吉非替尼是晚期非小细胞肺癌（NSCLC）化疗失败后常用的分子靶向药物，但最终仍出现耐药，机制不明。Connexin（Cx）组成的gap junction（GJ）可增强多种化疗药的细胞毒性，但肿瘤发展过程中常伴GJ缺失。我们前期研究表明，过表达Cx26可增加NSCLC耐药细胞对吉非替尼的敏感性，并上调E-cadherin表达、抑制上皮间质转化（EMT）及侵袭力。过表达Cx26还可抑制耐药细胞Akt活性，PI3K抑制剂可协同Cx26上调E-cadherin表达。用GJ功能抑制剂处理不影响Cx26表达诱导的E-cadherin上调。由此我们提出科学假设：Cx26可独立于GJ功能的形成，本身能抑制PI3K/Akt信号通路激活从而逆转EMT介导的NSCLC吉非替尼耐药。本课题将通过细胞、动物及临床标本明确Cx26对NSCLC的EMT及其介导的吉非替尼耐药的调控作用及分子机制，为临床应用奠定理论基础。

Gefitinib, a molecular-targeted drug, is widely used in non-small-cell lung cancer (NSCLC) patients at advanced stages who failed on other anticancer drugs. Despite initial responses, the patients eventually progress by unknown mechanisms of chemoresistance. It has been reported that cytotoxicity of various chemotherapeutic agents are enhanced by the presence of functional gap junctions (GJ) composed by connexins (Cx) between the targeted cells. Loss of GJIC is well accepted to be correlated with tumorigenic phenotypes. Our preliminary study showed that overexpression of Cx26 in H460 cells (a gefitinib-resistant NSCLC cell line) enhanced the sensitivity to gefitinib, upregulated the expression of E-cadherin, inhibited epithelial-mesenchymal transition (EMT) and invasive ability. Moreover, overexpression of Cx26 could inhibit the Akt activity, and combination treatment of Cx26 overexpression with specific PI3K inhibitor LY294002 resulted in a synergistic increase in E-cadherin expression in H460 cells. Specifically, our study showed that inhibition of gap junctional intercellular communication (GJIC) by oleamide (a widely accepted GJIC inhibitor) did not affect the enhanced effect on E-cadherin expression by Cx26 overexpression. Thus, we propose that Cx26 itself, reverses the EMT-mediated gefitinib resistance of NSCLC, most likely through inactivation of PI3K/Akt pathways in a GJIC-independent manner. Based on these findings, the present study will further explore the effect of Cx26 on EMT and its mediated gefitinib resistance of NSCLC as well as the underline molecular mechanisms in cells, animals and specimens of patients. Our study will lay an important theoretical basis for subsequent clinical application.