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The Hedgehog-Gli signaling in tumors and implications for therapy (CROSBI ID 596562)

Prilog sa skupa u zborniku | sažetak izlaganja sa skupa | međunarodna recenzija

Levanat, Sonja ; Car, Diana ; Sabol, Maja ; Musani, Vesna ; Ozretic, Petar ; Gojević, Ante ; Oresković, Slavko The Hedgehog-Gli signaling in tumors and implications for therapy // FEBS 3+ Meeting : From molecules to life and back : book of abstracts / Dumic, Jerka ; Kovarik, Zrinka ; Varljen, Jadranka (ur.). Zagreb: Hrvatsko Društvo za Biotehnologiju, 2012. str. 74-74

Podaci o odgovornosti

Levanat, Sonja ; Car, Diana ; Sabol, Maja ; Musani, Vesna ; Ozretic, Petar ; Gojević, Ante ; Oresković, Slavko

engleski

The Hedgehog-Gli signaling in tumors and implications for therapy

The Hedgehog-Gli (Hh-Gli) signaling pathway is a developmental pathway, which is often found aberrantly active in various tumors. The pathway is a highly coordinated and orchestrated network involving binding of the ligand Hedgehog (Hh) to its receptor, a twelve transmembrane protein, Patched (Ptch). This causes Ptch to release its repression over the coreceptor Smoothened (Smo), a seven transmembrane protein and triggers a cascade of events in the cytoplasm leading to activation of the transcription factor Gli and transcription of target genes. The Gli proteins are regulated by the Suppressor of Fused (SuFu), Protein Kinase A (PKA), Glycogen Synthase Kinase 3β (GSK3β) and Casein Kinase 1 (CK1). The involvement of the Hh-Gli signaling pathway in a variety of human cancers is still not completely elucidated but, preclinical in vitro and in vivo data demonstrate a role of this pathway in cancer pathogenesis, self-renewal and chemotherapy resistance. Our results on several different human cancers show different levels of pathway alterations. We found that the increased level of GSK3b is essential for survival of colon cancer cells and this alters Gli3 processing, keeping the Hh-Gli signaling pathway active. After GSK3 inhibition, Gli3 is processed into its repressor form, the Hh-Gli signaling pathway is downregulated and the proliferation of colon cancer cells is decreased. This suggests a major role for the interplay of GSK3 and Gli3 in the regulation of this pathway in colon cancer. On the other hand, in ovarian tumor pathogenesis we found a difference in SHH gene expression between borderline tumors and carcinoma, with significantly higher expression in borderline tumors compared to carcinoma. However, the upregulation of Hh-Gli signaling in almost all tested samples suggests that this is an early event in ovarian tumorigenesis regardless of tumor type. Our results support the involvment of the Hh-Gli signaling pathway in the pathogenesis of tumors. To date several Smo inhibitors have been proposed as potential candidates for cancer therapy either as a single agent or in combination regimens with conventional chemotherapy. Our results confirm the importance of investigating the role of the Hh-Gli signaling pathway in cancer and they emphasize the need for a better understanding of the modes of Hh-Gli pathway regulation in different tumors, its role in tumor response to traditional therapy, as well as the interactions of the Hh-Gli pathway with other signaling pathways in order to develop better therapies based on combinations with inhibitors of the Hh-Gli signaling pathway.

signaling ; Hedgehog-Gli ; SHH ; therapy

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Podaci o prilogu

74-74.

2012.

nije evidentirano

objavljeno

978-953-95551-4-4

Podaci o matičnoj publikaciji

FEBS 3+ Meeting : From molecules to life and back : book of abstracts

Dumic, Jerka ; Kovarik, Zrinka ; Varljen, Jadranka

Zagreb: Hrvatsko Društvo za Biotehnologiju

Podaci o skupu

FEBS3+ meeting: From Molecules to life and back

pozvano predavanje

13.06.2012-16.06.2012

Opatija, Hrvatska

Povezanost rada

Temeljne medicinske znanosti