TAp63 regulates oncogenic miR-155 to mediate migration and tumour growth

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• MicroRNA-155 (miR-155) is an oncogenic microRNA frequently upregulated in solid cancers.
• The precise regulatory mechanisms controlling miR-155 expression and its upregulation in cancer remain incompletely understood.
• Previous studies indicated p63 as a regulator of miR-155.

Purpose of the Study:

• To investigate the distinct roles of the major p63 isoforms, TAp63 and ΔNp63, in regulating miR-155 expression.
• To elucidate the molecular mechanisms underlying p63-mediated control of miR-155 in cancer.

Main Methods:

• Utilized knockdown and overexpression strategies for TAp63 and ΔNp63 isoforms.
• Assessed miR-155 levels in response to p63 isoform manipulation.
• Investigated direct binding of ΔNp63 to the miR-155 host gene using p63 response elements.
• Evaluated the impact of TAp63 knockdown and subsequent miR-155 elevation on cancer cell migration and tumor growth in vitro and in vivo.

Main Results:

• TAp63 knockdown led to elevated miR-155 levels, while TAp63 overexpression reduced them.
• The ΔNp63 isoform was found to directly bind to the p63 response element on the miR-155 host gene.
• Binding of ΔNp63 was enriched upon TAp63 knockdown, suggesting TAp63 may inhibit ΔNp63 binding.
• TAp63 knockdown, causing miR-155 elevation, enhanced cancer cell migration and tumor growth.
• Inhibition of miR-155 abrogated the migratory phenotype induced by TAp63 knockdown.

Conclusions:

• TAp63 plays a critical role in suppressing miR-155 expression.
• ΔNp63 directly binds to the miR-155 host gene, and its binding is influenced by TAp63 levels.
• miR-155 mediates the pro-migratory and tumor-promoting effects observed upon TAp63 knockdown, highlighting a novel regulatory axis in cancer progression.