Inflammation Promotes Invasion Through NF-κB/PP2Ac Pathway Dependent Manner In Pancreatic Cancer Cells

Background: In?ammation plays a multifaceted role in pancreatic cancer progression.Previous studies indicated that inflammatory stimulation could induce repression on protein phosphatase 2A(PP2A), a well accepted tumor suppressor.However, whether the repression on PP2 A participates in pancreatic cancer progression has not been verified. The experiment studyes the role of the NF-kappa B/PP2 Ac signaling pathway by which the inflammation promotes the metastasis of pancreatic cancer.Methods:1. In the present study, we used lipopolysaccharide(LPS), a potent activator of inflammation, to establish an in vitro inflammatory model2. We used DBTC induced chronic pancreatitis mouse model.3. By using these models, we investigated the relationship between inflammation and PP2 Ac expression in vivo and in vitro by using RT-PCR and Western blot.4. Activation of NF-κB pathway was measured by using Milliplex assay and luciferase reporter gene assay.5. Phosphorylation levels of JNK, ERK, PKC, Akt and IKK were measured by using Western blot.6. Proliferation was determined by MTT.7. Invasion was determined by Transwell.Results: Treatment of LPS repressed expression of phosphatase 2A catalytic subunit(PP2Ac). The down-regulation of PP2 Ac could also be detected in the DBTC-induced chronic pancreatitis mouse model. LPS induced activation of NF-κB pathway, the key pathway involved in inflammatory response, by inducing phosphorylation of IKK and IκB,which further leading to nucleus translocation and transcriptional activation of p65.Down-regulation of PP2 Ac could be attenuated by overexpression of dominant negative form of IKKα(DN-IKKα, S176/180A) or DN-IκBα(S32/36A), suggesting LPS repressedPP2Ac expression through a NF-κB pathway dependent manner. Luciferase reporter gene assay further verified that LPS down-regulated transcription of PP2 Ac through NF-κB pathway dependent manner. The down-regulation of PP2 Ac resulted in phosphorylation of oncogenic JNK, ERK, PKC, Akt and IKK, all of which are substrates of PP2 A. Cellular biology behavior investigations further confirmed that LPS had no effect on pancreatic cancer cell growth but promoted cell invasion through a PP2 Ac pathway dependent manner.Conclusions: Taken together, our present study provides a new mechanism involved in the inflammation-driven cancer progression through NF-κB pathway dependent repression on PP2 Ac.