Abstract
The failure of targeted therapy due to the resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, is considered a major problem in the treatment of non-small cell lung cancer (NSCLC) patients. Shisa3, a novel tumor suppressor, is associated with prolonged survival through promoting β-catenin degradation in NSCLC. Nevertheless, the relationship between Shisa3 and EGFR-TKIs resistance has not been elucidated. The correlation of shisa3 and EGFR-TKI resistance were determined by comparison of gene expression profiles in NSCLC patient tumor samples with different therapeutic benefits for EGFR-TKIs. The effect of Shisa3 on drug sensitivity, invasion, and migration in NSCLC cells and on tumor growth and drug susceptibility in mice models were examined by knockdown and overexpression of Shisa3. The underlying mechanism of Shisa3 was explored by microarray and pathway analysis. Finally, the correlation of Shisa3 expression and clinical effect for EGFR-TKIs was also calculated. We identified that Shisa3 was highly expressed in the tumor tissues of patients with partial response (PR) in EGFR-TKIs treatment and is down-regulated in gefitinib-resistant (PC9-Gef, H1975, H1650) cells compared to gefitinib-sensitive (PC9, HCC827) cells. The down-regulation of Shisa3 could induce gefitinib resistance and enhance invasiveness through PI3K/AKT/mTOR signaling predicted by microarray analysis. Furthermore, the down-regulated expression of Shisa3 could inhibit the activation of autophagy. Rather, the up-regulation of shisa3 could enhance gefitinib sensitivity by inhibit PI3K/AKT/mTOR signaling and the activation of autophagy. In addition, our data confirmed that Shisa3 was positively associated with clinical effect for EGFR-TKIs in 20 NSCLC patients. Our results reveal that the prospective role of Shisa3 as a novel biomarker for acquired gefitinib resistance and a potential target for NSCLC treatment.
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