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Mutant p53 increases exosome-mediated transfer of miR-21-3p and miR-769-3p to promote pulmonary metastasis.

ABSTRACT: Objective:Tumor metastasis is a complex, multistep process that depends on tumor cells and their communication with the tumor microenvironment. A p53 gain-of-function mutant has been shown to enhance the tumorigenesis, invasion, and metastasis abilities of tumor cells. This study aimed to investigate the roles of p53 R273H mutation in the tumor microenvironment. Methods:The in vitro and in vivo effects of the p53 R273H mutant on the invasion and metastasis of HCT116 cells were investigated. Exosomes from wild-type and HCT116-TP53(R273H) cells were cocultured with mouse embryonic fibroblasts (MEFs). The roles of differentially expressed exosomal microRNAs identified by microarray analysis were investigated. The functions of the p53 R273H mutant in tumor cells were also investigated via gene expression microarray and quantitative polymerase chain reaction (qPCR) analyses. Results:Introducing p53 R273H mutant into HCT116 cells significantly potentiated pulmonary metastasis in vivo. In the presence of exosomes derived from HCT116-TP53(R273H) cells, the exosomes were taken up by MEFs and became activated. Microarray analysis showed that the p53 R273H mutation increased the exosomal levels of miR-21-3p and miR-769-3p. Intriguingly, in clinical samples, miR-21-3p and miR-769-3p levels were significantly higher in patients with a p53 mutation than in those without this mutation. Furthermore, both miR-21-3p and miR-769-3p activated fibroblasts and exerted a synergistic effect via their target genes on the transforming growth factor-? (TGF-?)/Smad signaling pathway. The activated fibroblasts excreted cytokine TGF-? and may have reciprocally induced cancer cells to undergo epithelial-mesenchymal transition (EMT). Indeed, HCT116-TP53(R273H) cells showed increased expression of ZEB1 and SNAI2 and decreased transcription of several cell adhesion molecules. Conclusions:The mutant p53-exosomal miR-21-3p/miR-769-3p-fibroblast-cytokine circuit appears to be responsible for communication between tumor and stromal cells, with exosomal miRNAs acting as a bridge. miR-21-3p and miR-769-3p are potential predictive markers of pulmonary metastasis and candidate targets for therapeutic interventions.

SUBMITTER: Ju Q

PROVIDER: S-EPMC6613506 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Mutant p53 increases exosome-mediated transfer of miR-21-3p and miR-769-3p to promote pulmonary metastasis.

Ju Qiang Q Zhao Lina L Gao Jiajia J Zhou Lanping L Xu Yang Y Sun Yulin Y Zhao Xiaohang X

Chinese journal of cancer research = Chung-kuo yen cheng yen chiu 20190601 3

<h4>Objective</h4>Tumor metastasis is a complex, multistep process that depends on tumor cells and their communication with the tumor microenvironment. A p53 gain-of-function mutant has been shown to enhance the tumorigenesis, invasion, and metastasis abilities of tumor cells. This study aimed to investigate the roles of p53 R273H mutation in the tumor microenvironment.<h4>Methods</h4>The <i>in vitro</i> and <i>in vivo</i> effects of the p53 R273H mutant on the invasion and metastasis of HCT116 ...[more]

PMID: 31354222

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Project description:BackgroundCisplatin resistance is the main cause of poor clinical prognosis in patients with gastric cancer (GC). Yet, the exact mechanism underlying cisplatin resistance remains unclear. Recent studies have suggested that exocrine miRNAs found in the tumor microenvironment participate in tumor metastasis and drug resistance.MethodsExosomes isolated from BGC823 and BGC823/DDP culture medium were characterized by transmission electron microscopy and differential ultracentrifugation, and miRNA expression profiles of BGC823 and BGC823/DDP cells derived exosomes were analyzed using miRNA microarray. In vivo and in vitro assays were used to identify roles of exosomal miR-769-5p and clarify the mechanism of exosomal miR-769-5p regulated the crosstalk between sensitive and resistant GC cells.ResultsIn this study, we found that cisplatin-resistant GC cells communicated with the tumor microenvironment by secreting microvesicles. MiR-769-5p was upregulated in GC tissues and enriched in the serum exosomes of cisplatin-resistant patients. The biologically active miR-769-5p could be integrated into exosomes and delivered to sensitive cells, spreading cisplatin resistance. Underlying cellular and molecular mechanism was miR-769-5p targeting CASP9, thus inhibiting the downstream caspase pathway and promoting the degradation of the apoptosis-related protein p53 through the ubiquitin-proteasome pathway. Targeting miR-769-5p with its antagonist to treat cisplatin-resistant GC cells can restore the cisplatin response, confirming that exosomal miR-769-5p can act as a key regulator of cisplatin resistance in GC.ConclusionsThese findings indicate that exosome-transmitted miR-769-5p confers cisplatin resistance and progression in gastric cancer by targeting CASP9 and promoting the ubiquitination degradation of p53. These findings reveal exosomal miR-769-5p derived from drug-resistant cells can be used as a potential therapeutic predictor of anti-tumor chemotherapy to enhance the effect of anti-cancer chemotherapy, which provides a new treatment option for GC.

Project description:BackgroundMicroRNAs have an important role in diverse biological processes including tumorigenesis. MiR-223 has been reported to be deregulated in several human cancer types. However, its biological role has not been functionally characterized in lung squamous cell carcinoma (LSCC). The following study investigates the role of miR-223-3p in LSCC growth and metastasis and its underlying mechanism.MethodsMicroRNA profiling analyses were conducted to determine differential miRNAs expression levels in LSCC tumor tissues that successfully formed xenografts in immunocompromised mice (XG) and failed tumor tissues (no-XG). RT-PCR and in situ hybridization (ISH) was performed to evaluate the expression of miR-223-3p in 12 paired adjacent normal tissues and LSCC specimens. Cell proliferation and migration were assessed by CCK-8, colony formation and Transwell assay, respectively. The role of miR-223-3p in LSCC tumorigenesis was examined using xenograft nude models. Bioinformatics analysis, Dual-luciferase reporter assays, Chromatin immunoprecipitation (ChIP) assay and Western blot analysis were used to identify the direct target of miR-223-3p and its interactions.ResultsMiR-223-3p was downregulated in LSCC tissues that successfully formed xenografts (XG) compared with tumor tissues that failed (no-XG), which was also significantly reduced in LSCC tissues compared with the adjacent normal tissues. Gain- and loss-of function experiments showed that miR-223-3p inhibited proliferation and migration in vitro. More importantly, miR-223-3p overexpression greatly suppressed tumor growth in vivo. Mechanistically, we found that mutant p53 bound to the promoter region of miR-223 and reduced its transcription. Meanwhile, p53 is a direct target of miR-223-3p. Thus, miR-223-3p regulated mutant p53 expression in a feedback loop that inhibited cell proliferation and migration.ConclusionsOur study identified miR-223-3p, as a tumor suppressor gene, markedly inhibited cell proliferation and migration via miR-223-3p-mutant p53 feedback loop, which suggested miR-223-3p might be a new therapeutic target in LSCC bearing p53 mutations.

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Mutant p53 increases exosome-mediated transfer of miR-21-3p and miR-769-3p to promote pulmonary metastasis.

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Mutant p53 increases exosome-mediated transfer of miR-21-3p and miR-769-3p to promote pulmonary metastasis.

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