Targeting Hedgehog Pathway and DNA Methyltransferases in Uterine Leiomyosarcoma Cells

Autor(es)

Garcia, Natalia ^[1] ; Al-Hendy, Ayman ^[2] ; Baracat, Edmund C. ^[1] ; Carvalho, Katia Candido ^[1] ; Yang, Qiwei ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Lab Ginecol Estrut Mol LIM 58, Dept Obstet & Ginecol, Disciplina Ginecol, Hosp Clin Fac Med, Ave Dr Arnaldo 455, Sala 4121, BR-05403010 Sao Paulo - Brazil

^[2] Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 - USA

• Tipo de documento: Artigo Científico
• Fonte: CELLS; v. 10, n. 1 JAN 2021.
• Citações Web of Science: 0

Resumo

Uterine leiomyosarcoma (LMS) is an aggressive tumor that presents a poor prognosis, high rates of recurrence, and metastasis. Because of its rarity, there is no information available concerning LMS molecular mechanisms of origin and development. Here, we assessed the expression profile of Hedgehog (HH) signaling pathway markers and the effects of their pharmacological inhibition on uterine smooth muscle (UTSM), leiomyoma, and LMS cells. Additionally, we also evaluated the effects of DNMTs inhibition on LMS cell behavior. Cell proliferation, migration and apoptosis rates were evaluated by MTT, Scratch, and Annexin V assays, respectively. RNA expression and protein levels were assessed by qRT-PCR and Western blot. We found that SMO and GLIs (1, 2, and 3) expression was upregulated in LMS cells, with increased nuclear levels of GLI proteins. Treatment with LDE225 (SMOi) and Gant61 (GLIi) resulted in a significant reduction in Glis protein levels in LMS (p < 0.05). Additionally, the expression of DNMT (1, 3a, and 3b), as well as GLI1 nuclear expression, was significantly decreased after treatment with HH inhibitor in LMS cells. Our results showed that blocking of SMO, GLI, and DNMTs is able to inhibit LMS proliferation, migration, and invasion. Importantly, the combination of those treatments exhibited a potentiated effect on LMS malignant features due to HH pathway deactivation. (AU)

• Processo FAPESP: 17/24448-1 - Avaliação in vitro e in vivo dos efeitos dos inibidores SHH no leiomioma e Leiomiossarcoma uterino
• Beneficiário: Natália Garcia
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado