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Exosomal miR?663b exposed to TGF??1 promotes cervical cancer metastasis and epithelial?mesenchymal transition by targeting MGAT3.

ABSTRACT: Transforming growth factor (TGF)??1 is a key cytokine affecting the pathogenesis and progression of cervical cancer. Tumor?derived exosomes contain microRNAs (miRNAs/miRs) that interact with cancer and stromal cells, thereby contributing to tissue remodeling in the tumor microenvironment (TME). The present study was designed to clarify how TGF??1 affects tumor biological functions through exosomes released by cervical cancer cells. Deep RNA sequencing found that TGF??1 stimulated cervical cancer cells to secrete more miR?663b?containing exosomes, which could be transferred into new target cells to promote metastasis. Further studies have shown that miR?663b directly targets the 3'-untranslated regions (3'?UTR) of mannoside acetylglucosaminyltransferase 3 (MGAT3) and is involved in the epithelial?mesenchymal transition (EMT) process. Remarkably, the overexpression of MGAT3 suppressed cervical cancer cell metastasis promoted by exosomal miR?663b, causing increased expression of epithelial differentiation marker E?cadherin and decreased expression of mesenchymal markers N?cadherin and ??catenin. Throughout our study, online bioinformation tools and dual luciferase reporter assay were applied to identify MGAT3 as a novel direct target of miR?663b. Exosome PKH67?labeling experiment verified that exosomal miR?663b could be endocytosed by cervical cancer cells and subsequently influence its migration and invasion functions which were measured by wound healing and Transwell assays. The expression of miR?663b and MGAT3 and the regulation of the EMT pathway caused by MGAT3 were detected by quantitative real?time transcription?polymerase chain reaction (qPCR) and western blot analysis. These results, thus, provide evidence that cancer cell?derived exosomal miR?663b is endocytosed by cervical cancer cells adjacent or distant after TGF??1 exposure and inhibits the expression of MGAT3, thereby accelerating the EMT process and ultimately promoting local and distant metastasis.

SUBMITTER: You X

PROVIDER: S-EPMC7877003 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Exosomal miR‑663b exposed to TGF‑β1 promotes cervical cancer metastasis and epithelial‑mesenchymal transition by targeting MGAT3.

You Xuewu X Wang Ying Y Meng Jinyu J Han Sai S Liu Lu L Sun Yu Y Zhang Junhua J Sun Shuqin S Li Xinyue X Sun Wenxiong W Dong Yajie Y Zhang Youzhong Y

Oncology reports 20210302 4

Transforming growth factor (TGF)‑β1 is a key cytokine affecting the pathogenesis and progression of cervical cancer. Tumor‑derived exosomes contain microRNAs (miRNAs/miRs) that interact with cancer and stromal cells, thereby contributing to tissue remodeling in the tumor microenvironment (TME). The present study was designed to clarify how TGF‑β1 affects tumor biological functions through exosomes released by cervical cancer cells. Deep RNA sequencing found that TGF‑β1 stimulated cervical cancer ...[more]

PMID: 33649791

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Project description:AimsThe study aims to explore new potential treatments for cervical cancer.BackgroundCervical cancer is the second most common cancer in women, causing >250,000 deaths worldwide. Patients with cervical cancer are mainly treated with platinum compounds, which often cause severe toxic reactions. Furthermore, the long-term use of platinum compounds can reduce the sensitivity of cancer cells to chemotherapy and increase the drug resistance of cervical cancer. Therefore, exploring new treatment options is meaningful for cervical cancer.ObjectiveThe present study was to investigate the effect of sildenafil on the growth and epithelial-tomesenchymal transition (EMT) of cervical cancer.MethodsHeLa and SiHa cells were treated with sildenafil for different durations. Cell viability, clonogenicity, wound healing, and Transwell assays were performed. The levels of transforming growth factor-β1 (TGF-β1), transforming growth factor-β type I receptor (TβRI), phosphorylated (p-) Smad2 and p-Smad3 in cervical cancer samples were measured. TGF-β1, Smad2 or Smad3 were overexpressed in HeLa cells, and we measured the expression of EMT marker proteins and the changes in cell viability, colony formation, etc. Finally, HeLa cells were used to establish a nude mouse xenograft model with sildenafil treatment. The survival rate of mice and the tumor size were recorded.ResultsHigh concentrations of sildenafil (1.0-2.0 μM) reduced cell viability, the number of HeLa and SiHa colonies, and the invasion/migration ability of HeLa and SiHa cells in a dose- and time-dependent manner. The expression of TGF-β1, TβRI, p-Smad2 and p-Smad3 was significantly enhanced in cervical cancer samples and cervical cancer cell lines. Sildenafil inhibited the expression of TGF-β1-induced EMT marker proteins (Snail, vimentin, Twist, E-cadherin and N-cadherin) and p-Smad2/3 in HeLa cells. Overexpression of TGF-β1, Smad2, and Smad3 reversed the effect of sildenafil on EMT, viability, colony formation, migration, and invasion ability of HeLa cells. In the in vivo study, sildenafil significantly increased mouse survival rates and suppressed xenograft growth.ConclusionSildenafil inhibits the proliferation, invasion ability, and EMT of human cervical cancer cells by regulating the TGF-β1/Smad2/3 pathway.

Project description:BackgroundColorectal cancer (CRC) is the leading cause of cancer-related death worldwide. Exosome shave emerged as crucial regulators of intercellular communication and that abundant Circular RNAs (circRNAs) are enriched within exosomes. CircRNAs are novel members of noncoding RNAs regulating cancer proliferation and progression. However, the function and regulatory mechanism of cancer-derived exosomal circRNAs in CRC remains unclear.MethodsCRC cells-derived exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis (NTA) and western blot. CCK-8, wound healing and transwell assays, and flow cytometry assays were conducted to assess whether exosomes would affect the proliferation, metastasis, and apoptosis of CRC cells, respectively. Moreover, we performed the RNA sequencing and RT-qPCR to identify circRNAs in exosome-stimulated CRC cells. Fluorescence in situ hybridization (FISH) assay was used to detect the cellular distribution of circPACRGL. Bioinformatic analyses (StarBase 2.0) were used to pool the miRNA targets of circPACRGL. Luciferase assays were performed to verify the direct interaction. Finally, flow cytometry was used to detect the differentiation of N1-N2 neutrophils.ResultsOur study identified a novel CRC-derived exosomal circRNA, circPACRGL. We found circPACRGL was significantly upregulated in CRC cells after tumor-derived exosomes addition. Moreover, circPACRGL serves as a sponge for miR-142-3p/miR-506-3p to facilitate the transforming growth factor-β1 (TGF-β1) expression. As a result, circPACRGL promoted CRC cell proliferation, migration and invasion, as well as differentiation of N1 to N2 neutrophils via miR-142-3p/miR-506-3p-TGF-β1 axis.ConclusionOur study, the first to reveal that cancer-derived exosomal circPACRGL plays an oncogenic role in CRC proliferation and metastasis, providing mechanistic insights into the roles of circRNAs in CRC progression and a valuable marker for CRC treatment.

Dataset Information

Exosomal miR?663b exposed to TGF??1 promotes cervical cancer metastasis and epithelial?mesenchymal transition by targeting MGAT3.

Publications

Exosomal miR‑663b exposed to TGF‑β1 promotes cervical cancer metastasis and epithelial‑mesenchymal transition by targeting MGAT3.

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