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Multidimensional Coculture System to Model Lung Squamous Carcinoma Progression
Published on: March 17, 2020
MiR-223-3p functions as a tumor suppressor in lung squamous cell carcinoma by miR-223-3p-mutant p53 regulatory
Peng Luo1, Qi Wang2, Yuanyuan Ye3
1Department of Clinical Laboratory, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China.
Background:
MicroRNAs have an important role in diverse biological processes including tumorigenesis. MiR-223 has been reported to be deregulated in several human cancer types. However, its biological role has not been functionally characterized in lung squamous cell carcinoma (LSCC). The following study investigates the role of miR-223-3p in LSCC growth and metastasis and its underlying mechanism.
Methods:
MicroRNA profiling analyses were conducted to determine differential miRNAs expression levels in LSCC tumor tissues that successfully formed xenografts in immunocompromised mice (XG) and failed tumor tissues (no-XG). RT-PCR and in situ hybridization (ISH) was performed to evaluate the expression of miR-223-3p in 12 paired adjacent normal tissues and LSCC specimens. Cell proliferation and migration were assessed by CCK-8, colony formation and Transwell assay, respectively. The role of miR-223-3p in LSCC tumorigenesis was examined using xenograft nude models. Bioinformatics analysis, Dual-luciferase reporter assays, Chromatin immunoprecipitation (ChIP) assay and Western blot analysis were used to identify the direct target of miR-223-3p and its interactions.
Results:
MiR-223-3p was downregulated in LSCC tissues that successfully formed xenografts (XG) compared with tumor tissues that failed (no-XG), which was also significantly reduced in LSCC tissues compared with the adjacent normal tissues. Gain- and loss-of function experiments showed that miR-223-3p inhibited proliferation and migration in vitro. More importantly, miR-223-3p overexpression greatly suppressed tumor growth in vivo. Mechanistically, we found that mutant p53 bound to the promoter region of miR-223 and reduced its transcription. Meanwhile, p53 is a direct target of miR-223-3p. Thus, miR-223-3p regulated mutant p53 expression in a feedback loop that inhibited cell proliferation and migration.
Conclusions:
Our study identified miR-223-3p, as a tumor suppressor gene, markedly inhibited cell proliferation and migration via miR-223-3p-mutant p53 feedback loop, which suggested miR-223-3p might be a new therapeutic target in LSCC bearing p53 mutations.
Insights
MicroRNA-223-3p acts as a tumor suppressor in lung squamous cell carcinoma (LSCC). It inhibits cancer cell growth and metastasis by regulating the mutant p53 feedback loop, offering a potential therapeutic target.
Area of Science:
- Molecular oncology
- Cancer biology
- MicroRNA therapeutics
Background:
- MicroRNAs are crucial in biological processes, including tumorigenesis, with miR-223 implicated in various cancers.
- The specific role of miR-223-3p in lung squamous cell carcinoma (LSCC) progression and its mechanisms remain underexplored.
Purpose of the Study:
- To investigate the functional role of miR-223-3p in LSCC growth and metastasis.
- To elucidate the underlying molecular mechanisms, including its interaction with p53.
Main Methods:
- Differential microRNA expression profiling in LSCC xenografts and normal tissues.
- In vitro assays (CCK-8, colony formation, Transwell) and in vivo xenograft models to assess miR-223-3p function.
- Bioinformatics, luciferase reporter, ChIP, and Western blot assays to identify targets and interactions.
Main Results:
- MiR-223-3p was significantly downregulated in LSCC tissues, particularly in those forming xenografts.
- Overexpression of miR-223-3p suppressed LSCC cell proliferation and migration in vitro and tumor growth in vivo.
- MiR-223-3p directly targets mutant p53, forming a feedback loop that inhibits tumor progression.
Conclusions:
- MiR-223-3p functions as a tumor suppressor in LSCC by inhibiting proliferation and migration.
- The miR-223-3p-mutant p53 feedback loop is a key mechanism in LSCC.
- MiR-223-3p represents a promising therapeutic target for LSCC patients with p53 mutations.
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