Pregnancy-specific glycoprotein 9 acts as both a transcriptional target and a regulator of the canonical TGF-ß/Smad signaling to drive breast cancer progression.
Clin Transl Med
; 10(8): e245, 2020 Dec.
Article
em En
| MEDLINE
| ID: mdl-33377651
ABSTRACT
Pregnancy-specific glycoprotein 9 (PSG9) is a placental glycoprotein essential for the maintenance of normal gestation in mammals. Bioinformatics analysis of multiple publicly available datasets revealed aberrant PSG9 expression in breast tumors, but its functional and mechanistic role in breast cancer remains unexplored. Here, we report that PSG9 expression levels were elevated in tumor tissues and plasma specimens from breast cancer patients, and were associated with poor prognosis. Gain- or loss-of-function studies demonstrated that PSG9 promoted breast cancer cell proliferation, migration, and invasionin vitro, and enhanced tumor growth and lung colonization in vivo. Mechanistically, transforming growth factor-ß1 (TGF-ß1) transcriptionally activated PSG9 expression through enhancing the enrichment of Smad3 and Smad4 onto PSG9 promoter regions containing two putative Smad-binding elements (SBEs). Mutation of both SBEs in the PSG9 promoter, or knockdown of TGF-ß receptor 1 (TGFBR1), TGFBR2, Smad3, or Smad4 impaired the ability of TGF-ß1 to induce PSG9 expression. Consequently, PSG9 contributed to TGF-ß1-induced epithelial-mesenchymal transition (EMT) and breast cancer cell migration and invasion. Moreover, PSG9 enhanced the stability of Smad2, Smad3, and Smad4 proteins by blocking their proteasomal degradation, and regulated the expression of TGF-ß1 target genes involved in EMT and breast cancer progression, thus further amplifying the canonical TGF-ß/Smad signaling in breast cancer cells. Collectively, these findings establish PSG9 as a novel player in breast cancer progressionvia hijacking the canonical TGF-ß/Smad signaling, and identify PSG9 as a potential plasma biomarker for the early detection of breast cancer.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
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Outros_tipos
Base de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
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Screening_studies
Idioma:
En
Revista:
Clin Transl Med
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China