CD44基因多型性及環境因子對口腔癌易感性之影響

Interaction between CD44 gene polymorphisms and environmental factors on oral cancer susceptibility

周英二

CD44 ； 口腔癌 ； CD44 ； oral cancer

中山醫學大學醫學研究所學位論文

2014年

博士

楊順發

繁體中文

口腔鱗狀細胞癌 (oral squamous cell carcinoma, OSCC) 是臺灣男性排名第四的癌症死因。環境致癌因子的接觸暴露- 如抽菸、喝酒、嚼檳榔是引發口腔鱗狀細胞癌的主要成因。CD44糖蛋白家族是細胞外基質的主要連結分子同時也是玻尿酸受體 (hyaluronate receptor) 的家族成員之一，參與許多人體重要的生物機制如創傷癒合 (wound healing)、細胞凋亡(apoptosis) 以及細胞遷移 (cell migration)。CD44 也是一種已知的血清腫瘤標記 (tumor marker)，在腫瘤細胞的分化、侵襲與遠端轉移中扮演了重要角色。近來的研究發現 CD44 在口腔癌的表現量增加與腫瘤的轉移、復發、對化學治療的抵抗性還有較低的生存率有關，但CD44的基因多型性 (polymorphisms) 與環境因子對口腔癌易感性及臨床病理特性之間的關聯性仍不清楚。本研究利用即時定量聚合酶連鎖反應 (real-time polymerase chain reaction) 於 599 位口腔癌患者與 561 位非癌症對照組中分析了 6 個 CD44 單核苷酸多型性 (Single-nucleotide polymorphism, SNP) 與環境因子對口腔癌易感性及臨床病理特性之影響。我們首先確定了帶有 CD44 rs187115 多型性基因型為 AG, GG 或是 AG+GG 的人與口腔癌的易感性有關。在 731 位吸菸者中，帶有CD44 基因多型性與嚼檳榔習慣的人相較於 CD44 野生型 (wild type) 且沒有嚼檳榔習慣的人有 10.30-37.63 倍的風險罹患口腔癌。在552 位嚼檳榔者中，帶有 CD44 基因多型性與吸菸習慣的人相較於 CD44 野生型且沒有吸菸習慣的人有 4.23-16.11 倍的風險罹患口腔癌。我們也發現口腔癌第三期與第四期的患者相較於 CD44 野生型的人有較高的頻率帶有 CD44 rs187115 多型性基因型 (AG+GG) 。此次研究結果顯示 CD44 單核苷酸多型性與環境因子如抽菸、喝酒、嚼檳榔的交互作用確實會改變口腔癌的易感性。帶有 CD44 rs187115 突變核苷酸 AG 與 GG 基因型的患者有較高罹患口腔癌的風險並且這些患者可能具有對化學藥物治療的抵抗性，因此相較於正常基因者更有可能進展為晚期腫瘤。CD44 rs187115 多型性對於預測口腔腫瘤形成有潛在的顯著性，也或許可以作為臨床應用上預測OSCC患者預後的因子。

Oral squamous cell carcinoma (OSCC) is the fourth leading cause of male cancer death in Taiwan. Environmental carcinogens exposure are the major risks to develop OSCC. CD44 glycoproteins are members of the hyaluronate receptor and are associated with numerous fundamental biological processes, such as wound healing, apoptosis and cell migration. CD44, one of the well known tumor markers, plays crucial role in tumor cell differentiation, invasion and metastasis. Recent studies have demonstrated and suggested that the increased CD44 expression in OSCC is correlated with increased metastasis, recurrence, resistance to chemo-and radiation therapy, and decreased survival. However, the effects of CD44 gene SNPs and environmental carcinogens on oral cancer susceptibility and clinical features remain poorly investigated. In the present study, real-time polymerase chain reaction (PCR) was used to analyze six CD44 single-nucleotide polymorphisms (SNPs) in 599 oral cancer patients and 561 cancer-free controls with environmental risk factors to OSCC susceptibility and clinicopathological charecteristics. We determined that the CD44 rs187115 polymorphism carriers with the genotype AG, GG or AG+GG were associated with the oral cancer susceptibility. Among 731 smokers, CD44 polymorphisms carriers with the betel-nut chewing habit had a 10.30-37.63-fold greater risk of having oral cancer compared to CD44 wild-type (WT) carriers without the betel-nut chewing habit. Among 552 betel-nut chewers, CD44 polymorphisms carriers who smoked had a 4.23-16.11-fold greater risk of having oral cancer compared to those who carried the WT but did not smoke. Finally, we also observed that the stage III and IV oral cancer patients had higher frequencies of CD44 rs187115 polymorphisms with the variant genotype (AG+GG) compared with the wild-type carriers. These results suggest that gene-environment interactions between the CD44 polymorphisms and betel quid chewing, alcohol consumption and tobacco smoking might alter the susceptibility for oral cancer development. Patients with CD44 rs187115 variant genotypes (AG+GG) were correlated with higher risk of oral cancer development and these patients may posses chemoresistance to advanced- to late-stage oral cancer than wild-type carriers do. The CD44 rs187115 polymorphism has potential predictive significance in oral carcinogenesis and also may be applied as factors to predict the clinical stage in OSCC patients.