A microRNA 221- and 222-mediated feedback loop maintains constitutive activation of NFκB and STAT3 in colorectal cancer cells
- Sanhong Liu 1, Xiaohua Sun 1, Mingliang Wang 2, Yingyong Hou 3, Yu Zhan 1, Yuhang Jiang 1, Zhanjie Liu 1, Xinwei Cao 1, Pengfei Chen 1, Zhi Liu 1, Xi Chen 1, Yu Tao 1, Chen Xu 3, Jie Mao 1, Chunyan Cheng 1, Cuifeng Li 1, Yiming Hu 1, Lunshan Wang 1, Y Eugene Chin 1, Yufang Shi 1, Ulrich Siebenlist 4, Xiaoren Zhang 1
- Sanhong Liu 1, Xiaohua Sun 1, Mingliang Wang 2
- 1Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- 2General Surgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- 3Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
- 4Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
- 0Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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View abstract on PubMed
Summary
This summary is machine-generated.MicroRNAs miR-221 and miR-222 promote colorectal cancer (CRC) by activating nuclear factor κB (NF-κB) and STAT3 signaling pathways. Inhibiting these microRNAs suppressed tumor growth in preclinical models.
Area Of Science
- Molecular Biology
- Oncology
- Genetics
Background
- Constitutive activation of nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) is crucial for colorectal cancer (CRC) development and progression.
- The precise mechanisms of NF-κB and STAT3 activation in cancer cells remain incompletely understood.
Purpose Of The Study
- To investigate the role of microRNAs miR-221 and miR-222 in regulating NF-κB and STAT3 activation in human CRC cell lines.
- To explore the therapeutic potential of targeting miR-221 and miR-222 in CRC.
Main Methods
- Transfection of CRC cell lines (HCT116, RKO) with miR-221/miR-222 mimics or inhibitors.
- Dual luciferase reporter assays to measure NF-κB and STAT3 activity.
- Immunoblot and real-time PCR to quantify protein and mRNA levels.
- In vivo studies using a mouse model of colitis treated with miR-221/miR-222 sponges.
- Analysis of 57 paired human CRC and adjacent nontumor tissues.
Main Results
- miR-221 and miR-222 mimics activated NF-κB and STAT3, increasing their own expression in CRC cells.
- These microRNAs directly bind RelA mRNA, enhancing its stability, and bind PDLIM2 mRNA's 3' UTR, reducing RelA and STAT3 degradation.
- Inhibition of miR-221/miR-222 decreased CRC cell proliferation and colony formation.
- In vivo, miR-221/miR-222 sponges reduced tumor formation in mice.
- Human CRC tissues showed elevated miR-221/miR-222 and RelA/STAT3 mRNAs, with decreased PDLIM2 mRNA compared to nontumor tissues.
Conclusions
- miR-221 and miR-222 establish a positive feedback loop in CRC cells, upregulating RelA and STAT3 expression.
- Antagonizing miR-221 and miR-222 demonstrates potential for reducing colon tumor growth.
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