Inhibition of BIRC2 sensitizes α7-HPV related cervical squamous cell carcinoma to chemotherapy (215)

Abstract

<b>Objectives:</b> α7-Human papillomavirus (HPV)-related cervical squamous cell carcinoma (SCC) treated with radiotherapy, or concurrent chemoradiation (RT/CCRT) is associated with poor prognosis. We aimed to discover the underlying relevant biomarkers. <b>Methods:</b> We compared the genomic profiles of α7-HPV-related cervical SCC (2001-2014 cohort) with different responses to radiotherapy or concurrent chemoradiation by microRNA profiling (miR4.0 array) and human transcriptome array 2.0, then verified by a real-time reverse-transcriptase quantitative polymerase chain reaction in order to discover predictive biomarkers. <b>Results:</b> We found significantly lower expression of miR143-3p in tumors with treatment failure (<i>p</i> = 0.0309), while one of the miR143-3p targets baculoviral inhibitor of apoptosis protein (IAP) repeat-containing 2 <i>(BIRC2)</i> mRNA expression (<i>p</i> = 0.0261) and BIRC2 protein levels (<i>p</i> = 0.0023) were significantly higher than those without treatment failure. Moreover, we showed that miR-143-3p sensitizes chemotherapy via targeting <i>BIRC2.</i> Besides, a combination of <i>BIRC2</i> inhibitor (LCL161) and topotecan exerted synergistic effects on cancer cells and animal tumor models. With a pooled cohort of α7-HPV (including mixed infections with coexisting non-α7-HPV(s))-related cervical SCC treated between 1993 and 2014, high <i>BIRC2</i> expression was associated with significantly worse outcome (cancer-specific survival, HR: 1.42; <i>p</i> = 0.008, progression-free survival, HR: 1.64; <i>p</i> = 0.005). <b>Conclusions:</b> These results suggest <i>BIRC2</i> is a novel prognostic factor and therapeutic target for α7-HPV-related cervical SCC.Fig. 1