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Oncogenic properties and signaling basis of the PAX8‐GLIS3 fusion gene
Author(s) -
Basili Thais,
Dopeso Higinio,
Kim Sarah H.,
Ferrando Lorenzo,
Pareja Fresia,
Cruz Paula Arnaud,
Silva Edaise M.,
Stylianou Anthe,
Maroldi Ana,
Marchiò Caterina,
Rubin Brian P.,
Papotti Mauro,
Weigelt Britta,
Moreira Ferreira Carlos Gil,
Lapa e Silva José Roberto,
ReisFilho Jorge S.
Publication year - 2020
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.33040
Subject(s) - oncogene proteins , microbiology and biotechnology , gene , signal transduction , biology , fusion gene , genetics , fusion protein , signaling proteins , regulation of gene expression , cancer research , recombinant dna
Hyalinizing trabecular tumors of the thyroid are rare and mostly benign epithelial neoplasms of follicular cell origin, which have recently been shown to be underpinned by the PAX8‐GLIS3 fusion gene. In our study, we sought to investigate the potential oncogenic mechanisms of the PAX8‐GLIS3 fusion gene. Forced expression of PAX8‐GLIS3 was found to increase proliferation, clonogenic potential and migration of human nonmalignant thyroid (Nthy‐ori 3‐1) and embryonic kidney (HEK‐293) cells. Moreover, in xenografts, Nthy‐ori 3‐1 PAX8‐GLIS3 expressing cells generated significantly larger and more proliferative tumors compared to controls. These oncogenic effects were found to be mediated through activation of the Sonic Hedgehog (SHH) pathway. Targeting of smoothened (SMO), a key protein in the SHH pathway, using the small molecule inhibitor Cyclopamine partially reversed the increased proliferation, colony formation and migration in PAX8‐GLIS3 expressing cells. Our data demonstrate that the oncogenic effects of the PAX8 ‐ GLIS3 fusion gene are, at least in part, due to an increased activation of the SHH pathway.