title: Hedgehog Signaling Non-Canonical Activated by Pro-Inflammatory Cytokines in Pancreatic Ductal Adenocarcinoma.
abstract: Hedgehog(HH) pathway is found to be activated through a manner of canonical, or the non-canonical HH pathways. Distinct hyperplasia stroma around tumor cells is supposed to express pro-inflammatory cytokines abundantly, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), etc. in pancreatic ductal adenocarcinoma (PDAC) tissues. In this study we observed the effects of TNF-α and IL-1β on HH pathway activation in PDAC cells, and explored their activation manners. Our results showed that pro-inflammatory cytokines, TNF-α and IL-1β, could up-regulate the expression of GLI1 gene, increase its nuclear protein expression and promote malignant cell behaviors including migration, invasion, epithelial-mesenchymal transition (EMT) and drug resistance as well. Moreover, GLI1 promoter-reporter assay in combination with blocking either NF-κB or Smoothened (SMO) suggested that TNF-α and IL-1β could transcriptionally up-regulate expression of GLI1 completely via NF-κB, whereas ablation of SMO could not completely attenuate the regulation effects of TNF-α and IL-1β on GLI1 expression. Collectively, our results indicated that TNF-α and IL-1β in hyperplasia stroma can promote the PDAC cell development by activating HH pathway, through both the canonical and non-canonical HH activation ways.
authors.affiliation: Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.; No. 411 Hospital of PLA, Shanghai 200081, China.
authors.forename: Yuqiong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Jin
authors.affiliation: Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.; Department of Oncology, No. 150 Central Hospital of PLA, Luoyang, Henan Province 471000, China.
authors.forename: Quanjiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: No. 411 Hospital of PLA, Shanghai 200081, China.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wang
authors.affiliation: No. 411 Hospital of PLA, Shanghai 200081, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Shude
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
authors.forename: Zhaoshen
authors.initials: Z
authors.lastname: Li
keywords: IL-1β.; TNF-α; hedgehog signaling; hyperplasia stroma; pancreatic ductal adenocarcinoma