Loss of the transcriptional repressor TGIF1 results in enhanced Kras-driven development of pancreatic cancer

Ching Chieh Weng, Mei Jen Hsieh, Chia Chen Wu, Yu Chun Lin, Yan Shen Shan, Wen Chun Hung, Li Tzong Chen, Kuang Hung Cheng

研究成果: Article同行評審

15 引文 斯高帕斯(Scopus)

摘要

Background: The TG-interacting factor 1 (TGIF1) gene, which encodes a nuclear transcriptional corepressor of the TGFβ1/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.

原文English
文章編號96
期刊Molecular cancer
18
發行號1
DOIs
出版狀態Published - 2019 5月 20

All Science Journal Classification (ASJC) codes

  • 分子醫學
  • 腫瘤科
  • 癌症研究

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