1. Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
2. No. 411 Hospital of PLA, Shanghai 200081, China.
3. Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
4. Department of Oncology, No. 150 Central Hospital of PLA, Luoyang, Henan Province 471000, China.
*YQ. W., G.J. and QJ. L. contributed equally to this work as co-first authors.
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.
Keywords: pancreatic ductal adenocarcinoma, hedgehog signaling, hyperplasia stroma, TNF-α, IL-1β.