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MicroRNA-22 suppresses the growth, migration and invasion of colorectal cancer cells through a Sp1 negative feedback
Shu-Sen Xia1, Guang-Jun Zhang2,3, Zuo-Liang Liu2,3
1The Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
Abstract:
MicroRNAs have recently emerged as regulators of many biological processes including cell proliferation, development and differentiation. This study identified that miR-22 was statistically decreased in colorectal cancer clinical specimens and highly metastatic cell lines. Moreover, low miR-22 expression was associated with tumor metastasis, advanced clinical stage and relapse. Consistent with clinical observations, miR-22 significantly suppressed the ability of colorectal cancer cells to growth and metastasize in vitro and in vivo. Sp1 was validated as a target of miR-22, and ectopic expression of Sp1 compromised the inhibitory effects of miR-22. In addition, Sp1 repressed miR-22 transcription by binding to the miR-22 promoter, hence forming a negative feedback loop. Further study has shown that miR-22 suppresses the activity of PTEN/AKT pathway by Sp1. Our present results implicate the newly indentified miR-22/Sp1/PTEN/AKT axis might represent a potential therapeutic target for colorectal cancer.
Insights
MicroRNA-22 (miR-22) is decreased in colorectal cancer, suppressing tumor growth and metastasis. This study reveals a miR-22/Sp1/PTEN/AKT axis as a potential therapeutic target for colorectal cancer.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- MicroRNAs (miRNAs) are key regulators of biological processes.
- Dysregulation of miRNAs is implicated in various cancers, including colorectal cancer (CRC).
- Specific roles of miRNAs in CRC progression require further elucidation.
Purpose of the Study:
- To investigate the role of miR-22 in colorectal cancer.
- To identify the molecular targets and pathways regulated by miR-22 in CRC.
- To explore the therapeutic potential of the miR-22 axis in CRC.
Main Methods:
- Quantitative real-time PCR to assess miR-22 expression in CRC tissues and cell lines.
- In vitro and in vivo assays to evaluate the functional impact of miR-22 on CRC cell proliferation and metastasis.
- Western blotting and luciferase reporter assays to validate Sp1 as a direct target of miR-22.
- Chromatin immunoprecipitation assays to confirm Sp1 binding to the miR-22 promoter.
- Analysis of the PTEN/AKT signaling pathway.
Main Results:
- miR-22 expression was significantly decreased in colorectal cancer specimens and metastatic cell lines.
- Low miR-22 levels correlated with advanced tumor stage, metastasis, and relapse.
- miR-22 suppressed CRC cell growth and metastasis in vitro and in vivo.
- Sp1 was identified as a direct target of miR-22, and Sp1 overexpression counteracted miR-22's inhibitory effects.
- Sp1 repressed miR-22 transcription, forming a negative feedback loop.
- miR-22 suppressed the PTEN/AKT pathway activity via Sp1.
Conclusions:
- The miR-22/Sp1 axis forms a regulatory feedback loop in colorectal cancer.
- The identified miR-22/Sp1/PTEN/AKT signaling pathway is crucial for CRC progression.
- This axis represents a promising therapeutic target for colorectal cancer treatment.