifically methylates H3K4, is involved in tumor growth and metastasis, and its ectopic expression has been detected in aggressive malignancies. Our previous study had reported that SETD1A promoted gastric cancer (GC) proliferation and tumorigenesis. However, the function and molecular mechanisms of SETD1A in GC metastasis remain to be elucidated. Methods: Transwell migration and invasion assay were performed to determine GC cell migration and invasion. Lung metastasis assay was used to detect GC cell metastasis. Western Blot and Real-time qPCR were performed to measure the protein and mRNA levels, respectively. ChIP assay was performed to investigate the methylation of H3K4. The correlation between SETD1A and EMT associated key genes in GC were performed by bioinformatic analysis. Results: In this study, we found that overexpression of SETD1A promotes GC migration and invasion, whereas knockdown of SETD1A suppressed GC migration, invasion and metastasis. Furthermore, knockdown of SETD1A suppressed GC epithelial-mesenchymal transition (EMT) by increasing the expression of epithelial marker E-cadherin, and decreasing the expression of mesenchymal markers, including N-cadherin, Fibronectin and Vimentin. Mechanistically, knockdown of SETD1A reduced the EMT key transcriptional factors snail. SETD1A was recruited to the promoter of snail, where SETD1A could methylate H3K4. However, knockdown of SETD1A decreased the methylation of H3K4 on snail promoter. Rescue of snail restored SETD1A knockdown-induced GC migration and invasion inhibition. In addition, linear correlation between SETD1A and several key EMT genes, including E-cadherin, Fibronectin and snail, in GC specimens obtained from TCGA dataset. Conclusions: In summary, our data reveals that SETD1A mediated EMT process and induced metastasis through epigenetic reprogramming of snail.

scholarly journals miR-125b Promotes Colorectal Cancer Migration and Invasion by Dual-Targeting CFTR and CGN

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5710
Author(s):  
Xiaohui Zhang ◽  
Tingyu Li ◽  
Ya-Nan Han ◽  
Minghui Ge ◽  
Pei Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Rho Kinase ◽  
Causative Factor ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Metastasis contributes to the poor prognosis of colorectal cancer, the causative factor of which is not fully understood. Previously, we found that miR-125b (Accession number: MIMAT0000423) contributed to cetuximab resistance in colorectal cancer (CRC). In this study, we identified a novel mechanism by which miR-125b enhances metastasis by targeting cystic fibrosis transmembrane conductance regulator (CFTR) and the tight junction-associated adaptor cingulin (CGN) in CRC. We found that miR-125b expression was upregulated in primary CRC tumors and metastatic sites compared with adjacent normal tissues. Overexpression of miR-125b in CRC cells enhanced migration capacity, while knockdown of miR-125b decreased migration and invasion. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays identified CFTR and CGN as the target genes of miR-125b, and the inhibitory impact of CFTR and CGN on metastasis was further verified both in vitro and in vivo. Moreover, we found that miR-125b facilitated the epithelial-mesenchymal transition (EMT) process and the expression and secretion of urokinase plasminogen activator (uPA) by targeting CFTR and enhanced the Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) pathway activity by targeting CGN. Together, these findings suggest miR-125b as a key functional molecule in CRC and a promising biomarker for the diagnosis and treatment of CRC.

scholarly journals BTG1 Overexpression Might Promote Invasion and Metastasis of Colorectal Cancer via Decreasing Adhesion and Inducing Epithelial–Mesenchymal Transition

2020 ◽  
Vol 10 ◽  
Author(s):  
Shuang Zhao ◽  
Hang Xue ◽  
Chang-lai Hao ◽  
Hua-mao Jiang ◽  
Hua-chuan Zheng
Keyword(s):  
Colorectal Cancer ◽  
Mrna Expression ◽  
Cancer Patients ◽  
Epithelial Mesenchymal Transition ◽  
Tnm Staging ◽  
Clinicopathological Parameters ◽  
Migration And Invasion ◽  
Depth Of Invasion ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition

BTG (B-cell translocation gene) could inhibit cell proliferation, metastasis, and angiogenesis and regulate cell cycle progression and differentiation in a variety of cancer cell types. To clarify the role of BTG1 in invasion and metastasis, its expression was compared with the clinicopathological parameters of colorectal cancer by bioinformatics and immunohistochemical analyses. We also overexpressed BTG1 in HCT-15 cells and examined its effects on adhesion, migration, and metastasis with their related molecules screened. BTG1 mRNA expression was negatively correlated with its promoter methylation in colorectal cancer (P < 0.05). Among them, cg08832851 and cg05819371 hypermethylation and mRNA expression of BTG1 were positively related with poor prognosis of the colorectal cancer patients (P < 0.05). BTG1 expression was found to positively correlate with depth of invasion, venous invasion, lymph node metastasis, distant metastasis, and TNM staging of colorectal cancer (P < 0.05) but negatively with serum levels of CEA and CA19-9 (P < 0.05). According to the TCGA database, BTG1 mRNA expression was lower in well-, moderately, and poorly differentiated than mucinous adenocarcinomas and positively correlated with ras or BRAF mutation (P < 0.05). Kaplan–Meier analysis showed the negative correlation between BTG1 mRNA expression and overall survival rate of all cancer patients (P < 0.05). BTG1 overexpression weakened adhesion and strengthened migration and invasion of HCT-15 cells (P < 0.05). There was E-cadherin hypoexpression, N-cadherin and MMP-9 hyperexpression, Zeb1 and Vimentin mRNA overexpression, a high expression of CEA mRNA and protein, and a strong secretion of CEA in BTG1 transfectants, compared with the control or mock. It was suggested that BTG1 expression might promote invasion and metastasis by decreasing adhesion, and inducing epithelial–mesenchymal transition.

scholarly journals lncRNA LINC00460 Functions as a Competing Endogenous RNA and Regulates Expression of BGN by Sponging miR-149-5p in Colorectal Cancer

2021 ◽  
Vol 20 ◽  
pp. 153303382096423
Author(s):  
Tingyan Ruan ◽  
Shourong Lu ◽  
Junying Xu ◽  
Ju-Ying Zhou
Keyword(s):  
Colorectal Cancer ◽  
Tumor Metastasis ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Binding Interaction ◽  
Expression Levels ◽  
Cancer Tissues

Background and Aim: There are an increasing number of studies indicating the important roles served by long non-coding RNAs (lncRNAs) in the development of different types of cancer. LINC00460 is a novel identified lncRNA that was found to be upregulated in colorectal cancer. However, the biological roles of LINC00460 in colorectal cancer have yet to be fully elucidated. This study was aimed to investigate the functions and molecular mechanisms of LINC00460 on colorectal cancer metastasis. Methods: Expression of LINC00460 and biglycan (BGN) in colorectal cancer tissues and cell lines were quantified by real time PCR or western blotting assay. Cell migration and invasion assays were performed to determine the effect of LINC00460 on tumor metastasis in vitro. The binding interaction between microRNA-149-5p and LINC00460 was revealed by luciferase reporter assay. Results: In the present study, lncRNA LINC00460 was shown to be upregulated in colorectal cancer tissues, and overexpression of LINC00460 significantly promoted metastasis of colorectal cancer in vitro. Furthermore, miR-149-5p interacted with LINC00460, and they negatively regulated expression of each other. Transfection of miR-149-5p mimics partially counteracted the tumor metastasis-promoting effects induced by LINC00460 overexpression. Finally, overexpression of LINC00460 upregulated the expression levels of biglycan, a target gene of miR-149-5p, which has also been identified as an oncogenic driver in colorectal cancer. Conclusion: Taken together, the present study demonstrated that LINC00460 promoted metastasis of CRC by sponging miR-149-5p and thereby affecting biglycan expression levels.

scholarly journals CAB39 mediates epithelial-mesenchymal transition via activation of NF-κB signaling to facilitate bladder cancer invasion and metastasis

2021 ◽  
Author(s):  
Haichao Chao ◽  
Lifen Peng ◽  
Leihong Deng ◽  
Zhaojun Yu ◽  
Huanhuan Deng ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cell Lines ◽  
Nude Mice ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Biological Activities ◽  
Expression Patterns ◽  
Critical Role ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition

Abstract Background Bladder cancer (BC) is the most common urinary cancer among men with a high mortality rate despite of constant advancement in medical and therapeutic treatment. Recent evidence demonstrated that CAB39 plays a critical role in BC pathogenesis by exhibiting various biological activities, but the underlying molecular mechanisms remain unclear. The aim of this research was to define the expression patterns of CAB39 in normal and tumor tissues and explore its biological function in epithelia-mesenchymal transition (EMT) in human BC. Methods Immunohistochemistry and Quantitative RT-PCR analyses were used respectively to examine the expression of CAB39 in BC tissues and cell lines with different metastatic potentials. In addition, the clinical significance of CAB39 expression was also evaluated. Wound-healing assay, cell invasion assay, and CCK8 proliferation assay in cell lines in which CAB39 was knocked down by shRNA, as well as xenograft tumor models in nude mice, were performed to assess the effect of CAB39 reduction on invasion, migration, and proliferation of BC cells. The GSEA database was used to analyze panel of genes enriched as a result of elevated CAB39 expression in BC cells, and the results were validated by western blot analysis. Results The level of CAB39 protein was up-regulated in invasive but not in noninvasive bladder cancer tissues. Elevated expression of CAB39 was inversely correlated with prognosis of the malignant disease. Additionally, CAB39 was differentially expressed in T24, 5637, and J82 bladder cancer cell lines with highest expression in T24, the most invasive cell line among the three. However, shRNA-mediated attenuation of endogenous CAB39 in T24 and 5637 cell lines reversed such invasive and metastatic effects as demonstrated by the inhibition of tumorigenesis in nude mice xenografts. Furthermore, we demonstrated that CAB39 could mediate EMT through upregulation of N-cadherin and downregulation of E-cadherin in BC via NF-kB signaling pathway. Conclusions Our study reveals a previously unknown mechanism of CAB39-mediated EMT in promoting invasion and metastasis of BC and provides a rationale for future investigation of CAB39 as a potential target for the development of novel therapeutic agents to fight the malignancy.

scholarly journals Jiedu Sangen Decoction Inhibits the Invasion and Metastasis of Colorectal Cancer Cells by Regulating EMT through the Hippo Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Li Yuan ◽  
Mengmeng Zhou ◽  
Harpreet S. Wasan ◽  
Kai Zhang ◽  
Zhaoyi Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Binding Motif ◽  
Hippo Signaling ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Hippo Signaling Pathway ◽  
Sw480 Cells

Colorectal cancer (CRC) is one of the most common malignant tumors affecting the digestive tract. Moreover, the invasion and metastasis of CRC are the main reason therapy is usually inefficient. Decreased intercellular adhesion and enhanced cell motility induced by epithelial-mesenchymal transition (EMT) provide the basic conditions for the invasion and metastasis of the epithelial tumor cells of CRC. The Jiedu Sangen Decoction (JSD) is a prescription that has been used for more than 50 years in the treatment of CRC in the Zhejiang Hospital of Traditional Chinese Medicine. The aim of this study was to investigate the mechanism of JSD-triggered inhibition of invasion and metastasis in colon cancer. In vitro, the EMT model of the SW480 cells was induced by using epithelial growth factor (50 ng/mL). In vivo, the murine model of liver metastasis was constructed by inoculating mice with the SW480 cells. The effects of JSD on cell migration, invasion, and proliferation were determined using the transwell assay and CCK-8 assay. Moreover, the proteins related to the EMT process and the Hippo signaling pathway in the cancerous tissues and cell lines were determined by western blotting and immunostaining. JSD could significantly inhibit the proliferation, migration, and invasion of CRC cells and reverse their EMT status (all, P < 0.05). Moreover, after intervention with JSD, the levels of E-Cadherin (E-cad) increased, whereas the expression levels of N-Cadherin (N-cad), Yes-associated protein (YAP), and the transcriptional coactivator with the PDZ-binding motif (TAZ) decreased in both the SW480 cells and the tumor tissues. In summary, JSD reversed EMT and inhibited the invasion and metastasis of CRC cells through the Hippo signaling pathway.

Exposure to desflurane anesthesia confers colorectal cancer cells metastatic capacity through deregulation of miR-34a/LOXL3 

2020 ◽  
Author(s):  
Junyi Ren ◽  
Xiaopeng Wang ◽  
Gang Wei ◽  
Yajing Meng
Keyword(s):  
Colorectal Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Protective Role ◽  
Tumor Formation ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Elevated Expression ◽  
Public Datasets

Abstract Background: Due to high potency and low toxicity, desflurane has been wildly used during surgery. Recent evidence that the use of desflurane was associated with colorectal cancer (CRC) tumor metastasis and poor prognosis raising concerns about the safety of desflurane. However, the mechanism was uncovered.Methods: CRC cells were exposed to desflurane, the changes in morphology and epithelial-mesenchymal transition (EMT)-related genes were evaluated. Transwell assay was used to study the migration and invasion effect. Xenograft was performed to study the tumor formation ability of desflurane-treated cells in vivo. Dual luciferase reporter assay was conducted to verify the target of miR-34a. Knockdown or overexpression of LOXL3 was used to investigate the mechanism of desflurane-induced EMT. The association of LOXL3 with CRC molecular subtypes and clinical relevance was studied by analysis of public datasets. Results: Exposure to desflurane induced EMT, migration, and invasion in CRC cells. Mice injected with desflurane-treated cells formed more tumors in the lungs. Downregulation of miR-34a and upregulation of LOXL3 were required for desflurane-induced EMT in CRC cells. LOXL3 was a direct target of miR-34a. Overexpression of LOXL3 rescued miR-34a-repressed EMT after exposure to desflurane. Elevated expression of LOXL3 was enriched in CMS4 and CRIS-B subtypes. Patients with high expression of LOXL3 showed more lymph node metastasis, as well as poor survival.Conclusion: Desflurane induced EMT and metastasis in CRC through deregulation of miR-34a/LOXL3 axis. Clinical miR-34a mimic or inhibitor targeting LOXL3 might have a potential protective role when CRC patients anesthetized by desflurane.

scholarly journals Tumor-Derived Extracellular Vesicles Promote Activation of Carcinoma-Associated Fibroblasts and Facilitate Invasion and Metastasis of Ovarian Cancer by Carrying miR-630

2021 ◽  
Vol 9 ◽  
Author(s):  
Yulan Cui ◽  
Deying Wang ◽  
Min Xie
Keyword(s):  
Ovarian Cancer ◽  
Extracellular Vesicles ◽  
Epithelial Mesenchymal Transition ◽  
Expression Patterns ◽  
Xenograft Model ◽  
Migration And Invasion ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Carcinoma Associated Fibroblasts

Ovarian cancer (OC) is a lethal gynecological malignancy. Extracellular vesicles (EVs) are crucial media in cell-to-cell communication by carrying microRNAs (miRs). The current study aims to investigate the underlying mechanism of miR-630 carried by OC cell-derived EVs in regard to invasion and metastasis of OC cells. miRs related to OC metastasis were searched and screened. The expression patterns of screened miRs in human normal fibroblasts (NFs) and carcinoma-associated fibroblasts (CAFs) were detected using RT-qPCR. miR-630 related to OC metastasis and CAFs activation was analyzed further. The levels of FAP and α-SMA were detected using Western blotting and immunofluorescence. The migration of NFs was measured using Transwell assay. OC cell-derived EVs were isolated and identified. Uptake of EVs by NFs was observed using immunofluorescence staining. The culture supernatant of NFs was collected and used to culture the low metastasis cell line OVCAR8. The migration and invasion of OC cells and epithelial mesenchymal transition (EMT) were measured. Moreover, a xenograft model was established by injecting OVCAR8 cells of different groups into nude mice. Lastly, the effect of EV-pretreated NFs on invasion and metastasis of OC cells was observed in vivo. miR-630 was upregulated in OC cells and CAFs, and further associated with CAF activation and OC metastasis. miR-630 overexpression increased the levels of FAP and α-SMA in NFs, resulting in the transformation of NFs into CAFs. EVs carried miR-630 into NFs and EVs promoted CAF activation. miR-630 targeted KLF6. miR-630 inhibition or KLF6 overexpression attenuated EVs-induced CAF activation. EVs activated the NF-κB pathway via the miR-630/KLF6 axis. The conditioned medium of NFs pretreated with EVs promoted the invasion and metastasis of OVCAR8 cells, while downregulating miR-630 in EVs partially inhibited the promotive effect of NFs. EV-pretreated NFs promoted invasion and metastasis of OC in vivo. In conclusion, EVs carried miR-630 into NFs, thereby facilitating CAF activation and promoting invasion and metastasis of OC by inhibiting KLF6 and activating the NF-κB pathway. Our findings might offer a novel mechanism of invasion and metastasis of OC from the perspective of tumor microenvironment.

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