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Cells. 2019 Feb 6;8(2). pii: E128. doi: 10.3390/cells8020128.

Regulation of Survivin Isoform Expression by GLI Proteins in Ovarian Cancer.

Author information

1
Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia. diana.trnski@irb.hr.
2
Zagreb Health School, Medvedgradska 55, 10000 Zagreb, Croatia. majagr79@gmail.com.
3
Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia. levanat@irb.hr.
4
Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia. pozretic@irb.hr.
5
Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia. nikolina.rincic@gmail.com.
6
Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia. tajana.majic-vidakovic@pporahovica.hr.
7
PP Orahovica, Pustara 1, 33513 Zdenci, Croatia. tajana.majic-vidakovic@pporahovica.hr.
8
Department of Obstetrics and Gynaecology, University Hospital Centre Zagreb, Petrova 13, 10000 Zagreb, Croatia. drzkal@gmail.com.
9
School of Medicine, University of Zagreb, Petrova 13, 10000 Zagreb, Croatia. drzkal@gmail.com.
10
Department of Obstetrics and Gynaecology, University Hospital Centre Zagreb, Petrova 13, 10000 Zagreb, Croatia. imaurac@yahoo.com.
11
Department of Obstetrics and Gynaecology, University Hospital Centre Zagreb, Petrova 13, 10000 Zagreb, Croatia. oreskovic@hdgo.hr.
12
School of Medicine, University of Zagreb, Petrova 13, 10000 Zagreb, Croatia. oreskovic@hdgo.hr.
13
Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia. maja.sabol@irb.hr.
14
Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia. vmusani@irb.hr.

Abstract

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 (BIRC5), 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, 2α, 2B, 3B, and Δex3) 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 BIRC5 polymorphisms in isoform expression. Clinical samples showed the same pattern of survivin isoform expression as in the cell line, and several BIRC5 polymorphisms showed the correlation with isoform expression. Our results showed that survivin isoforms are regulated both by different GLI proteins and BIRC5 polymorphisms in OC.

KEYWORDS:

GLI proteins; Hedgehog signaling; isoform expression; ovarian cancer; polymorphisms; survivin

PMID:
30736319
DOI:
10.3390/cells8020128
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