上皮生長因子受器可移行至粒線體且可調節粒線體動態平衡並促進非小細胞肺癌之轉移

Abstract

粒線體功能失常被發現與癌症產生有相關連。在本篇研究中，我們利用同位素相對標記與絕對定量技術（isobaric tag for relative and absolute quantitation, iTRAQ）分析具有不同侵襲能力的肺癌細胞中其粒線體蛋白質的組成有何不同。我們發現上皮生長因子受器（Epidermal growth factor recptor, EGFR）在具有高度侵襲能力的CL1-5細胞粒線體中量較多。另外，我們發現EGF可以使EGFR移至粒線體中並引起粒線體的形態改變分裂。也因此粒線體EGFR促使能量產升上升、細胞運動能力增加，且造成粒線體分布到運動偽足前側。另外，無論EGFR磷酸化與否，EGFR都可以影響粒線體形態。粒線體中EGFR被發現可與粒線體融合蛋白Mfn1交互作用，在mitEGFR表現的細胞中過量表現Mfn1後，可發現Mfn1可以回復mitEGFR所造成細胞特性改變，諸如粒線體形態改變、能量產生與細胞運動能力，發現mitEGFR可能是藉由影響Mfn1聚合而影響粒線體形態。有趣的是，由臨床病人檢體發現，粒線體中EGFR表現與病人存活率呈現負相關，且相較於原位癌部位，在淋巴癌轉移部位之粒線體EGFR表現量相對較多。總結來說，本篇研究發現EGFR可藉由EGF引起的內吞現象轉位到粒線體中，並且造成粒線體形態分裂，而引起能量產生改變、粒線體分布於運動偽足前端，進而使癌細胞運動能力上升。粒線體EGFR的存在可能與癌細胞侵襲相關，且可做為癌症預後因子。

Dysfunction of the mitochondria, the versatile cellular organelles, is shown to be related to cancer progression. In the present study, the iTRAQ was exploited to analyze mitochondrial proteomics of lung cancer cell lines with variable migration abilities. We found that EGFR is highly expressed in highly invasive lung cancer cell mitochondria. We demonstrated that the mitochondrial translocation of EGFR by EGF induces mitochondrial fission, and upregulates energy production, causes mitochondrial redistribution in the lamellipodia, and enhances cell motility. Besides, EGFR can still regulate mitochondria dynamics and cell motility, independent of its phosphorylation status. Furthermore, EGFR was found to interact with mitofusion1 (Mfn1), a mitochondrial protein which causes mitochondria fusion by polymerization to regulate mitochondrial dynamics. Overexpressing Mfn1 significantly reversed the phenotypes resulted from mitochondrial translocation of EGFR. Corresponding to the above finding, the EGFR expression in cytosol rather than on the cell surface is reversely correlated to the overall survival of NSCLC patients. Notably, the cytosolic EGFR expression levels in the lymph node-locating tumor cells are higher than that of the paired primary tumor sites. Collectively, our results show that mitochondrial EGFR plays an important role on mitochondrial morphology, energy production and distributions, which further promotes cellular motility. Accordingly, mitochondrial EGFR expression is involved in cancer invasion and can serve as a diagnostic marker for predicting NSCLC malignancy.