神經母細胞瘤中與AHR和MYCN相關之蛋白質交互作用網路的研究

Abstract

神經母細胞瘤是源自交感神經系統的異構腫瘤，有著多變的臨床與生物行為，是兒童常見癌症之一。為了研究神經母細胞瘤複雜的調節機制，許多預後生物因子被找到，特別是 v-myc myelocytomatosis viral related oncogene (MYCN) 。帶有多倍數 MYCN 的病人預後則非常差。然而，MYCN 表現後導致癌症發生的機轉仍然十分不清楚。 微陣列晶片技術是強而有力並且高通量的方法，用以精確的了解整體性的基因表現變化。在我們的研究中，我們總共進行了 20 片台灣神經母細胞瘤病人的微陣列晶片實驗。除此之外，我們使用生物路徑比對以及電腦模擬預測，來建構蛋白質交互作用網路。 我們用三倍變化為篩選標準，展示了有 2718 個基因有差異性的表現。經過非主觀的階層式分群法，我們發現 MYCN 增幅的微陣列晶片樣本會與 MYCN未增幅的分別開來。藉由生物路徑比對，aryl hydrocarbon receptor (AHR) 路徑是顯著表現的路徑之一，而 MYCN 與 AHR 的基因表現有著高度的相關性，除此之外，我們建構了蛋白質交互作用網路， MYCN 在網路中會透過兩個節點而連結到 AHR ，而預測結果與 MYCN 直接連結的基因還有與 AHR 直接連結的兩組基因表現檔案，都顯示了高度相關。 我們的發現指出了 MYCN 和 AHR 有著高度相關，而且 AHR 也可能在神經母細胞瘤發展中扮演重要的角色。 AHR 與 MYCN 參與的交互作用網路對於了解 MYCN 表現的調節機制會有相當大的幫助。此研究將有可能為神經母細胞瘤的治療帶來一道曙光。

Neuroblastoma, a heterogeneous tumor with variable clinical and biological behavior, is one of the most common pediatric cancers that derived from sympathetic nervous system. To explore the heterogeneous behavior of neuroblastoma, many prognostic biological markers have been discovered, especially v-myc myelocytomatosis viral related oncogene (MYCN) amplification predict a poor prognosis. However, the regulatory mechanism by MYCN expression still has been unclear. The microarray technique is a powerful and high-throughput method for accurately determining changes in global gene expressions. In this study, we performed microarray experiment to measure gene expression profiles of 20 Taiwanese neuroblastoma patients. Furthermore, we used pathway mapping and in silico interaction prediction to elucidate and construct the protein interaction network. We showed that 2718 genes are differentially expressed between neuroblastoma and control samples using 3-fold change as cut-off. By using unsupervised hierarchical clustering, we found that MYCN-amplified samples separated from not-amplified samples. By pathway mapping, the aryl hydrocarbon receptor (AHR) pathway was significant and MYCN and AHR have highly correlation in the expression profile. In addition, we constructed the protein network which MCYN connect through 2 nodes with AHR network and the gene expressions of MYCN- and AHR- interacted proteins are highly relevant. Our findings indicate that MYCN and AHR have highly correlation and AHR may also play an important role in neuroblastoma development. The protein-protein interaction network of AHR and MYCN involved in neuroblastoma is useful to know the regulatory mechanism by MYCN expression. This study shed light on neuroblastoma therapy.