MiR-21 controls in situ expansion of CCR6⁺ regulatory T cells through PTEN/AKT pathway in breast cancer.
Our recent evidence showed that prior expansion of CCR6(+) Foxp3(+) regulatory T cells (Tregs) was important for their dominant enrichment in tumor tissue, which was closely related to poor prognosis of breast cancer patients. However, the underlying regulation mechanism of expansion of CCR6(+) Tregs in situ remains largely unknown. In this study, we reported that miR-21 was highly expressed in CCR6(+) Tregs in tumor tissues from a murine breast cancer model. And silencing of miR-21 could significantly reduce the proliferation of CCR6(+) Tregs in vitro. Adoptive cell-transfer assay further showed that silencing of miR-21 could alter the enrichment of CCR6(+) Tregs in the tumor mass and endow effectively antitumor effect of CD8(+) T cells using a murine breast cancer model. Mechanistic evidence showed that silencing of miR-21 enhanced the expression of its target phosphatase and tensin homolog deleted on chromosome ten (PTEN) and subsequently altered the activation of Akt pathway, which was ultimately responsible for reduced proliferation activity of CCR6(+) Tregs. Finally, we further revealed that miR-21 was also highly expressed on CCR6(+) Tregs in clinical breast cancer patients. Therefore, miR-21 can act as a fine tuner in the regulation of PTEN/Akt pathway transduction in the expansion of CCR6(+) Tregs in tumor sites and provided a novel insight into the development of therapeutic strategies for promoting T-cell immunity by regulating distinct subset of Tregs through targeting specific miRNAs.
Department of Immunology, Zunyi Medical College, Guizhou, China.
Yan
Y
Hu
Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China.
Chunhong
C
Wang
Department of Immunology, Zunyi Medical College, Guizhou, China.
Yongju
Y
Li
Department of Immunology, Zunyi Medical College, Guizhou, China.
Juanjuan
J
Zhao
Department of Immunology, Zunyi Medical College, Guizhou, China.
Chao
C
Chen
Department of Medical Physics, Zunyi Medical College, Guizhou, China.
Ya
Y
Zhou
Department of Immunology, Zunyi Medical College, Guizhou, China.
Yijin
Y
Tao
Department of Immunology, Zunyi Medical College, Guizhou, China.
Mengmeng
M
Guo
Department of Immunology, Zunyi Medical College, Guizhou, China.
Nalin
N
Qin
Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China.
Tao
T
Ren
Institute for Immunobiology, Shanghai Medical College of Fudan University, Shanghai, China.
Zhenke
Z
Wen
Department of Immunology, Zunyi Medical College, Guizhou, China.
Lin
L
Xu
D000818:Animals; D015415:Biomarkers; D001943:Breast Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D054399:Receptors, CCR6 / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*
D015415:Biomarkers; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D054399:Receptors, CCR6; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase