期刊
MOLECULAR CANCER
卷 15, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12943-016-0521-7
关键词
Esophageal cancer stem-like cells; Sphere formation cells; STAT3; miR-181b; Proliferation; CYLD
资金
- Twelfth Five-Year National Science and Technology Support Program [2012BAI29B06]
- Administration of Ocean and Fisheries of Guangdong Province Program [A1201301C06, GD2013-B02-003]
- Science and Technology Program Project of Guangdong Province [2013B091000010]
- China Postdoctoral Science Foundation [2015M572414]
- Fundamental Research Funds for the Central Universities [21615410]
- Guangdong Natural Science Foundation [2016A030310096]
Background: Recent studies have suggested that cancer cells contain subpopulations that can initiate tumor growth, self-renew, and maintain tumor cell growth. However, for esophageal cancer cells, the relationship between STAT3, microRNAs and cancer stem cells remains unclear. Methods: Serum-free culture was used to enrich esophageal cancer stem-like cells ( ECSLC). Flow cytometry determined the proportion of ECSLC. qPCR were performed to examine expression level of stemness factors, mesenchymal markers, ATP-binding cassette ( ABC) transporters, STAT3, miR-181b, CYLD. Western blot were performed to analyze the expression of STAT3, p-STAT3 and CYLD ( cylindromatosis). BALB/ c mice xenograft studies were conducted to evaluate the tumorigenicity of enriched ECSLC. Sphere formation assay and colony formation assays were employed to analyze the relationship between STAT3 and miR-181b. Luciferase assays were used to evaluate activity which CYLD is a target of miR-181b. Results: Sphere formation cells ( SFCs) with properties of ECSLC were enriched. Enriched SFCs in serum-free suspension culture exhibited cancer stem-like cell properties and increased single-positive CD44 + CD24-, stemness factor, mesenchymal marker expression ABC transporters and tumorigenicity in vivo compared with the parental cells. Additionally, we found that reciprocal activation between STAT3 and miR-181b regulated SFCs proliferation. Moreover, STAT3 directly activated miR-181b transcription in SFCs and miR-181b then potentiated p-STAT3 activity. Luciferase assays indicated that CYLD was a direct and functional target of miR-181b. Conclusion: The mutual regulation between STAT3 and miR-181b in SFCs was required for proliferation and apoptosis resistance. STAT3 and miR-181b control each other's expression in a positive feedback loop that regulates SFCs via CYLD pathway. These findings maybe is helpful for targeting ECSLC and providing approach for esophageal cancer treatments.
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