Phospho-ΔNp63α-responsive microRNAs contribute to the regulation of necroptosis in squamous cell carcinoma upon cisplatin exposure

• ΔNp63α-regulated microRNAs affect the expression of CYLD, RIPK1, and MLKL.
• ΔNp63α-regulated microRNAs modulate formation of necroptotic protein complexes.
• miR-101-3p mimic increases the resistance of sensitive tumor cells to cisplatin.
• RIPK1 siRNA increases the resistance of sensitive tumor cells to cisplatin.
• Necroptotic inhibitors increase the resistance of sensitive tumor cells to cisplatin.
• miR-101-3p inhibitor increases the sensitivity of tumor cells to cisplatin.

This study shows that specific microRNAs differentially regulated by ΔNp63α in cisplatin-sensitive and resistant squamous cell carcinoma (SSC) cells of larynx and tongue affect the expression of members of the necroptotic pathway CYLD, RIPK1, and MLKL. Different degrees of protein interaction between necroptotic signaling intermediates were also observed in SCC cells sensitive or resistant to cisplatin. Modulation of RIPK1 with miR-101-3p mimic or inhibitor, as well as with siRNA, or chemical inhibitors was shown to affect sensitivity of SCC cells to cisplatin. This is the first report showing the modulatory effect of ΔNp63α-responsive microRNAs on the specific members of necroptotic pathway in SCC tumor cells variably responding to platinum chemotherapy.