癌症自1982年起，即為台灣地區十大死亡原因之首位，儘管目前分子醫學研究已相當進步，但對於肺癌分子致癌機制仍未完全釐清。目前所知，癌症形成的原因與訊息傳遞途徑中部分的基因變異造成細胞內的調控機制發生變化有密切的關係，其中Wingless 訊息傳遞途徑 (WNT signaling pathway) 的變異在許多的癌症都有發現，而β-catenin基因是WNT signaling pathway中已知重要的致癌基因，在許多的癌症研究中都已經知道在細胞核中會有β-catenin蛋白大量累積的情況發生。因此我們首先利用免疫組織染色法分析β-catenin蛋白在78個台灣地區非小細胞肺癌 (non-small cell lung cancer, NSCLC) 病人樣本中變異的情形。研究結果顯示: 55% (43/78) 病人的細胞核中β-catenin蛋白有不正常的累積現象，同時發現這些病人多為上皮細胞肺癌 (Squamous carcinoma, SQ) (P=0.014)。另外過去的報告發現β-catenin基因的突變頻率在癌症病患中並不高，因此我們懷疑β-catenin蛋白在細胞核不正常累積的情形，可能與上游調控蛋白，如AXIN2與BTRCP降解 (protein degradation) 調控蛋白及ICAT轉錄 (transcription) 調控蛋白發生變異有關。所以本研究進一步分析78位台灣地區非小細胞肺癌病人，WNT signaling pathway中AXIN2、BTRCP及ICAT的變異。本研究利用免疫組織染色法分析AXIN2、BTRCP及ICAT蛋白低表達的頻率，並以反轉錄聚合酵素反應分析組織細胞中AXIN2、BTRCP及ICAT基因mRNA是否異常，以及偵測AXIN2，BTRCP及ICAT基因啟動子高度甲基化 (promoter hypermethylation) 及基因發生異質性喪失 (loss of heterozygosity, LOH) 頻率的變異分析。本研究結果發現AXIN2、BTRCP及ICAT任一蛋白發生變異的頻率高達67% (52/78)，而且這些病人的β-catenin蛋白都有不正常累積在細胞核的情形 (P=0.036)。在AXIN2基因實驗結果部份：78位病人發現LOH的頻率為32%，啟動子高度甲基化頻率為38%，而其蛋白質和mRNA低表現頻率分別為35%和44%，並且其蛋白質和mRNA變異和早期肺癌病人有關 (P=0.047; P=0.028)。在BTRCP基因實驗結果部份： LOH的頻率為26%，啟動子高度甲基化頻率為50%，且其變異與肺癌型式為SQ和有抽菸習慣的病人有關 (P=0.001; P=0.082)；蛋白質和RNA低表現頻率分別為32%和29%。在ICAT基因實驗結果部份：LOH的頻率為23%，且其變異與年紀大的病人有關 (P=0.007)；啟動子高度甲基化頻率為42%，且其變異多發生在女性病患 (P=0.017)；而其蛋白質和RNA低表現頻率分別為35% 和29%。
本研究為首篇針對WNT signaling pathway中AXIN2、BTRCP及ICAT基因對細胞核中β-catenin蛋白不正常的累積關係之研究，而研究結果亦顯示：細胞核中β-catenin蛋白不正常的累積是因為上游的基因AXIN2、BTRCP及ICAT發生變異，並且AXIN2、BTRCP及ICAT基因變異主要是因為啟動子高度甲基化所致，因此我們推測 WNT signaling pathway中的β-catenin/AXIN2/BTRCP/ICAT 調控路徑變異在非小細胞肺癌的形成中扮演重要角色。

Background: Lung cancer is the leading and second cause of cancer deaths among women and men in Taiwan, respectively. However, the molecular mechanisms involved in lung tumorigenesis in Taiwan remain poorly defined. Previous studies have shown the β-catenin plays an important role in the wingless (Wnt) signaling pathway. The β-catenin protein overexpressed in many tumors but only a few patients showed mutations in the β-catenin gene. It is possible that β-catenin protein accumulation results from alternative mechanisms other than mutation. Aim: The present study investigated the possibility of alterations of AXIN2, BTRCP, and, ICAT which are putative tumor suppressor genes in regulating the Wnt signaling pathway, leading to β-catenin protein stabilization. Patients and Methods: The alterations including promoter hypermethylation, loss of heterozygosity (LOH), low mRNA and protein expression of the AXIN2, BTRCP, and, ICAT genes were examined by the methylation specific-PCR, LOH, reverse-transcriptase PCR, and immunohistochemistry analyses, respectively, in 78 non-small cell lung cancer (NSCLC) tumorigenesis in Taiwan. Results: We found that the frequency of AXIN2 LOH and promoter hypermethylation was 32% (22/68) and 38% (30/78), respectively. In addition, 35% (27/78) and 44% (34/78) NSCLC patients had decreased or loss of AXIN2 protein and mRNA expression, respectively. The abnormal AXIN2 protein and mRNA expression was found more frequently in early-staged patients (P=0.047; P=0.028). With regard to BTRCP gene alteration analyses, the frequency of BTRCP LOH and promoter hypermethylation was 26% (14/53) and 50% (39/78), respectively. The BTRCP promoter hypermethylation was found more frequently in squamous carcinoma (SQ) and smoking patients (P=0.001; P=0.082). Note that 32% (25/78) and 29% (23/78) NSCLC patients had decreased or loss of BTRCP protein and mRNA expression, respectively. With regard to ICAT gene alteration analyses, the frequency of ICAT LOH and promoter hypermethylation was 42% (33/71) and 32% (23/78), respectively. The ICAT promoter hypermethylation was found more frequently in elderly patients (P=0.017). The ICAT LOH was found more frequently in female patients (P=0.007). There were 35% (27/78) and 29% (23/78) of NSCLC patients had decreased or loss of ICAT protein and mRNA expression, respectively. Overall, 67% (52/78) of NSCLC tumors had alteration in at least one of the three Wnt upstream effectors. The β-catenin deregulation was significantly attributable to low mRNA/protein expression of AXIN2 (P = 0.004) and BTRCP (P = 0.013). In addition, β-catenin overexpression and low expression of AXIN2/BTRCP/ICAT were frequent in SQ patients (P = 0.014). A high concordance was observed between low protein/mRNA expression and promoter hypermethylation (P < 0.001) for the AXIN2, BTRCP, and ICAT genes. Conclusion: The study was the first report which comprehensively examined the alteration of the Wnt signaling pathway genes, AXIN2, BTRCP, and ICAT at DNA, RNA and protein levels in lung cancer. Our data suggest that deregulation of the β-catenin/AXIN2/BTRCP/ICAT pathway is important in the pathogenesis of a subset of NSCLC and that promoter hypermethylation is the predominant mechanism in AXIN2, BTRCP, and ICAT alterations.

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