GPNMB作為表皮生長因子受體突變之肺癌診斷標的

Abstract

在亞洲，非小型細胞肺癌的基因型態與西方國家有極大的差別，其中又以表皮生長因子受器 (Epidermal Growth Factor Receptor, EGFR) 的突變型態最為顯著。許多研究指出，突變型的表皮生長因子受器，無須經由表皮生長因子 (Epidermal Growth Factor, EGF) 的刺激就能形成雙聚合體 (dimerization) ，進而造成下游訊號的持續活化。目前，對於在這些非小型細胞肺癌中，是否具有一些特殊的膜蛋白可協助參與調控這些突變型表皮生長因子受器，進而使其不斷地活化下游相關的訊息傳遞仍不十分清楚；因此，我們實驗室先前便利用膜蛋白質體的分析技術，配合許多蛋白質交互作用之資料庫訊息分析 (STRING database)，發現有多種膜蛋白的表現會與突變型表皮生長因子受器有所關聯， Glycoprotein non-metastatic b (GPNMB) 便為其中的一個顯著蛋白。本研究中，我們透過多種體外研究的模式，探討GPNMB蛋白質的表現與突變型表皮生長因子受器之間的關聯性。實驗結果顯示，在帶有突變型表皮生長因子的細胞中，GPNMB 蛋白質的表現會大量增加。同時，當在帶有突變型表皮生長因子受器的肺癌細胞表現GPNMB蛋白質時，GPNMB蛋白質會透過酵素的切割，進而使其被釋放到細胞的培養基 (conditioned medium) 中，且其表現量與細胞的遷移能力 (cell migration ability) 呈現高度的正相關性。 本研究希望能釐清未來我們是否能利用釋放型GPNMB蛋白質的偵測，作為評估帶有突變型表皮生長因子受器的病人病情的指標。 此項研究的建立，將能更有效的提升帶有突變型表皮生長因子受器之非小型肺癌病患的病程管理。

In Asia, EGFR is the most common type of oncogenic driver mutation among non-small cell lung cancer patients. Lung cancer cells carrying EGFR mutations are mostly ligand-independent, and some do not require homodimerization to activate downstream signaling pathways. However, it is unclear whether there are any EGFR associated membrane proteins that facilitate the activation of EGFR mutants. Our lab employed membrane proteomic analysis and STRING databases evaluation, and discovered the expression of GPNMB, a type I transmembrane glycoprotein, is correlated with EGFR mutation status. Herein, we inspected the relationship between GPNMB and EGFR mutation in non-small cell lung cancer (NSCLCs). We verified that GPNMB protein was preferentially expressed in cells harboring EGFR mutation. Interestingly, we found that GPNMB may be shed into conditioned medium especially in EGFR mutation, and was highly correlated with cell migration ability. This study enlightened our understanding of the relationship between GPNMB and EGFR mutation and provides a potential biomarker for management of the disease progression of lung cancer patients with EGFR mutation.