肺癌自民國七十一年開始一直是台灣癌症的第一大死亡原因。已知抽煙是肺癌發生的重要病因，但是台灣地區女性有 90%以上是不抽菸者。因此不抽者罹患肺癌之病因學研究，是當前我國重要的醫藥衛生研究課題。最近本研究室發現不抽煙女性肺癌患者的高危險性人類乳突瘤病毒 16 和 18 型 (Human papillomarvirus 16/18) 的感染率遠高於男性肺癌患者。且 HPV 16/18 可能透過 E6/E7 致癌蛋白去活化 p53 和 Rb 蛋白之致癌路徑而參與肺癌形成。為了確定 HPV 感染確實參與肺癌之形成，本計畫選取有和沒有 HPV 感染之各兩個第一期女性肺腺癌腫瘤組織，進行 LCM-9600 spots-cDNA microarray 分析，並比較 Interferone-related genes, NF-kB-related 和 Cell-cycle and DNA synthesis related genes 等三類與 HPV 感染相關之基因表現在 HPV 感染與沒有感染之費腫瘤間是否有顯著差異？結果發現 HPV 感染之肺腫瘤組織在調控細胞週期、訊號傳遞以及轉錄調控因子相關基因的表現大部分高於沒有 HPV 感染之肺腫瘤組織，而在免疫相關基因的表現上則相反。因此肺腫瘤組織中 HPV 感染可能會改變免疫功能，並促進細胞增生的能力進而促進肺腫瘤化。為確定 HPV 確實參與肺腫瘤化，需提出 HPV DNA 會嵌至肺細胞之染色體，本研究選取先前以 in situ RT-PCR 確定會表現 HPV E6 或 E7 mRNA 的 15 個肺腫瘤組織進行 RS-PCR 及 DNA 自動定序分析以了解 HPV 嵌入人類染色體之位置，至今完成分析的初步結果顯示， HPV 嵌入的位置主要在 X 染色體及 1 號染色體。以上初步結果進一步確定 HPV 感染確實會參與台灣不抽煙女性肺癌患者肺癌之形成。
Lung cancer is the leading cause of cancer death in Taiwan since 1982. Cigarette smoking is considered to be the most risk factor of lung cancer. However, a half of lung cancer cases in Taiwan were not explained by cigarette smoking, especially for Taiwanese women because 90% of women are nonsmokers. Therefore, the aetiological studies of nonsmoking lung cancer is an important medical issue in Taiwan. Our recent report indicated that high prevalence of HPV 16/18 infections in nonsmoking female lung tumors compared with nonsmoking male and smoking male cases may be as a risk factor of lung cancer in Taiwanese women nonsmokers. To verify HPV infections were involved in lung tumorigenesis, LCM-cDNA microarray analysis was performed to compare the different gene expression profiles including interferon-related genes, NF-kB-related genes, and cell-cycle and DNA synthesis related genes, between two pairs of HPV-infected and non-infected stage I-female lung adenocarcinomas. Our results showed that cell-cycle and DNA synthesis related genes, and NF-kB-related genes in HPV-infected tumors were significantly up-regulated compared with non-infected lung tumors. However, interferon-related genes were down-regulated in HPV-infected lung tumors compared with non-infected tumors. These results suggest HPV infection may alter expression of genes that influence of immune function and tumor progression. To further verify HPV infection is involved in lung tumorigenesis, 15 lung tumors with HPV E6 and/or E7 mRNA expressions that have been confirmed by in situ-RT-PCR, were performed by RS-PCR and direct DNA sequencing to elucidate HPV DNA integrated chromosome locations in lung tumor tissues. Our preliminary data showed that HPV DNA was integrated at Xp11.3-11.4, Xp22.31-22.13, and chromosome 1. The putative novel genes will be further verified whether are involved in HPV-associated lung tumorigenesis.
