HOTTIP基因多型性及環境因子對口腔癌易感性之影響

口腔鱗狀細胞癌 (oral squamous cell carcinoma, OSCC) 是國人十大癌症死亡原因排名第五名。口腔癌的形成是一個複雜的過程，通常是多種因素相互作用的結果。其中，環境致癌因子如煙、酒、檳榔，是引發口腔鱗狀細胞癌的主要原因。HOTTIP (HOXA transcript at the distal tip) 基因是一種長鏈非編碼 RNA (Long non-coding RNA)，它位於人類基因組的 HOXA 基因簇中，可促進多種腫瘤的腫瘤進展，並參與幹細胞自我更新和修復的過程、免疫逃脫和 Wnt/β-catenin 訊號路徑。然而，HOTTIP 的基因多型性在口腔鱗狀細胞癌易感性及臨床病理特性的生物學功能和機制仍不清楚。透過生物資訊分析和實驗證實，我們試圖釐清 HOTTIP 的基因多型性可以作為口腔癌的易感基因，並進一步證明 HOTTIP 可以提供作為口腔癌症的診斷和治療新的標靶。本研究中收集了 1205 位口腔癌病人與 1192 位非癌症對照組的血液萃取 DNA，利用即時定量聚合酶連鎖反應(real-time polymerase chain reaction)的分析方式探討 4 個 HOTTIP 基因多型性與環境因子對口腔癌易感性及臨床病理特性之影響。研究中觀察 HOTTIP 基因中 rs3807598，rs17501292，rs2067087，rs1859168 四種基因多型性的變異。實驗結果發現，帶有這四個 HOTTIP基因多型性的人與口腔癌易感性無關。而環境因子包括抽煙、喝酒、吃檳榔的交互作用確實會改變口腔癌的易感性。再進一步分析發現，比較 HOTTIP rs3807598 與 HOTTIP rs2067087 基因型在老年口腔癌病患，發現帶有 HOTTIP rs3807598 突變核苷酸 GC 與 CC 基因型的患者在癌症分期與淋巴轉移有顯著差異。而帶有 HOTTIP rs2067087 突變核苷酸 CG 與 GG 基因型的患者在癌症分期有統計顯著差異。綜合上述我們的研究結果證明，HOTTIP rs3807598 與 HOTTIP rs2067087 基因多型性對於預測口腔癌形成有潛在的顯著性，也許可以作為臨床應用預測 OSCC 患者預後的因子。

Oral squamous cell carcinoma (OSCC) is the fifth leading cause of cancer death worldwide. The carcinogenesis formation of oral cancer is a complex process that is usually the result from the interaction of multiple factors. The main cause of OSCC are environmental carcinogens such as tobacco, alcohol, and betel nut. The HOTTIP (HOXA transcript at the distal tip) gene is a long non-coding RNA. It can promote tumor progression and participate in stem cell self-renewal and repair processes, immune escape, and the Wnt/β-catenin signaling pathway. However, the biological functions and mechanisms of HOTTIP genetic polymorphisms in OSCC susceptibility and clinicopathological characteristics remained unclear. Through bioinformatics analysis and experimental confirmation, we use RT-PCR (real-time polymerase chain reaction) to analyze four HOTTIP single-nucleotide polymorphisms (SNPs) in 1205 oral cancer patients and 1192 cancer-free controls with environment risk factors to OSCC susceptibility and clinicopathological characteristics. The results of the study found that these four HOTTIP polymorphic genotypes are not associated with susceptibility to oral cancer. The interaction of environmental factors including smoking, drinking, and eating betel nut can indeed change the susceptibility to oral cancer. Further analysis found that there was a significant difference in cancer stage between patients with HOTTIP rs3807598 GC and CC genotypes and HOTTIP rs2067087 CG and GG genotypes. The result of this study have demonstrated that the HOTTIP rs3807598 and HOTTIP rs2067087 polymorphic genotypes are potentially significant in predicting the formation of oral cancer and may be applied as possible clinical factors to predict the prognosis of OSCC patients.