第四章 討論
四、 LRH-1 對麩醯胺酸代謝的影響
細胞癌化後會經歷提高無氧之糖解作用 (glycolysis) 以及增加對麩醯胺酸 (glutamine) 依賴程度的代謝轉變 [95]。麩醯胺酸為血清中含量很高的胺基酸，經 SLC1A5 進入細胞，以粒線體內之 GLS 轉變成麩胺酸 (glutamate)；接著 GLUD 可 將麩胺酸代謝成α-KG 並進入 TCA cycle，維持細胞生合成及能量的恆定。此外，
麩胺酸可藉由麩醯胺酸合成酶 (glutamine synehetase，GS；由 GLUL 基因轉錄) 逆 向合成麩醯胺酸 (附圖一) [76]。
先前Xu 的團隊將小鼠肝細胞專一性剔除 Lrh-1 基因並誘發肝癌形成 [78]，發
現許多和麩醯胺酸代謝相關的基因表現降低，包括Gls2。但 Gls1 並無受到影響，
可能是因GLS2 為較特定表現於肝臟、腦、胰臟等器官的型式，而 GLS 則較為廣
泛 [76]；另 Slc1A5 及 Glud1 的表現亦無改變。而後作者證實 LRH-1 可直接調控 Gls2，其下游產生之 α-KG 可活化 mTORC1 以促進細胞增生。此外，於 HepG2 抑 制LRH-1 亦觀察到 GLS2 表現降低。此小鼠模式說明 LRH-1 可透過促進 GLS2 的 表現，參與調控麩醯胺酸的代謝。
另外 Kung 等人以乳癌細胞為研究對象 [96]，發現不同類型的乳癌細胞對麩 醯胺酸有不同的需求及調控方式。文獻中作者以探討乳管型 (luminal-type，如：
MCF7、T47D) 及基底型 (basal-type，如：MDA-MB-231) 為主，發現 luminal-type 的乳癌細胞對麩醯胺酸缺乏的環境有較高的抗性，反而在缺乏葡萄糖的情況下受 到較明顯的影響，為麩醯胺酸非依賴型 (glutamine-independent)。由於 luminal-type
的乳癌細胞可表現GATA3 [97]，作者發現 GATA3 可促進 GLUL 轉錄以生成 GS，
使luminal-type 的乳癌細胞具有自行合成麩醯胺酸的能力，降低其對外界的依賴。
此外作者發現GATA3 會抑制 GLS 及 GLS2 表現，維持 glutamine-independent 的特 性。我的實驗於MCF7 抑制 LRH-1 表現 (圖十三 A；表七)，顯示 GLS 及 GLUD1 都因抑制 LRH-1 而減少，推測 LRH-1 影響 MCF7 代謝麩醯胺酸。而 SLC1A5 及 GLUL 皆無影響，可能是因為其 glutamine-independent 的特性，對外界之麩醯胺酸 需求較低；而GATA3 可促 GLUL 表現，或許緩解了 LRH-1 的抑制作用。
Basal-type 的乳癌細胞則對缺乏麩醯胺酸的環境變化敏感，並有顯著較高的麩 醯胺酸攝取量，屬於麩醯胺酸依賴型 (glutamine-dependent)。偵測麩醯胺酸代謝相 關的基因表現，發現basal-type 表現之 GLS 顯著較 luminal-type 高，而 GLS2 表現 較少。且basal-type 不像 luminal-type 有 GATA3 可生成 GS [97]，更增加其對麩醯 胺酸的需求。我們於MDA-MB-231 抑制 LRH-1 的結果如圖十三 B 及表七，發現 每個基因都顯著受到LRH-1 抑制的影響，尤其是 GLS 及 GLUD1 的抑制程度都比 MCF7 多。而於 MCF7 無變化的 SLC1A5 在 MDA-MB-231 顯著降低表現，反映麩 醯胺酸高攝取量的現象。整體來看，抑制LRH-1 於 MDA-MB-231 有顯著影響，說 明 LRH-1 於 MDA-MB-231 會影響麩醯胺酸代謝；且抑制效果較 MCF7 明顯，符 合MDA-MB-231 之 glutamine-dependent 的特性。
ChREBP 的目標基因包括糖解作用、糖質新生 (gluconeogenesis)、脂質合成 (lipogenesis) 等代謝路徑的相關基因，先前的研究指出 ChREBP 於癌細胞之代謝轉 換扮演關鍵角色 [86]。我觀察 MCF7 及 MDA-MB-231 在抑制 LRH-1 後 ChREBP 的表現，發現兩細胞株之ChREBP 皆受到抑制，說明 LRH-1 可能影響乳癌細胞對 葡萄糖的代謝轉換 (圖十三；表七)。
自NCBI Gene Expression Omnibus (GEO) (http://ncbi.nlm.nih.gov/geo/) 可獲得 已 發 表 之 LRH-1 的 染 色 質 免 疫 沉 澱 – 定 序 (chromatin immunoprecipitation-sequencing，ChIP-seq) 數據 (GSM1143122)。根據該數據資料分析 SLC1A5、GLS、
GLUD1、GLUL 及 ChREBP 基因前方 5k 的啟動子序列，皆沒有發現 LRH-1 的結
合訊號；且透過線上軟體 PROMO-ALGGEN 檢測每個基因 5k 的啟動子序列，亦
無找到 LRH-1 的結合序列。此結果說明 LRH-1 對乳癌細胞之麩醯胺酸代謝的影
響，可能是以間接調控的方式進行。
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