探討Role of Kelch-Like ECH-Associated Protein 1 (KEAP1)在人類肺腺癌移動與浸襲之角色

Abstract

在非小細胞肺癌(Non-small cell lung cancer)的研究證明，KEAP1 (Kelch-like ECH-associated protein 1)表現量降低使NRF2 (NF-E2-related factor 2)在細胞核內大量累積，造成phase II基因的大量表現，促進肺癌細胞的生長和存活能力。部分研究者推論KEAP1與NRF2在NSCLC的發展扮演重要角色，但NRF2在肺癌病人的組織染色分析發現NRF2和病人的預後以及存活並沒有顯著關聯，顯示KEAP1可能尚有功能未被釐清。本論文對52個肺腺癌病人檢體進行免疫組織染色分析，結果顯示早期患者的腫瘤組織KEAP1表現量高，末期患者的KEAP1表現量則非常低。統計學上的分析發現KEAP1表現高的病人存活的時間較低表現病人為長。我們發現在不同的肺腺癌細胞株，KEAP1的表現和浸襲能力呈現負相關。抑制KEAP1的表現將會增加細胞的浸襲能力；若大量表現KEAP1，則能有效抑制細胞的浸襲能力。更進一步的研究發現，大量表現的KEAP1可能透由降解RhoA抑制應力纖維 (stress fiber) 的形成，進而抑制細胞的浸襲能力。最後藉由活體動物實驗中，再次證明抑制KEAP1表現後增強了癌細胞的浸襲能力，並且促進了癌細胞的腫瘤發生能力(tumorigenesis)。總結實驗結果，我們首次發現KEAP1的表現能影響癌細胞的浸襲能力，這樣的過程可能與RhoA有關。

Previous studies revealed that weakened KEAP1 (Kelch liked ECH-associated protein 1) expression enhanced NRF2 (NF-E2-related factor 2) nuclear accumulation and elevated antioxidant responsive element (ARE)-mediated induction of phase II detoxifying and oxidative stress enzyme genes such as antioxidative and antixenobiotic stress enzymes and drug efflux pumps in non-small cell lung cancer, suggesting that gave lung cancer cells multiple advantages for proliferation. However, recent studies indicated that NRF2 was not correlated with reduced survival or overall survival of NSCLC. In this study, KEAP1 protein expression in 52 lung adenocarcinoma specimens was investigated immunohistochemically and was significantly correlated with overall survival. We found KEAP1 expressed higher in early stage lung adenocarcinoma than in late stage adenocarcinoma. Also, KEAP1 had ability to inhibit lung adenocarcinoma migration and invasion. At the mean time, we found that RhoA may be involved in this process. Moreover, in vivo animal study showed weakened KEAP1 expression promoted metastasis ability and primary tumorigenesis. In conclusion, our data suggested that KEAP1 may mediate lung adenocarcinoma migratory and invasive abilities through degradation of RhoA.