Hypoxia activates the hedgehog signaling pathway in a ligand‐independent manner by upregulation of Smo transcription in pancreatic cancer

Abstract

The hedgehog (Hh) signaling pathway is activated in various types of cancer including pancreatic ductal adenocarcinoma. It has been shown that extremely low oxygen tension (below 1% O 2 ) is found in tumor tissue including pancreatic ductal adenocarcinoma cells (PDAC) and increases the invasiveness of PDAC. To investigate the contribution of the Hh pathway to hypoxia-induced invasiveness, we examined how hypoxia affects Hh pathway activation and the invasiveness of PDAC. In the present study, three human PDAC lines were cultured under normoxic (20% O 2 ) or hypoxic (1% O 2 ) conditions. Hypoxia upregulated the transcription of Sonic hedgehog (Shh), Smoothened (Smo), Gli1 and matrix metalloproteinase9 (MMP9) and increased the invasiveness of PDAC. Significantly, neither the addition of recombinant Shh (rhShh) nor the silencing of Shh affected the transcription of these genes and the invasiveness of PDAC. On the other hand, silencing of Smo decreased the transcription of Gli1 and MMP9 and PDAC invasiveness. Silencing of Gli1 or MMP9 decreased PDAC invasiveness. These results suggest that hypoxia activates the Hh pathway of PDAC by increasing the transcription of Smo in a ligand-independent manner and increases PDAC invasiveness. (Cancer Sci 2011; 102: 1144-1150

Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway

“…Activation of MMPs has been detected in almost all type of human cancers, which is closely correlated to advanced tumor stage, increasing tumor invasion and metastasis. Onishi et al reported that the Hh signaling pathway up-regulated cell migration and invasion in human cancers by increasing expressions of MMP-9 [50] . However, the relationship among the Hh signaling pathway, MAPK/ERK pathway and MMP-9 remains unclear.…”

“…Overexpression of MMP-9 is also a key factor for tumor invasion and metastasis [47,48,55] . Moreover, the Hh signaling pathway may enhance migration and invasion of cancer cells by increasing the expression of MMP-9 [49,50] .…”

“…The Hh signaling pathway up-regulates cell migration and invasion in human gliomas and in pancreatic cancer by increasing the expressions of MMP-9 [49,50] . In addition, Smo and MMP-9 were overexpressed and associated with invasion and metastasis in HCC tissues [51] .…”

Hedgehog signaling pathway as a therapeutic target in various types of cancer

“…Moreover, we reported that Hh signaling contributes to invasiveness under hypoxic conditions, which is observed in regions that are distant from the supporting tumor vasculature and is characteristic of pancreatic cancer. (53,54) In this report it is demonstrated that hypoxia-induced invasiveness is caused by increased transcription of Smo and that this invasiveness is ligand independent. Collectively, Hh signaling is believed to significantly contribute to cancer invasiveness.…”

Anticancer Effect of Phellinus linteus; Potential Clinical Application in Treating Pancreatic Ductal Adenocarcinoma

“…Based on the previous observation that HIF-1α and Hedgehog (Hh) signal pathway independently regulate the proliferation and invasiveness under the hypoxia [46], Onish et al [47], demonstrated PSK decreased proliferation in PDAC cells under hypoxia, and it definitely inhibited invasiveness of human pancreatic ductal cell lines (ASPC-1, and SUIT-2). PSK was also noted to decrease the expression of HIF-1α and hedgehog (Hh) signaling-related molecules under hypoxia, in turn, this inhibition of HIF-1α and Hh signaling reduced proliferation and invasiveness in PDAC cells under hypoxic condition.…”