Desmoglein-2 modulates tumor progression and osimertinib drug resistance through the EGFR/Src/PAK1 pathway in lung adenocarcinoma
Desmoglein-2 modulates tumor progression and osimertinib drug resistance through the EGFR/Src/PAK1 pathway in lung adenocarcinoma
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Desmoglein-2 通过 EGFR/Src/PAK1 通路调节肺腺癌的肿瘤进展和奥希替尼耐药性
DOI：
10.1016/j.canlet.2020.04.001
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发表时间：
2020-07-28
期刊：
影响因子：
9.7
通讯作者：
He, Jie
中科院分区：
文献类型：
--
作者：
Jin, Runsen;Wang, Xinfeng;He, Jie
桥粒芯糖蛋白-2（DSG 2）是钙粘蛋白超家族的成员，与细胞间粘附和肿瘤发生有关。在这里，我们证明了肺腺癌（LUAD）细胞系和组织中DSG 2的高表达与LUAD患者的预后不良相关。值得注意的是，DSG 2过表达促进细胞增殖和迁移，并增加对EGFR酪氨酸激酶抑制剂奥希替尼的耐药性，而DSG 2沉默可以逆转这些结果。此外，细胞膜中DSG 2与EGFR之间的直接相互作用刺激EGFR信号传导以促进肿瘤发生，并且DSG 2的缺失导致EGFR易位到细胞质中。此外，DSG 2是EGFR与Src结合所必需的;因此，DSG 2沉默通过抑制EGFR-Src-Racl-PAK 1信号传导途径抑制肿瘤细胞恶性肿瘤。与这些发现一致，使用H1975细胞的裸鼠异种移植模型证明DSG 2促进体内LUAD细胞生长并增加奥希替尼耐药性。总的来说，这些观察结果首次阐明了DSG 2通过EGFR信号传导在肺腺癌的发展和进展中的独特作用。
Desmoglein-2 (DSG2), a member of the cadherin superfamily, has been implicated in cell-cell adhesion and tumorigenesis. Here, we demonstrate that high DSG2 expression in both lung adenocarcinoma (LUAD) cell lines and tissues is associated with poor prognosis in LUAD patients. Notably, DSG2 overexpression promoted cell proliferation and migration, and increased resistance to the EGFR tyrosine kinase inhibitor osimertinib, whereas DSG2 silencing could reverse these results. Moreover, direct interaction between DSG2 and EGFR in the cell membrane stimulated EGFR signaling to promote tumorigenesis, and loss of DSG2 resulted in EGFR translocation into the cytoplasm. In addition, DSG2 was required for EGFR binding to Src; consequently, DSG2 silencing inhibited tumor cell malignancy via suppression of the EGFR-Src-Racl-PAK1 signaling pathway. Consistent with these findings, a nude mouse xenograft model using H1975 cells demonstrated that DSG2 promoted LUAD cell growth in vivo and increased osimertinib resistance. Collectively, these observations are the first to elucidate a unique role for DSG2 in the development and progression of lung adenocarcinoma via EGFR signaling.