p53-Independent Negative Regulation of p21/Cyclin-Dependent Kinase–Interacting Protein 1 by the Sonic Hedgehog-Glioma-Associated Oncogene 1 Pathway in Gastric Carcinoma Cells

Abstract

The activation of Hedgehog (Hh) signaling has been implicated in the growth of various tumor types, including gastric carcinoma. However, the precise mechanisms of Hh activation and suppression of tumor growth by the blockade of Hh signaling in gastric carcinoma cells remain unknown. The aim of this study was to elucidate the mechanism of abnormal Hh signaling and the key molecules contributing to dysregulated growth of gastric carcinoma. The Sonic hedgehog (Shh) ligand and its receptor Patched were expressed in all five gastric carcinoma cell lines examined (MKN1, MKN7, MKN45, MKN74, and AGS cells). The blockade of Hh signaling with anti-Shh antibody inhibited the growth of all five gastric carcinoma cell lines. Shh was overexpressed (mean, 12.8-fold) in 8 of 14 (57.0%) cancerous tissue samples from patients with gastric carcinoma as compared with expression in the surrounding noncancerous tissues. The disruption of glioma-associated oncogene 1 (Gli1) by small interfering RNA induced an increase in p21/cyclin-dependent kinase-interacting protein 1 (CIP1), interfered with the G 1 -S transition, and suppressed cell proliferation. The stimulation or inhibition of Hh signaling did not affect p53 activity and the induction of p21/CIP1 expression and the G 1 arrest by inhibition of Hh signaling were not affected by the p53 status. These findings suggest that the overexpression of Shh contributes to constitutive Hh activation and that this signaling pathway negatively regulates p21/CIP1 through a Gli1-dependent and p53-independent mechanism in gastric carcinoma cells. (Cancer Res 2005; 65(23): 10822-9)

Inhibition of smoothened decreases proliferation of synoviocytes in rheumatoid arthritis

“…26 In addition, Shh signaling has been described to negatively regulate p21/CIP1, a suppressor of the G 1 /S transition. 27 We now demonstrate that the disruption of Smo by siRNA negatively regulated the expression of cyclin D1 and E1 while increasing p21/CIP1 expression in FLSs, further validating observations previously reported in other cell types. Thus, our results suggest that Shh signaling promotes cell cycle progression in FLSs through interactions with G 1 cyclins and a cyclin-dependent kinase inhibitor, providing further support for the role of Shh in the proliferation of FLSs.…”

Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: It's inhibition leads to growth suppression and apoptosis

“…This might be consistent with a recent report showing that G 1 arrest by inhibition of Hh signaling was not affected by p53 status. (30) In addition, we showed that longterm treatment with cylopamine induced the apoptosis of ovarian carcinoma cells in vitro. These findings suggest that suppression of the Hh signal pathway may be a promising candidate as a new treatment strategy for ovarian carcinoma.…”

Expression and Clinical Significance of Hedgehog Signaling Pathway Related Components in Colorectal Cancer

“…SHH was overexpressed 12.8-fold of tumor tissues as compared with that in the surrounding non-cancerous gastric tissue. There was no correlation between the levels of SHH mRNA expression and the pathologic or clinical features of the tumor, including tumor type, size, location, and stag (Ohta et al, 2005). The elevated expression of Hh target genes PTCH1 or GLI1 occurred in 63 of the 99 primary gastric cancers.…”