Circulating miR-221/222 reduces CD4+ T cells by inhibiting CD4 expression in colorectal cancer.

Many patients with cancers have low levels of CD4+ in their peripheral blood. However, the molecular mechanism is still unclear. Here, we found that the blood levels of miR-221 and miR-222 were dramatically increased in patients with colorectal cancer (CRC), and both circulating miR-211 and miR-222 served as sensitive diagnostic markers with an area under the curve of 0.8790 and 0.9148, respectively. Transfection of either miR-221 or miR-222 resulted in the reduction of the surface CD4 antigen level but not the surface CD8 antigen level. The luciferase reporter assay showed that miR-221/222 directly regulated CD4 expression in human primary T cells. These data showed that miR-221/222 levels were upregulated in the blood of patients with CRC and that the expression of CD4 in human primary T cells was inhibited by miR-221/222. These findings provide a novel strategy for modulating the number of CD4+ T cells in the blood and further adjusting the microenvironment suitable for immunotherapy.

[1]  Yongxu Zhao,et al.  Bcl-3 promotes Wnt signaling by maintaining the acetylation of β-catenin at lysine 49 in colorectal cancer , 2020, Signal Transduction and Targeted Therapy.

[2]  Chen Wang,et al.  Exosomal miRNA profiling before and after surgery revealed potential diagnostic and prognostic markers for lung adenocarcinoma. , 2020, Acta biochimica et biophysica Sinica.

[3]  D. Sahoo,et al.  miR-221 targets QKI to enhance the tumorigenic capacity of human colorectal cancer stem cells. , 2019, Cancer research.

[4]  R. Nenutil,et al.  Circulating T cell subsets are associated with clinical outcome of anti-VEGF-based 1st-line treatment of metastatic colorectal cancer patients: a prospective study with focus on primary tumor sidedness , 2019, BMC Cancer.

[5]  P. Hrelia,et al.  Prognostic Role of miR-221 and miR-222 Expression in Cancer Patients: A Systematic Review and Meta-Analysis , 2019, Cancers.

[6]  Boxi Kang,et al.  Lineage tracking reveals dynamic relationships of T cells in colorectal cancer , 2018, Nature.

[7]  J. Borst,et al.  CD4+ T cell help in cancer immunology and immunotherapy , 2018, Nature Reviews Immunology.

[8]  A. Benson,et al.  Updates on immunotherapy for colorectal cancer. , 2018, Journal of gastrointestinal oncology.

[9]  F. Marincola,et al.  International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study , 2018, The Lancet.

[10]  Chen Wang,et al.  Non-coding RNAs as biomarkers for acute myocardial infarction , 2018, Acta Pharmacologica Sinica.

[11]  Kirsten A. Ward-Hartstonge,et al.  Regulatory T-cell heterogeneity and the cancer immune response , 2017, Clinical & translational immunology.

[12]  Ji Yeon Lee,et al.  Impact Of Circulating T Helper 1 And 17 Cells in the Blood on Regional Lymph Node Invasion in Colorectal Cancer , 2017, Journal of Cancer.

[13]  J. Guinney,et al.  Erratum: Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer (Nature reviews. Cancer (2017) 17 2 (79-92)) , 2017 .

[14]  B. Gustavsson,et al.  Regulatory T Cells from Colon Cancer Patients Inhibit Effector T-cell Migration through an Adenosine-Dependent Mechanism , 2016, Cancer Immunology Research.

[15]  Baljit Singh,et al.  Circulating plasma microRNAs as a screening method for detection of colorectal adenomas , 2015, The Lancet.

[16]  H. Ohdan,et al.  Successful treatment of conversion chemotherapy for initially unresectable synchronous colorectal liver metastasis. , 2015, World journal of gastroenterology.

[17]  Ye Xu,et al.  FOXP3+ Tregs: heterogeneous phenotypes and conflicting impacts on survival outcomes in patients with colorectal cancer , 2015, Immunologic Research.

[18]  Xi Chen,et al.  A microRNA 221- and 222-Mediated Feedback Loop, via PDLIM2, Maintains Constitutive Activation of NFκB and STAT3 in Colorectal Cancer Cells , 2014 .

[19]  Jun Yu,et al.  microRNA-221 and microRNA-18a identification in stool as potential biomarkers for the non-invasive diagnosis of colorectal carcinoma , 2014, British Journal of Cancer.

[20]  Huawei Zeng,et al.  Decreased levels of miR-224 and the passenger strand of miR-221 increase MBD2, suppressing maspin and promoting colorectal tumor growth and metastasis in mice. , 2013, Gastroenterology.

[21]  Lewis C Cantley,et al.  A colorectal cancer classification system that associates cellular phenotype and responses to therapy , 2013, Nature Medicine.

[22]  J. Sun,et al.  EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers , 2011, Nature Medicine.

[23]  J. Galon,et al.  Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. , 2011, Cancer research.

[24]  Wei Wang,et al.  MicroRNA-221 inhibits CDKN1C/p57 expression in human colorectal carcinoma , 2011, Acta Pharmacologica Sinica.

[25]  Tongyu Lin,et al.  Circulating miR‐221 directly amplified from plasma is a potential diagnostic and prognostic marker of colorectal cancer and is correlated with p53 expression , 2010, Journal of gastroenterology and hepatology.

[26]  Hansjuerg Alder,et al.  miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. , 2009, Cancer cell.

[27]  V. Narry Kim,et al.  Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer , 2009, Nucleic acids research.

[28]  X. Chen,et al.  Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases , 2008, Cell Research.

[29]  S. Fox,et al.  Increased frequency of regulatory T cells in peripheral blood and tumour infiltrating lymphocytes in colorectal cancer patients. , 2007, Cancer immunity.

[30]  Z. Trajanoski,et al.  Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome , 2006, Science.

[31]  Z. Trajanoski,et al.  Effector memory T cells, early metastasis, and survival in colorectal cancer. , 2005, The New England journal of medicine.