Naslov
Imaging the Hh-Gli signalling network in various tumor types

Autori
Trnski, Diana ; Sabol, Maja ; Ozretic, Petar ; Musani, Vesna ; Horvat, Lucija ; Weber, Igor ; Levanat, Sonja

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
3rd Croatian Microscopy Congress with international participation / Ambriovic Ristov , Andreja ; Gajović, Andreja ; Weber, Igor ; Vidoš, Ana - Zagreb : Institut Ruđer Bošković, 2015, 30-31

ISBN
978-953-7941-05-5

Skup
3rd Croatian Microscopy Congress with international participation

Mjesto i datum
Zadar, Hrvatska, 26.04.2015. - 29.04.2015

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Hh-Gli signaling; confocal microscopy; tumors

Sažetak
In adult organisms, the Hedgehog-Gli pathway contributes to homeostasis and regeneration of certain tissues such as skin and bone, it is active almost exclusively in somatic stem cells, but aberrant activation of the Hh pathway has been linked to tumorigenesis. The pathway activation begins when the ligand Shh binds to its receptor, Patched (Ptch1), resulting in the de-repression of the co-receptor Smoothened (Smo). This triggers a cascade of events in the cytoplasm leading to activation of the transcription factors Gli and transcription of their target genes. The Gli proteins are regulated by the Suppressor of Fused (SuFu), and 3 kinases, including GSK3β, that regulate the processing of Gli proteins. Today it is generally recognized that this pathway is activated in various types of cancer through different mechanisms and it contributes to cancer proliferation, progression and invasiveness. Therefore, this pathway is anticipated to provide a new avenue for cancer therapy. In our research we used confocal imaging to study the mechanisms of pathway activation in several tumor types. We tracked the changes in localization of pathway components on various levels of the signaling cascade that might indicate pathway modulation. We have observed pathway activation in ovarian dermoids and ovarian carcinomas. We have shown that ovarian dermoid and carcinoma cells respond to pathway activation and inhibition on the upper level of the cascade. On cellular level this can be seen as internalization of the receptor in complex with ligand after pathway activation, and decreasing the localization of the pathway effector Gli1 in the nucleus after pathway inhibition. These results indicate that the Hh-Gli signaling pathway is activated canonically in ovarian tumors (Sabol et al 2012). On the other hand, in breast cancer we observed a cross-talk between Hh-Gli signaling (Shh ligand) and the estrogen receptor, creating a potentially new signaling network (Sabol et al, 2014). Furthermore, in colon cancer cells we observed noncanonical hyperactivation of the pathway caused by the deregulated regulatory kinase GSK3β. Deregulated GSK3β activity leads to overproduction of activator form of Gli3 and to pathway hyperactivation. Inhibition of GSK3β leads to increased co-localization of GSK3β and Gli3 indicating improved regulation of Gli3 processing and results in pathway downregulation (Gojević 2011, Trnski 2015). This suggests a major role for the interplay of GSK3β and Gli3 in the regulation of this pathway in colon cancer (publication in preparation). The importance of investigating Hh-Gli signaling and its mechanisms of activation is underlined by the estimates that the pathway may be active in one third of all cancers. Better understanding of the modes of Hh-Gli pathway regulation, as well as of interactions of the pathway with other signaling pathways, has an obvious potential for development of better therapies that would be based on combined effects of the Hh-Gli and other pathways inhibitors.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

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