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Article: Tumor-secreted exosomal miR-141 activates tumor-stroma interactions and controls premetastatic niche formation in ovarian cancer metastasis

TitleTumor-secreted exosomal miR-141 activates tumor-stroma interactions and controls premetastatic niche formation in ovarian cancer metastasis
Authors
Keywordscancer-associated fibroblasts
Hippo/YAP1/pathway
miR-141
Ovarian cancer
Peritoneal metastases
Tumor-stroma interactions
Issue Date9-Jan-2023
PublisherBioMed Central
Citation
Molecular Cancer, 2023, v. 22, n. 1 How to Cite?
Abstract

Background

Metastatic colonization is one of the critical steps in tumor metastasis. A pre-metastatic niche is required for metastatic colonization and is determined by tumor-stroma interactions, yet the mechanistic underpinnings remain incompletely understood.

Methods

PCR-based miRNome profiling, qPCR, immunofluorescent analyses evaluated the expression of exosomal miR-141 and cell-to-cell communication. LC-MS/MS proteomic profiling and Dual-Luciferase analyses identified YAP1 as the direct target of miR-141. Human cytokine profiling, ChIP, luciferase reporter assays, and subcellular fractionation analyses confirmed YAP1 in modulating GROα production. A series of in vitro tumorigenic assays, an ex vivo model and Yap1 stromal conditional knockout (cKO) mouse model demonstrated the roles of miR-141/YAP1/GROα/CXCR1/2 signaling cascade. RNAi, CRISPR/Cas9 and CRISPRi systems were used for gene silencing. Blood sera, OvCa tumor tissue samples, and tissue array were included for clinical correlations.

Results

Hsa-miR-141-3p (miR-141), an exosomal miRNA, is highly secreted by ovarian cancer cells and reprograms stromal fibroblasts into proinflammatory cancer-associated fibroblasts (CAFs), facilitating metastatic colonization. A mechanistic study showed that miR-141 targeted YAP1, a critical effector of the Hippo pathway, reducing the nuclear YAP1/TAZ ratio and enhancing GROα production from stromal fibroblasts. Stromal-specific knockout (cKO) of Yap1 in murine models shaped the GROα-enriched microenvironment, facilitating in vivo tumor colonization, but this effect was reversed after Cxcr1/2 depletion in OvCa cells. The YAP1/GROα correlation was demonstrated in clinical samples, highlighting the clinical relevance of this research and providing a potential therapeutic intervention for impeding premetastatic niche formation and metastatic progression of ovarian cancers.

Conclusions

This study uncovers miR-141 as an OvCa-derived exosomal microRNA mediating the tumor-stroma interactions and the formation of tumor-promoting stromal niche through activating YAP1/GROα/CXCRs signaling cascade, providing new insight into therapy for OvCa patients with peritoneal metastases.


Persistent Identifierhttp://hdl.handle.net/10722/329072
ISSN
2023 Impact Factor: 27.7
2023 SCImago Journal Rankings: 8.222
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorMo, YL-
dc.contributor.authorLeung, LL-
dc.contributor.authorMak, CSL-
dc.contributor.authorWang, XY-
dc.contributor.authorChan, WS-
dc.contributor.authorHui, LMN-
dc.contributor.authorTang, HWM-
dc.contributor.authorSiu, MKY-
dc.contributor.authorSharma, R-
dc.contributor.authorXu, DK-
dc.contributor.authorTsui, SKW-
dc.contributor.authorNgan, HYS-
dc.contributor.authorYung, MMH-
dc.contributor.authorChan, KKL-
dc.contributor.authorChan, DW-
dc.date.accessioned2023-08-05T07:55:04Z-
dc.date.available2023-08-05T07:55:04Z-
dc.date.issued2023-01-09-
dc.identifier.citationMolecular Cancer, 2023, v. 22, n. 1-
dc.identifier.issn1476-4598-
dc.identifier.urihttp://hdl.handle.net/10722/329072-
dc.description.abstract<h3>Background</h3><p>Metastatic colonization is one of the critical steps in tumor metastasis. A pre-metastatic niche is required for metastatic colonization and is determined by tumor-stroma interactions, yet the mechanistic underpinnings remain incompletely understood.</p><h3>Methods</h3><p>PCR-based miRNome profiling, qPCR, immunofluorescent analyses evaluated the expression of exosomal miR-141 and cell-to-cell communication. LC-MS/MS proteomic profiling and Dual-Luciferase analyses identified YAP1 as the direct target of miR-141. Human cytokine profiling, ChIP, luciferase reporter assays, and subcellular fractionation analyses confirmed YAP1 in modulating GROα production. A series of in vitro tumorigenic assays, an ex vivo model and Yap1 stromal conditional knockout (cKO) mouse model demonstrated the roles of miR-141/YAP1/GROα/CXCR1/2 signaling cascade. RNAi, CRISPR/Cas9 and CRISPRi systems were used for gene silencing. Blood sera, OvCa tumor tissue samples, and tissue array were included for clinical correlations.</p><h3>Results</h3><p>Hsa-miR-141-3p (miR-141), an exosomal miRNA, is highly secreted by ovarian cancer cells and reprograms stromal fibroblasts into proinflammatory cancer-associated fibroblasts (CAFs), facilitating metastatic colonization. A mechanistic study showed that miR-141 targeted YAP1, a critical effector of the Hippo pathway, reducing the nuclear YAP1/TAZ ratio and enhancing GROα production from stromal fibroblasts. Stromal-specific knockout (cKO) of Yap1 in murine models shaped the GROα-enriched microenvironment, facilitating in vivo tumor colonization, but this effect was reversed after Cxcr1/2 depletion in OvCa cells. The YAP1/GROα correlation was demonstrated in clinical samples, highlighting the clinical relevance of this research and providing a potential therapeutic intervention for impeding premetastatic niche formation and metastatic progression of ovarian cancers.</p><h3>Conclusions</h3><p>This study uncovers miR-141 as an OvCa-derived exosomal microRNA mediating the tumor-stroma interactions and the formation of tumor-promoting stromal niche through activating YAP1/GROα/CXCRs signaling cascade, providing new insight into therapy for OvCa patients with peritoneal metastases.</p>-
dc.languageeng-
dc.publisherBioMed Central-
dc.relation.ispartofMolecular Cancer-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectcancer-associated fibroblasts-
dc.subjectHippo/YAP1/pathway-
dc.subjectmiR-141-
dc.subjectOvarian cancer-
dc.subjectPeritoneal metastases-
dc.subjectTumor-stroma interactions-
dc.titleTumor-secreted exosomal miR-141 activates tumor-stroma interactions and controls premetastatic niche formation in ovarian cancer metastasis-
dc.typeArticle-
dc.identifier.doi10.1186/s12943-022-01703-9-
dc.identifier.scopuseid_2-s2.0-85145938344-
dc.identifier.volume22-
dc.identifier.issue1-
dc.identifier.eissn1476-4598-
dc.identifier.isiWOS:000911429800001-
dc.identifier.issnl1476-4598-

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