Hedgehog pathway improves cell survival against EGFR-TKI treatment through induction of HGF and AKT in lung adenocarcinoma

• Main Authors: Sheng-Ping Yang, 楊笙平
• Other Authors: Cheng-Wen Wu
• Format: Others
• Language: en_US
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/69605216240367574173

碩士 === 國立陽明大學 === 微生物及免疫學研究所 === 102 === Hedgehog stemness pathway plays an important role both in development and in cancer progression. Aberrant activation of Hedgehog pathway has been identified in several cancers, but its importance in lung adenocarcinoma remains unclear. We investigated the gene expressions of a series of Hedgehog component and found that only HHIP, the negative regulator of Hedgehog pathway, was significantly repressed in lung tumors. In contrast, GLI1, the main transcription factor of Hedgehog pathway, showed similar expression level between tumor and paired normal adjacent tissue. We then found that the gene expression of GLI1 can be induced in specific conditions such as serum-starvation or EGFR-TKI treatment, while the overexpression of HHIP can block such induction.　The induction of GLI1 then activated HGF expression and AKT phosphorylation, and improved cell survival and clonogenicity in the presence of EGFR-TKI treatment. Accordingly, the combined treatment of EGFR-TKI with the inhibitors of GLI1 or MET showed a synergistic inhibitor effect on clonogenicity of lung cancer cells. In summary, our results suggested that Hedgehog pathway is a survival signaling in lung cancer that can be induced in response to drug treatment, and the suppression of HHIP is necessary for such induction. The activation of Hedgehog pathway then induced HGF expression and the phosphorylation of MET and AKT, a novel cross-talk that has not been described in literatures. Our data also implied that the combined treatment of EGFR-TKI and GLI1 inhibitor can overcome the primary resistance, which may be applied in clinic for the treatment of lung adenocarcinoma with EGFR mutations.