Regulation of Survivin Isoform Expression by GLI Proteins in Ovarian Cancer

• Main Authors: Diana Trnski, Maja Gregorić, Sonja Levanat, Petar Ozretić, Nikolina Rinčić, Tajana Majić Vidaković, Držislav Kalafatić, Ivana Maurac, Slavko Orešković, Maja Sabol, Vesna Musani
• Format: Article
• Language: English
• Published: MDPI AG 2019-02-01
• Series: Cells
• Subjects: Hedgehog signaling; GLI proteins; survivin; ovarian cancer; isoform expression; polymorphisms
• Online Access: https://www.mdpi.com/2073-4409/8/2/128

Ovarian cancer (OC) is the most lethal female gynecological malignancy, mostly due to diagnosis in late stages when treatment options are limited. Hedgehog-GLI (HH-GLI) signaling is a major developmental pathway involved in organogenesis and stem cell maintenance, and is activated in OC. One of its targets is survivin (<i>BIRC5</i>), an inhibitor of apoptosis protein (IAP) that plays a role in multiple processes, including proliferation and cell survival. We wanted to investigate the role of different GLI proteins in the regulation of survivin isoform expression (WT, 2&#945;, 2B, 3B, and &#916;ex3) in the SKOV-3 OC cell line. We demonstrated that survivin isoforms are downregulated in GLI1 and GLI2 knock-out cell lines, but not in the GLI3 knock-out. Treatment of GLI1 knock-out cells with GANT-61 shows an additional inhibitory effect on several isoforms. Additionally, we examined the expression of survivin isoforms in OC samples and the potential role of <i>BIRC5</i> polymorphisms in isoform expression. Clinical samples showed the same pattern of survivin isoform expression as in the cell line, and several <i>BIRC5</i> polymorphisms showed the correlation with isoform expression. Our results showed that survivin isoforms are regulated both by different GLI proteins and <i>BIRC5</i> polymorphisms in OC.