FAM129A regulates autophagy in thyroid carcinomas in an oncogene-dependent manner

Autor(es)

Nozima, Bruno Heidi ^[1] ; Mendes, Thais Biude ^[1] ; da Silva Pereira, Gustavo Jose ^[2] ; Araldi, Rodrigo Pinheiro ^[1] ; Miazato Iwamura, Edna Sadayo ^[3] ; Smaili, Soraya Soubhi ^[2] ; Griz Carvalheira, Gianna Maria ^[1] ; Cerutti, Janete Maria ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Genet Bases Thyroid Tumors Lab, Dept Morphol & Genet, Div Genet, Sao Paulo, SP - Brazil

^[2] Univ Fed Sao Paulo, Calcium Signaling & Cell Death Lab, Dept Pharmacol, Sao Paulo, SP - Brazil

^[3] Univ Fed Sao Paulo, Lab Patol Mol, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Endocrine-Related Cancer; v. 26, n. 1, p. 227-238, JAN 2019.
• Citações Web of Science: 2

Resumo

We previously proposed that high expression of FAM129A can be used as a thyroid carcinoma biomarker in preoperative diagnostic exams of thyroid nodules. Here, we identify that FAM129A expression is increased under nutrient and growth factor depletion in a normal thyroid cell line (PCCL3), overlapping with increased expression of autophagy-related protein and inhibition of AKT/mTOR/p70S6K. Supplementation of insulin, TSH and serum to the medium was able to reduce the expression of both FAM129A and autophagy-related protein and reestablish the AKT/mTOR/p70S6K axis. To determine the direct role of FAM129A on autophagy, FAM129A was transfected into PCCL3 cells. Its overexpression induced autophagic vesicles formation, evidenced by transmission electron microscopy. Co-expression of FAM129A and mCherry-EGFP-LC3B in PCCL3 showed an increased yellow puncta formation, suggesting that FAM129Ainduces autophagy. To further confirm its role on autophagy, we knockdown FAM129A in two thyroid carcinoma cell lines (TPC1 and FTC-236). Unexpectedly, FAM129A silencing increased autophagic flux, suggesting that FAM129A inhibits autophagy in these models. We next co-transfected PCCL3 cells with FAM129A and RET/PTC1 and tested autophagy in this context. Co-expression of FAM129A and RET/PTC1 oncogene in PCCL3 cells, inhibited RET/PTC1-induced autophagy. Together, our data suggest that, in normal cells FAM129A induces autophagy in order to maintain cell homeostasis and provide substrates under starvation conditions. Instead, in cancer cells, decreased autophagy may help the cells to overcome cell death. FAM129A regulates autophagy in a cell- and/or context-dependent manner. Our data reinforce the concept that autophagy can be used as a strategy for cancer treatment. (AU)

• Processo FAPESP: 14/06570-6 - Sequenciamento completo do exoma, Paired-end RNA e genoma: novos insights sobre a natureza genética do câncer de tiróide na idade adulta e na faixa etária pediátrica e aplicações na prática clínica
• Beneficiário: Janete Maria Cerutti
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/03867-5 - Análise da variação no número de cópias (CNV) de segmentos de DNA em pacientes de uma família com síndrome nem 2ª e mutação p.G533C no gene RET: identificação de regiões associadas à gênese e progressão do carcinoma medular da tiróide
• Beneficiário: Janete Maria Cerutti
• Modalidade de apoio: Auxílio à Pesquisa - Regular