四氫皮質酮和其異構體對於神經母細胞瘤治療之研究

Abstract

神經母細胞瘤是嬰兒期最常見的顱外實體腫瘤，起源於胚胎發育期間神經脊細胞的異常增生，通常發生於與交感神經系統相關的區域。芳香烴接受器（Aryl hydrocarbon receptor, AHR）為一種配體活化的轉錄因子，已知能促進神經母細胞瘤細胞的分化。四氫皮質酮（Tetrahydrocorticosterone, THB）作為一種內源性糖皮質激素，近期被鑑定為可活化AHR的內源性配體，並能調控斑馬魚的神經生成與神經分化。此外，一種結構上與THB相似的合成化合物，稱為Compound Y，亦已被開發。基於上述發現，本研究假設Compound Y與THB可透過活化AHR，促進神經母細胞瘤細胞分化，進而抑制其增生。在本研究中，Compound Y與THB皆可有效抑制神經母細胞瘤細胞的增生，並提升神經分化標誌物，包括生長相關蛋白43（GAP43）與神經元特異性烯醇酶（NSE）的表現。此外，本研究亦建立一套以GAP43啟動子活性為基礎的螢光酶篩選平台，以加速分化促進劑的篩選流程。利用來自TH-MYCN轉基因小鼠的原代神經母細胞瘤細胞進行體外實驗，進一步確認Compound Y具有抑制細胞增生的作用。體內分析亦顯示，Compound Y能顯著延緩腫瘤進展並延長TH-MYCN小鼠的存活時間。綜合以上結果，Compound Y與THB具備透過AHR介導的分化機制治療神經母細胞瘤的潛力，為未來的治療策略提供重要依據。

Neuroblastoma is the most common extracranial solid tumor in infancy, originating from aberrant proliferation of neural crest cells during embryonic development and typically arising in regions associated with the sympathetic nervous system. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, has been shown to promote the differentiation of neuroblastoma cells. Tetrahydrocorticosterone (THB), a glucocorticoid, was recently identified as an endogenous AHR activator that regulates neurogenesis and neural differentiation in zebrafish. In addition, a synthetic compound structurally similar to THB, referred to as Compound Y, has been developed. Based on these findings, it was hypothesized that both Compound Y and THB promote neuroblastoma cell differentiation through AHR activation, thereby inhibiting cell proliferation. In this study, both Compound Y and THB were demonstrated to inhibit neuroblastoma cell proliferation while enhancing the expression of neural differentiation markers, including growth-associated protein 43 (GAP43) and neuron-specific enolase (NSE). To facilitate efficient identification of differentiation-inducing compounds, a luciferase-based screening platform targeting GAP43 promoter activity was established. Additionally, ex vivo experiments using primary neuroblastoma cells derived from TH-MYCN transgenic mice confirmed the growth-inhibitory effects of Compound Y. In vivo analysis further demonstrated that Compound Y significantly slowed tumor progression and prolonged survival in TH-MYCN mice. Collectively, these findings highlight the therapeutic potential of Compound Y and THB in neuroblastoma treatment by targeting AHR-mediated differentiation pathways.