2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647009摘要：肺癌，尤其是非小細胞肺癌，為當今世上最常見的致死癌症之ㄧ，而癌轉移則是導致癌症病患死亡的主因。對早期的非小細胞肺癌病人而言，經治療後的五年疾病復發率約為40%，而目前的腫瘤分期系統並不足以預測其存活率與復發率且治療結果並不令人滿意。現今的研究顯示，東西方種族間存在著相當不同的遺傳因素，導致在肺癌發生與進程以及對分子標靶療法的療效上有明顯的不同。最近的報導發現，相較於其他種族，亞洲人種的基因組中存在有包括單核酸多型性與基因拷貝數變異等在內的大量遺傳變異。此外，肺癌分子診斷與預後預測系統及分子標靶療法皆是依據西方族群的資訊所建立，未必完全適用於亞洲族群。因此，建立以亞洲種族為基礎的預後生物標記與開發有潛力的分子靶基因，有其急迫性。早先，我們從一位國人的肺癌病患組織建立了一系列具有不同侵襲能力的肺腺癌細胞株。在這個研究中，我們將運用結合基因表現微陣列與比較基因體雜交法的整合式晶片研究策略，分析這些細胞株的基因表現與基因拷貝數，我們將尤其著重於探索具新穎性的基因或是未知功能的基因，我們將以體外與體內的研究方法，探討他們在肺癌進程上的角色以及這些基因潛在的調控機制。最後，我們將評估這些基因作為預測肺癌病患存活率與復發率的預後生物標記與分子標靶療法的標的基因。現在初步的結果，我們已經發掘了Shisa3、C4ORF18 和SPANXA1 等三個可能的抑癌轉移基因，就我們所知，Shisa3 和C4ORF18 從未有任何文獻報導，是屬於全然的新穎性基因，SPANX 家族的基因也從未在肺癌研究上被提及，我們發現這三個基因皆會抑制體外肺癌細胞的侵襲能力，但對於細胞增殖與細胞不著地群落形成試驗卻有不同的影響。一個針對43 位非小細胞肺癌病患的初步臨床結果發現，以即時定量反轉錄鏈鎖反應偵測C4ORF18 的基因表現，得知C4ORF18 高表現的病患，其存活率卻會明顯的降低，在初步的體內免疫缺陷鼠癌轉移試驗中發現，C4ORF18 和SPANXA1 會降低小鼠肺部轉移的腫瘤數目。我們的研究或許可以提供解釋癌症轉移機制的線索以及開發基因療法的策略。<br> Abstract: Lung cancer, predominantly non–small-cell lung cancer (NSCLC), is the most commoncause of cancer deaths worldwide, and metastasis is the major cause leading to mortalityfor cancer patients. The relapse rate among patients with early-stage NSCLC is 40% within5 years after potentially curative treatment. The current staging system for NSCLC isinadequate for predicting the survival/relapse of patients and the therapeutic outcome is notsatisfactory. Current reports showed that there are quite different genetic factorscontributing lung cancer initiation and progression as well as the efficacy of moleculartargeting therapy between Western and Asian populations. Recently, a lot of variationsincluding single nucleotide polymorphisms and copy number variations in Asian genomewere identified compared to other populations. Moreover, the molecular diagnostic andprognostic systems and molecular therapeutic targets that were developed based on thestudies in Caucasian population might be not completely suitable for Asian populations.Hence, it is urgently needed to establish the Asian-based prognostic biomarkers andpotential molecular targeting genes. We have previously established a series of lungadenocarcinoma cell lines with varying degrees of invasiveness from a Taiwanese lungcancer patient. In this study, we will analyze this lung cancer cell line model by anintegrated microarray approach that combines gene expression microarray and array CGH.We will be interested to identify and focus the novel genes whose copy number orexpression could inference cancer metastasis/tumorigenesis. Their roles in cancerprogression will be explored in vitro and in vivo and the underlying regulatory mechanismswill be elucidated. Finally, we will evaluated the possibility whether theses identified genescould serve as prognostic biomarkers for prediction of lung cancer patients’ survival andrelapse and act as the targets of molecular targeted therapy. Preliminarily, we haveidentified three potential metastasis suppressor genes, Shisa3, C4ORF18 and SPANXA1,.Shisa3 and C4ORF18 are never reported and the role of SPANX family in lung cancer hasnot been speculated, to the best of out knowledge. We found that Shisa3, C4ORF18 andSPANXA1 inhibit the invasion ability of lung cancer cells. The effect of these genes on cellproliferation and anchorage-independent colony formation is controversial. A preliminaryresult indicates that the higher expression of C4ORF18 was significantly correlated withshorter survival of lung cancer patients assayed by real-time quantitative RT-PCR in 43NSCLC patients. In vivo mice metastasis assays also indicated that C4ORF18 andSPANXA1 reduce the number of tumor foci in lungs as inoculating tumor cell viaintravenous injection in SCID mice (n=3). Our study herein may provide the clues tointerpret the mechanism of metastasis and develop the strategies of gene therapy.非小細胞肺癌癌轉移預後癌侵襲存活率NSCLCmetastasisprognosisinvasionsurvival