WNT1-誘導型訊息路徑蛋白1基因多型性對肝癌發生的影響

Impact of WNT1-inducible signaling pathway protein 1 polymorphism polymorphisms on hepatocellular cell carcinoma development

陳志典(Chih-Tien Chen)

指導教授 ： 楊順發

中山醫學大學/醫學院/醫學研究所/博士(2019年)

https://doi.org/10.6834/CSMU201900141

摘要

肝癌 (hepatocellular carcinoma, HCC) 在台灣所有癌症死亡中位居第二位。WNT1-誘導型訊息路徑蛋白1 (WNT1-inducible signaling pathway protein 1, WISP1) 是CCN蛋白家族中的一員，且為β-連環蛋白 (β-catenin) 之下游標靶物。WISP1的異常表現與致癌作用有密切相關，而在肝癌的疾病發展過程中，WISP1則扮演一個抑制腫瘤成長的角色。先前已有許多文獻針對WISP1之基因多型性(single nucleotide polymorphism, SNP)與癌症或疾病之間的關聯性進行研究，但WISP1之基因多型性與肝癌的相關性卻完全無文獻探討。因此，本篇研究中，我們擬觀察WISP1之基因多型性與肝癌之臨床病理特徵的相關性。本篇研究針對共332名肝癌患者與664名健康對照組，透過即時聚合酶連鎖反應 (real-time polymerase chain reaction, real-time PCR) 分析了WISP1 rs2977530、rs2977537、rs2929973、rs2929970、rs62514004以及rs16893344 等六組基因多型性。研究發現在肝癌病患中，WISP1 rs62514004帶有A/G+G/G基因型，以及rs16893344帶有C/T+T/T基因型者，與野生型 (wild type) 攜帶者有較低演變成後期臨床階段肝癌的風險。其他四個基因型( rs2977530、rs2977537、rs2929973、rs2929970) 的基因變異與肝癌之臨床病理特徵則無明顯的相關性。此外，帶有rs62514004與rs16893344單套型G-T基因的個體，其數據顯示出與飲酒習慣相結合後，對於肝癌發展有更高的風險與協同效應。我們的結果顯示，具有WISP1 rs62514004以及rs16893344基因多型性基因變異的肝癌患者，與肝癌發展有相關性，因此可作為肝癌治療上之標記或治療標靶。

關鍵字

肝癌 ； WNT1-誘導型訊息路徑蛋白1 ； 基因多型性

並列摘要

Hepatocellular carcinoma (HCC) is the second of cancer death in Taiwan. WNT1-inducible signaling pathway protein 1 (WISP1) is a member of CCN protein family and a downstream target of β-catenin. Aberrant WISP1 expression is associated with carcinogenesis. Low expression levels of WISP1 may influence disease-free and overall survival of HCC. Dysregulation of WISP1 single-nucleotide polymorphism (SNP) may be associated with susceptibility to various cancers or diseases. However, no study has investigated the involvement of the SNP of WISP1 in HCC. In the current study, we focused on examining WISP1 SNP to elucidate HCC clinicopathologic characteristics. The WISP1 SNPs rs2977530, rs2977537, rs2929973, rs2929970, rs62514004, and rs16893344 were analyzed by real-time polymerase chain reaction in 332 patients with HCC and 664 cancer-free controls. The patients with higher frequencies of WISP1 rs62514004 (AG + GG) and rs16893344 (CT + TT) variants revealed a lower risk to reach a later clinical stage compared with their wild-type carriers. The rs2977530, rs2977537, rs2929973, and rs2929970 SNPs showed no significant association with the clinicopathologic statuses. Furthermore, individuals who carried WISP1 rs62514004 and rs16893344 haplotype G-T showed a greater synergistic effect combined with alcohol drinking on HCC development. Our results demonstrated that the HCC patients with WISP1 SNPs are associated with HCC development, and WISP1 SNPs may serve as markers or therapeutic targets for HCC.

並列關鍵字

Hepatocellular carcinoma ； WISP1 ； Gene polymorphism

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