engleski

Hedgehog-GLI signaling controls proliferation and invasiveness of head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the 6th most malignant tumor type. They usually develop in men over 50 years of age, and are most often associated with smoking, alcohol consumption, bad oral hygiene and infection with human papillomaviruses. HNSCC is mostly treated surgically, and only higher stages (III or IV) receive radio- or chemotherapy after surgery. Chemotherapy is very general, cisplatin is most commonly used. The prognosis for high stages is poor, and there is a requirement for better and more effective therapeutics. One of the signaling pathways involved in the development of HNSCC is the Hedgehog-GLI (HH- GLI) signaling pathway. HH-GLI is a proliferative pathway mostly active during embryonic development, and deactivated in differentiated adult tissues, except in the stem cell compartment where it is involved in stem cell maintenance and response to injury. Its aberrant activation is associated with many tumors, and this occurs by different mechanisms in different tumor types. Pathway activation results in accumulation of transcription factors GLI (GLI1, GLI2 or GLI3), which are responsible for transcription of genes involved in proliferation, cell cycle, self-renewal, angiogenesis and epithelial- mesenchymal transition. In this work we wanted to examine the effect of several HH-GLI pathway inhibitors on HNSCC cell proliferation, migration and colony formation capabilities, and to determine which of the three GLI proteins is the main effector of the pathway. We tested the effect of cyclopamine, GANT-61 and lithium chloride on properties of 5 HNSCC cell lines, and analyzed expression of GLI proteins by Western blot. All the cell lines show better responsiveness to downstream inhibitors such as GANT-61 and lithium chloride in comparison to the upstream inhibitor cyclopamine, suggesting that the pathway is at least partly activated non- canonically. GLI3 was found to be the most expressed on both RNA and protein levels, and it was the most responsive of all three GLI proteins to pathway inhibition. Until now most publications have focused on GLI1 protein, and no data is available on the role of GLI3 in HNSCC. In this work we have demonstrated that GLI3 plays a major role in HNSCC cell lines.

HNSCC ; GLI ; GANT-61 ; LiCl

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