In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 5320-5320
Abstract:
Sonic hedgehog signaling pathway plays an important role in the metastasis of various organs. Recently, we found that increased shh producing cells correlate with enhanced migration, invasiveness and increased lymphangiogenesis in Non-small-cell lung cancer (NSCLC), but the mechanism is unknown. In this study, we investigated the function of shh pathway in human NSCLC. We performed immunohistochemistry on lung tumor biopsies and the result showed the expressions of shh, Gli1, VEGF-D and LYVE1 were enhanced in lymph node metastasis specimens compared to lymph node negative lung cancer specimens. We also investigated the role of shh signaling in the invasiveness and the motility of NSCLC. We found that Shh N-terminal peptide (N-shh) enhanced cell motility and invasiveness in NSCLC, and this process was inhibited by AAD-cyclopamine (SMO inhibitor). We observed that the mRNA expressions of shh, Gli1, VEGF-D and LYVE1 were enhanced by N-shh treatment, whereas no increase of these factors was observed when KAAD-Cyclopamine (a Shh signaling inhibitor) was treated together. In addition, we confirmed that Shh-induced lymphangiogenesis and motility/invasiveness of NSCLC are also reduced by LY294002, PI-3 Kinase/Akt inhibitor meaning that shh pathway and PI-3 Kinase/Akt are strongly related. Thus, we investigated the functional relationship between Shh and Akt signaling in the metastatic progression in NSCLC. Phosphorylation of Akt was enhanced by N-Shh, but regulated by KAAD-cyclopamine or LY294002. We further analyzed the effects of shh signaling in vitro by stimulating a HMVEC with N-shh and we observed N-shh enhanced the tube formation on matrigel, but the enhancement was inhibited upon cyclopamine or LY294002 treatment. The ROS production was increased in shh-overexpressing cells. These results indicate that shh signaling pathway can contribute to ROS generation enhancing the metastatic and lymphangiogenetic potential of tumor cells. Our findings suggest that Shh-Akt signaling processes through ROS and the activation of these pathway increases the metastatic potential of non-small cell lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5320. doi:1538-7445.AM2012-5320
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2012-5320
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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