探討化合物Y抑制神經母細胞瘤轉移之效果;Investigation on the metastasis inhibiting effects of compound Y in neuroblastom

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题名:	探討化合物Y抑制神經母細胞瘤轉移之效果;Investigation on the metastasis inhibiting effects of compound Y in neuroblastom
作者:	蔡俊發;TSAI, CHUN-FA
贡献者:	生命科學系
关键词:	神經母細胞瘤;芳香烴受體;Neuroblastoma;Aryl hydrocarbon receptor;AHR
日期:	2024-01-29
上传时间:	2024-09-19 15:22:28 (UTC+8)
出版者:	國立中央大學
摘要:	神經母細胞瘤（神母）是一種周圍神經系統的兒童癌症，約 50% 的神經母細胞瘤患者在診斷時已發生惡性轉移，因此開發抗轉移藥物是當前神母治療的當務之急。芳香烴受體（Aryl hydrocarbon receptor, AHR）是新發現的神母有利預後因子，AHR的表達與神母腫瘤的組織分化程度呈正相關，並預測患者更好的存活率。此外，我們之前的研究表明，內源性配體犬尿氨酸（Kynurenine, Kyn）激活AHR可顯著抑制神母轉移。然而，Kyn 限制神母轉移的有效劑量較高，這可能限制其作為治療藥物之潛力。化合物Y是我們新鑑定的AHR內源性配體，比Kyn具有更高激活AHR訊息傳遞路徑的能力，為了研究化合物Y是否也對神母轉移具有抑製作用，此研究利用了SK-N-BE(2)C 和 SK-N-SH 兩株神經母細胞瘤細胞來驗證化合物Y對轉移相關細胞行為的影響，包括細胞貼附、遷移和侵襲。首先透過化合物Y處理後的AHR下游基因CYP1A1增加證實化合物 Y 具活化AHR的效果。接著利用化合物 Y處理過後之細胞分別進行傷口癒合實驗、Tans-well 細胞侵犯實驗以及細胞貼附實驗，發現在給予化合物 Y治療過後之細胞的爬行能力與侵犯能力均有明顯下降的趨勢，相反地，細胞的貼附能力反而因為化合物 Y處理而增加，這些變化均與先前Kyn處理後之結果類似。此外，由於上皮細胞間質轉化（epithelial-mesenchymal transition，EMT）是癌症轉移的關鍵機制，為了解化合物 Y造成上述細胞行為變化之可能機制，我透過qPCR的方式觀察ＥＭＴ相關基因的變化，發現在化合物 Y處理過後會導致Vimentin、Slug的表達下降以及E-鈣粘蛋白（E-cadherin）的表達上調；同時也發現腫瘤轉移抑制基因KISS-1的mRNA表達也受到化合物 Y的刺激而上升，顯示其抑制轉移的潛力。總結，這項研究證實化合物Ｙ確實可以透過活化AHR進而調節KISS-1及ＥＭＴ相關基因的表達，從而抑制神經母細胞瘤細胞的轉移相關特性。;Neuroblastoma (NB) is a childhood cancer of the peripheral nervous system. About 50% of patients with neuroblastoma have developed malignant metastases at diagnosis. Developing an anti-metastasis drug is urgent for the current NB treatment. Aryl hydrocarbon receptor (AHR) is a new-identified favorable prognostic factor of NB. The expression of AHR positively correlated with the differentiation histology of the NB tumors and predicted better survival of the patients. In addition, our previous study has suggested that activation of AHR by the endogenous ligand kynurenine (Kyn) significantly inhibits NB metastasis. However, the effective dose of Kyn for restricting NB metastasis is high which may limit its therapeutic potential. Compound Y is a novel endogenous ligand of AHR and shows a higher ability than Kyn to activate AHR signaling. To investigate whether compound Y also has inhibiting effects on NB metastasis, SK-N-BE(2)C and SK-N-SH NB cells were treated with compound Y followed by several in vitro analyses. First, the effect of compound Y on AHR activation was confirmed by the upregulation of CYP1A1. Then, to test compound Y’s effect on NB metastasis, wound healing, trans-well invasion assays, and cell adhesion assays were investigated. I found that compound Y inhibits the migration and invasion ability of the two NB cell lines. Reversely, compound Y treatments promote the adhesion of NB cells. These findings are similar to our previous observation of using Kyn as a treatment. Since epithelial-mesenchymal transition (EMT) is a key process of tumor metastasis, the EMT-related genes were analyzed by real-time PCR to verify the underlying mechanism of compound Y treatment. The results show that Vimentin and Slug were downregulated and E-cadherin was upregulated by compound Y. In addition, the tumor metastasis suppressor gene KISS-1 was also upregulated by compound Y indicating its anti-metastasis potential. Altogether, this study suggests that compound Y could affect the expression of EMT-related genes and KISS-1 through AHR activation, resulting in the restriction of NB metastasis.
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