研究背景: 食道鱗狀細胞癌 (Esophageal squamous cell carcinoma, ESCC) 是國人男性癌症死因的第五位。合併化放療 (Concurrent chemoradiation therapy, CCRT) 是目前臨床上對於食道癌的第一線治療，但常因治療前腫瘤進程已產生抗性而導致治療無效。先前，我們發現食道鱗狀細胞癌細胞的合併化放療抗性與抑癌轉錄因子SOX17的啟動子高度甲基化 (promoter hypermethylation)，所導致的SOX17表現低下有高度的關聯。此外，最近我們透過RNA定序分析發現，受NRF2調控的保護細胞的基因在有化放療抗性的病人中高表現。然而，SOX17和NRF2之間的關係以及對於食道鱗狀癌細胞合併化放療抗性如何調節的分子機制仍有待發掘探究。
研究目的: 本研究目的旨在探究在食道鱗狀癌細胞的合併化放療抗性中，SOX17和NRF2的調控機轉，希望藉此建立生物分子指標做為預測食道鱗狀細胞癌患者的合併化放療效性評估。
研究結果: 首先，我們使用轉錄因子結合位預測工具找到NRF2啟動子上含有七個SOX17結合位。接著，啟動子活性 (promoter activity) 分析及染色質免疫沉澱 (chromatin immunoprecipitation; ChIP) 分析結果顯示，在三組有抗性以及無抗性的食道鱗狀細胞癌中，首次揭露SOX17能轉錄調控並抑制NRF2的啟動子活性。我們進一步地確認了，SOX17會抑制NRF2信使核糖核酸和蛋白質，以及NRF2下游基因的表現。在臨床檢體實驗中，我們收集115位食道鱗狀細胞癌病患的內視鏡切片樣本，確認了其中有五個NRF2下游基因，相較於合併化放療效性較好的病患，其在合併化放療效性較差的病患中的表現量顯著上調。此外，藉由免疫組織化學染色法偵測SOX17和NRF2在細胞核中的蛋白表現程度，發現SOX17蛋白表現量低下並且NRF2蛋白表現量高升的情形，明顯在合併化放療效性較差的病患中被觀察到。Kaplan-Meier survival分析中，證實SOX17蛋白表現量低下或是NRF2蛋白表現量高升是具有預測食道鱗狀細胞癌病患的合併化放療治療效性和存活時間的能力。最後，我們在細胞實驗與動物實驗中證實，對於合併化放療有抗性的食道鱗狀細胞癌細胞的增生、移動以及癌幹細胞特性，會因為SOX17過表達而被削弱，相反的，在SOX17和NRF2同時過表達下被激活。
結論： 我們論述了一個新穎的轉錄因子SOX17對NRF2進行負向轉錄調控機制，並且這條路徑失調，不論在細胞、動物或臨床模型中，都將導致食道癌產生合併化放療的抗性。此外，SOX17和NRF2的免疫反應性以及NRF2下游基因表達有潛力作為生物分子指標，預測食道鱗狀細胞癌患者的合併化放療效性評估。
關鍵字：食道鱗狀細胞癌；合併化放療抗性；SOX17；NRF2轉錄成癮；轉錄因子；轉錄調控機制

Background: Esophageal squamous cell carcinoma (ESCC) is the 5th leading cause of cancer death in Taiwanese male. The concurrent chemoradiation therapy (CCRT) is the standard first-line treatment for ESCC patients, but often failed due to acquired resistance. Previously, we found that CCRT resistance of ESCC is associated with low expression of tumor suppressor-like transcription factor SOX17 due to promoter hypermethylation. In addition, our recent RNA-sequencing analyses showed high mRNA level of cytoprotective genes regulated by NRF2 transcription factor in the CCRT resistant patients. However, the underlying mechanism between SOX17 and NRF2 in regulation of CCRT resistance in ESCC needs to be explored.
Purpose: This study aimed to investigate the mechanisms of SOX17-NRF2 axis in CCRT resistance in ESCC, and thereby to identify molecular biomarkers for predicting CCRT responses.
Results: Firstly, we used transcription factor binding prediction tool and found that NRF2 promoter possessed seven SOX17 binding sites. Next, the promoter activity and chromatin immunoprecipitation assays showed that SOX17 was a transcriptional suppressor of NRF2 promoter in three pairs of parental and resistant CCRT cell lines. We further confirmed that SOX17 downregulated the mRNA and protein level of NRF2 and NRF2 downstream genes. Clinically, by recruiting 115 patient samples, we validated that the expressions of five NRF2 downstream genes were markedly up-regulated in CCRT poor-responders as compared to that in good-responders. In addition, nuclear level of SOX17 and NRF2 by immunohistochemical staining showed that SOX17low and NRF2high express pattern was predominantly found in CCRT poor-responders. Kaplan-Meier survival analysis demonstrated that SOX17low or NRF2high predicted CCRT response and survival time of ESCC patients. Finally, proliferation, migration and stemness of CCRT-resistant ESCC cell lines were attenuated by SOX17 overexpression while induced by reconstituted cells co-overexpressing SOX17 and NRF2 both in vitro and in vivo.
Conclusions: We delineate a novel mechanism that SOX17 negatively regulates NRF2 and disruption of SOX17-NRF2 axis leads to the acquire CCRT resistance in cell, animal and clinical models. In addition, the SOX17/NRF2 immunoreactivity and expression of NRF2 downstream genes may act as molecular biomarkers to predict the CCRT response of ESCC patients.
Key words: Esophageal squamous cell carcinoma; concurrent chemoradiation therapy resistance; SOX17; NRF2 addition; transcription factor; transcriptional regulation mechanism.

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