LncRNA-HOTAIR基因多型性與口腔癌的相關性分析

Association of lncRNA-HOTAIR polymorphisms with oral cancer risk

吳吉美(Chi-Mei Wu)

指導教授 ： 楊順發

中山醫學大學/醫學院/醫學研究所/碩士(2018年)

摘要

口腔癌 (oral cancer) 是指發生在口腔部位的惡性腫瘤，其中以口腔鱗狀細胞癌 (oral squamous cell carcinoma, OSCC) 最為常見，約佔所有口腔癌的90%以上；口腔癌的發生和口腔長期受到刺激而產生細胞病變有相當密切的關係，尤其以嚼食檳榔 (Betel quid chewing) 為主要原因，長鏈非編碼RNA (long non-coding RNAs, LncRNA) 是一不會轉譯成蛋白的轉錄物，長度大於200個核苷酸。HOTAIR (HOX antisense intergenic RNA) 是位於12號染色體上的LncRNA，介於HOXC11與HOXC12之間，長度約2,158個核苷酸。過去已有研究證實，HOTAIR與許多癌症有關，例如：頭頸癌、子宮頸癌及胃癌。然而，目前口腔癌與LncRNA HOTAIR基因多型性 (polymorphisms) 之相關性仍不清楚。因此，本研究收集了907位男性OSCC患者與1,200位健康對照 (cancer-free control) 男性受試者，分析四個LncRNA HOTAIR單核苷酸多型性 (single neucleotide polymorphism, SNP) - rs920778、rs1899663、rs4759314、rs12427129，並統計分析與OSCC臨床資料及危險因子之相關性。研究觀察到rs1899663與OSCC之風險相關，經校正3個干擾因子：抽菸、喝酒及嚼檳榔後達統計上顯著意義 (AOR, 2.227；95% CI, 1.197~4.146；P=0.012) 。進一步分析發現，排除3種環境因素中的每一種習慣性暴露後，除rs1899663之外，未嚼食檳榔之OSCC患者，rs920778攜帶TC (heterozygote) 及TC+CC基因型，相較於攜帶TT (wild-type) 基因型，有較高風險更容易罹患OSCC (TC: odds ratio [OR], 1.472; 95% CI, 1.069~2.029; P=0.018; TC+CC: OR, 1.448; 95% CI, 1.060~1.977; P=0.020)。此外，在HOTAIR SNP與未嚼食檳榔患者臨床狀態之相關性，除了臨床腫瘤分期較晚期外，發現rs920778與大腫瘤的發生 (OR,1.891; 95%CI, 1.027~3.484; P=0.04) 和rs4759314增加淋巴結轉移 (OR, 4.140; 95% CI, 1.785~9.602; P=0.001) 相關。結果證實HOTAIR基因多型性與嚼食檳榔之交互作用影響了口腔癌的病程與發展。

關鍵字

口腔癌、基因多型性、長鏈非編碼RNA

並列摘要

Oral cancer is a malignant tumor that occurs in the oral cavity. Among them, oral squamous cell carcinoma (OSCC) is the most common and accounts for more than 90% of all oral cancers. Occurrence of oral cancer is closely related to long-term stimulation of the oral cavity to produce cytopathies, and the main reason is the chewing of betel nut. Long non-coding RNAs (LncRNAs) are transcripts that do not translate into proteins and are longer than 200 nucleotides in length. HOTAIR (HOX antisense intergenic RNA) is a LncRNA located on chromosome 12, which is between HOXC11 and HOXC12 and has a length of about 2158 nucleotides. Previous studies have confirmed that HOTAIR is associated with many cancers such as head and neck cancer, cervical cancer, and gastric cancer. However, the correlation between oral cancer and polymorphisms of the LncRNA HOTAIR gene has not been explored. Four single-nucleotide polymorphisms of the HOTAIR gene rs920778, rs1899663, rs4759314, and rs12427129 were tested in 1,200 control participants and 907 patients with OSCC. We detected a significant association of rs1899663 with the risk of OSCC (adjusted odds ratio, 2.227; 95% confidence interval [95% CI], 1.197 to 4.146; P = 0.012) after adjustment for 3 potential confounders: smoking, betel quid chewing, and alcohol consumption. In further analyses where habitual exposure to each of 3 environmental factors was excluded, we found that, in addition to rs1899663, non–betel quid users who carried the polymorphic allele of rs920778 were more prone to develop OSCC than were those homozygous for wild-type allele (TC: odds ratio OR, 1.472; 95% CI, 1.069 to 2.029; P = 0.018; TC+CC: OR, 1.448; 95% CI, 1.060 to 1.977; P = 0.020). Moreover, in exploring the relationship between HOTAIR gene polymorphisms and the clinical status of only patients with OSCC who were non–betel quid chewers (excluding the advanced clinical stage), we found that rs920778 and rs4759314 were correlated with the development of large-size tumors (OR, 1.891; 95% CI, 1.027 to 3.484; P = 0.04) and increased lymph node metastasis (OR, 4.140; 95% CI, 1.785 to 9.602; P = 0.001), respectively. Our results reveal an interactive effect of HOTAIR gene polymorphisms and betel quid chewing on the development and progression of oral cancer.

並列關鍵字

oral cancer, single nucleotide polymorphism, LncRNA, HOTAIR

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