Loss of the transcriptional repressor TGIF1 results in enhanced Kras-driven development of pancreatic cancer.
Mol Cancer
; 18(1): 96, 2019 05 20.
Article
en En
| MEDLINE
| ID: mdl-31109321
BACKGROUND: The TG-interacting factor 1 (TGIF1) gene, which encodes a nuclear transcriptional corepressor of the TGFß1/Smad signaling pathway, has been implicated in the pathogenesis of various types of human cancer; however, its role in pancreatic ductal adenocarcinoma (PDAC) has yet to be elucidated. METHODS: The expression of TGIF1 in human and murine PDAC specimens were detected by IHC analysis. The functions of TGIF1 in in vivo PDAC growth, dissemination, and metastasis were assessed using conditional inactivation of TGIF1 in well-established autochthonous mouse models of PDAC. Primary cells from TGIF1 null or wild type PDAC mice were examined by assays for cell proliferation, migration, invasion, soft agar and xenograft tumorigenesis. Gene expression profiling, pathway analyses, epigenetic changes associated with TGIF1 loss, and in vitro and in vivo effects of 4-MU were assessed. RESULTS: Conditional deletion of TGIF1 in the mouse pancreas had no discernible effect on pancreatic development or physiology. Notably, TGIF1 loss induced KrasG12D-driven PDAC models exhibited shorter latency and greater propensity for distant metastases. Deciphering the molecular mechanisms highlighted the TGIF1 loss-induced activation of the hyaluronan synthase 2 (HAS2)-CD44 signaling pathway and upregulation of the immune checkpoint regulator PD-L1 to facilitate the epithelial-mesenchymal transition (EMT) and tumor immune suppression. We also founded that TGIF1 might function as an epigenetic regulator and response for aberrant EMT gene expression during PDAC progression. CONCLUSIONS: Our results imply that targeting the HAS2 pathway in TGIF1 loss of PDAC could be a promising therapeutic strategy for improving the clinical efficacy against PDAC metastasis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
/
Proteínas Represoras
/
Proteínas Proto-Oncogénicas p21(ras)
/
Proteínas de Homeodominio
/
Perfilación de la Expresión Génica
/
Carcinoma Ductal Pancreático
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Mol Cancer
Asunto de la revista:
NEOPLASIAS
Año:
2019
Tipo del documento:
Article
País de afiliación:
Taiwán
Pais de publicación:
Reino Unido