Abstract:
:Gallbladder cancer (GBC) is a highly malignant bile duct cancer with poor prognosis due to early invasion and metastasis. However, the molecular mechanisms through which GBC cells interact with the tumor microenvironment (TME) remain poorly understood. Here, we examined the role of the tumor suppressor apoptosis-stimulating of p53 protein 2 (ASPP2) in regulating GBC invasion and metastasis and macrophage recruitment. The clinicopathological significance of ASPP2 expression was measured by immunohistochemical analysis in 72 patients with GBC. Lentivirus-mediated knockdown or overexpression of ASPP2 was used to investigate the biological functions and molecular mechanisms of ASPP2 in GBC cells. Our data showed that downregulation of ASPP2 in patients with GBC was linked to poor prognosis. Knockdown of ASPP2 induced epithelial-mesenchymal transition (EMT) in GBC cells and influenced the TME. Mechanistically, we further confirmed that ASPP2 affected the expression and protein binding between atypical protein kinase C (aPKC)-ι and glioma-associated oncogene homolog 1 (GLI1). ASPP2 also induced C-C motif chemokine ligand (CCL) 2, CCL5, and tumor necrosis factor-α secretion by cancer cells, thereby promoting macrophage recruitment. The latter also induced EMT-like changes in GBC. Furthermore, ASPP2 deficiency regulated GLI1 transcriptional activity via the noncanonical Hedgehog (Hh) pathway and aPKC-ι/GLI1 signaling loop and promoted GLI1 nuclear localization and binding to the promoters of target genes. Our findings revealed that downregulation of ASPP2 promoted GBC invasion and metastasis through the aPKC-ι/GLI1 pathway and enhanced macrophage recruitment. Thus, ASPP2/aPKC-ι/GLI1 pathway may be a potential therapeutic target for the treatment of GBC.
journal_name
Cell Death Disjournal_title
Cell death & diseaseauthors
Tian L,Deng Z,Xu L,Yang T,Yao W,Ji L,Lu Y,Zhang J,Liu Y,Wang Jdoi
10.1038/s41419-018-1145-1subject
Has Abstractpub_date
2018-11-02 00:00:00pages
1115issue
11issn
2041-4889pii
10.1038/s41419-018-1145-1journal_volume
9pub_type
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