VOPP1在肺腺癌中透過提高E-cadherin表現量進而抑制細胞移動能力

Abstract

肺癌是致死率相當高的一種癌症。由於近幾年研究人員發現EGFR的突變可能和肺癌的形成有關，尤其是在亞州地區，是以有一系列針對EGFR相關的研究不斷的被加以報導；其中科學家發現當位於第七號染色體上的EGFR基因拷貝數目擴增時，常伴隨著有VOPP1（vesicular, overexpressed in cancer, prosurvival protein 1）基因的共同擴增現象產生。儘管目前已知VOPP1是一個具有促進細胞存活（pro-survival）能力的基因，但其在癌化過程中所扮演的角色與其和EGFR訊號因子間的關聯性仍不十分清楚。在本篇論文中，我們首先利用實驗室所建立的兩組細胞株模組CL1-5 / CL1-0（具有不同癌侵襲能力）以及PC9 / PC9 IR（對於標靶藥物Iressa不同反應性），建立VOPP1 overexpression 與knock down的穩定表現細胞；進一步，利用這些細胞進行一系列的功能性檢測，藉以瞭解VOPP1對於細胞移動能力、細胞凋亡，細胞增生及其對標把藥物治療之反應之影響。實驗結果顯示，當細胞大量表現VOPP1蛋白質時，可能藉由調控鈣黏著素E的表現進而抑制細胞的移動能力。不僅如此，我們的結果也發現，抑制VOPP1可以使對於標靶藥物Irresa具有抗藥性之PC9IR細胞株回復對Iressa的敏感度；同時我們也發現大量表現VOPP1時，對癌細胞生長速率並不會有太大的變化，但抑制VOPP1的表現量則會使得癌細胞生長速率減緩。綜合以上的研究結果，我們可以了解VOPP1在抑制癌轉移及標靶藥物抗藥性的治療上均扮演著極為重要的角色；未來若能針對其相關作用機轉作進一步的研究將有助於肺癌病患的治療。

Lung cancer is the leading cause of cancer-related mortality in the world. Recently, scientists find that EGFR mutation may correlate with lung cancer occurrence especially in Asia. For this reason, more and more references about EGFR and its signaling regulation have been reported. One of them is the finding about co-amplification of EGFR and VOPP1（vesicular, overexpressed in cancer, prosurvival protein 1）on chromosome 7. Until now, we only understand that VOPP1 can promote cell survival but the detail mechanism of VOPP1 in cancer progression and its cross-talk associated with EGFR signaling are still unclear. In this study, we first established VOPP1 overexpression and knock down stable cells in CL1-5/ CL1-0 and PC9/ PC9IR cell models. Then, we used these cell lines to explore the functional role of VOPP1 in cancer cell migration, apoptosis, cell proliferation and sensitivity of target therapy. Our results showed that VOPP1 could inhibit cell migration through up regulate the expression of E-cadherin. Not only this effect, we also observed that knock down the expression of VOPP1 in PC9IR cells can increase the sensitivity of Irresa. In cell proliferation, we also found that overexpression VOPP1 could not affect cell proliferation rate in all our experimental cells, but knock down the expression of VOPP1 in CL1-5 and PC9IR cells may attenuate cell proliferation in both cells. Collectively, we understand that VOPP1 play an important role in suppression of cancer metastasis and resistance of target therapy. It should be helpful for lung cancer treatment to clarify the detail mechanism of how VOPP1 involved in cell migration and drug resistance in the future.