EMT and induction of miR-21 mediate metastasis development in Trp53-deficient tumours

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Missense mutations in the TP53 gene are linked to tumor metastasis.
• The role of complete p53 loss of function in tumor metastasis remains largely unexplored.

Purpose of the Study:

• To investigate the metastatic potential of squamous cell carcinomas resulting from complete Trp53 gene ablation in mouse epidermis.
• To elucidate the molecular mechanisms underlying metastasis driven by p53 loss.

Main Methods:

• Specific ablation of the Trp53 gene in mouse epidermis to generate squamous cell carcinomas.
• Biochemical analyses, genome-wide mRNA, and miRNA profiling of primary tumors and metastases.
• In vitro and in vivo functional assays using mouse keratinocytes and a metastatic spindle cell line.
• Analysis of mTOR and Stat3 signaling pathways.

Main Results:

• Trp53-deficient squamous cell carcinomas exhibited high metastatic potential.
• Metastasis was associated with early induction of epithelial-mesenchymal transition (EMT) and deregulated miRNA expression.
• Increased miR-21 expression was observed in prometastatic mouse tumors and human tumors with p53 mutations and metastasis.
• Augmented miR-21, mediated by mTOR and Stat3, enhanced keratinocyte invasiveness.
• miR-21 blockade inhibited metastasis development in a metastatic cell line.

Conclusions:

• Complete loss of p53 function in epithelial cells drives tumor metastasis.
• Early induction of EMT and aberrant miR-21 expression are key molecular mechanisms.
• Targeting miR-21 may offer a therapeutic strategy for p53-deficient metastatic cancers.