Nuclear Factor-κB Contributes to Hedgehog Signaling Pathway Activation through Sonic Hedgehog Induction in Pancreatic Cancer

Abstract

The hedgehog (Hh) signaling pathway, which functions as an organizer in embryonic development, is implicated in the development of various tumors. In pancreatic cancer, pathway activation is reported to result from aberrant expression of the ligand, sonic Hh (Shh). However, the details of the mechanisms regulating Shh expression are not yet known. We hypothesized that nuclear factor-KB (NF-KB), a hallmark transcription factor in inflammatory responses, contributes to the overexpression of Shh in pancreatic cancer. In the present study, we found a close positive correlation between NF-KB p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma. We showed that blockade of NF-KB suppressed constitutive expression of Shh mRNA in pancreatic cancer cells. Further activation of NF-KB by inflammatory stimuli, including interleukin-1B, tumor necrosis factor-A, and lipopolysaccharide, induced overexpression of Shh, resulting in activation of the Hh pathway. Overexpression of Shh induced by these stimuli was also suppressed by blockade of NF-KB. NF-KB-induced Shh expression actually activated the Hh pathway in a ligand-dependent manner and enhanced cell proliferation in pancreatic cancer cells. In addition, inhibition of the Hh pathway as well as NF-KB suppressed the enhanced cell proliferation. Our data suggest that NF-KB activation is one of the mechanisms underlying Shh overexpression in pancreatic cancer and that proliferation of pancreatic cancer cells is accelerated by NF-KB activation in part through Shh overexpression.

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“…In most cell types, NF-kB is predominantly a heterodimer composed of the p50 and p65 subunits (Place et al, 2005). Constitutive activation of NF-kB is found in many types of solid tumors (Lu et al, 2004;Nakashima et al, 2006). Other transcriptional regulators whose activities are affected by PI3K/AKT signaling include MIZ-1, p53, activator protein 1 (AP-1), c-Myc, b-catenin and HIF1a (Bader et al, 2005).…”

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“…Constitutive activation of NF-jB is found in many types of solid tumors. 15,16 In contrast to the pleiotropic stimuli that lead to its positive regulation, the known signaling mechanisms that underlie the negative regulation of NF-jB are very few. 17 In addition to the inhibitor of jB kinase (IKK) complex, a number of endogenous molecules that negatively regulate the activation of NF-jB have been identified.…”

Differential expression profiles of the Hedgehog signaling pathway between microsatellite-stable and microsatellite-unstable colorectal cancers

“…The SHH signaling pathway may play a central role in the pathogenesis of CRC and the maintenance of Hh signaling pathways for CRC tumorigenesis (14,15). In certain tumors, such as basal cell carcinoma and central nervous system tumors, active muta- (13,16,17). The Hh pathway plays a significant role in hepatocellular carcinoma development and invasion (18).…”