探討中心粒結合蛋白 55 誘導食道鱗狀上皮細胞癌增生之分子機制

食道癌是一種具有高度侵襲性的癌症之一，生存率低且預後差，其術後五年存活率只有 10%~20%。食道鱗狀上皮細胞癌 (Esophageal squamous cell carcinoma, ESCC) 是食道癌的其中一個病理亞型，是亞洲最常見的亞型，在台灣有 90%以上的食道癌患者都是屬於 ESCC 的類型。因此發展治療 ESCC 之新方法及探討新興分子標靶治療尤為重要。先前有文獻指出，癌細胞在迅速擴張時需要攝取大量的養份和能量，此時癌細胞可能透過改變代謝途徑來加速能量攝取。其中，脂質生合成也是癌細胞快速獲取能量來源的代謝途徑之一。中心粒結合蛋白 55 (Centrosomal associated protein 55, CEP55) 亦可被稱為 c10orf3 或 FLJ10540，是中心粒結合蛋白的家族成員之一，主要參與細胞生長和分裂等功能。目前許多文獻指出 CEP55 在多種癌症中大量表現，例如:大腸直腸癌、肝癌、乳癌和食道癌等，但 CEP55 在 ESCC 中的分子機轉以及與脂質生合成之間的關聯性尚未被釐清，因此我們需要繼續探討 CEP55 和脂質生合成在 ESCC 的進展中是否有值得研究的病理分子機制。根據 GEPIA (Gene Expression Profiling Interactive Analysis) 數據庫和實驗結果顯示，脂質生合成相關基因 SREBP1、 FASN、SCD1 與 CEP55 呈現正相關，此外 CEP55 同時會增加脂質生合成相關蛋白的蛋白表現量還有細胞內脂滴的累積。更深入的研究，發現 CEP55 會與 EGFR 結合並且透過 EGFR/SREBP1 信號路徑促進脂質生合成蛋白的蛋白表現量以及造成細胞內脂滴累積的現象，並且同時增強 ESCC 細胞的生長能力。最後，我們發現將 CEP55 抑制時會導致細胞內活性氧物質 (Reactive oxygen species, ROS) 增加，同時藉由 GPX4 造成細胞發生鐵依賴性細胞死亡。總而言之，本篇研究證實，CEP55 可透過促進脂質生合成來增強 ESCC 細胞的生長能力，並且藉由減少細胞內 ROS，使 ESCC 避免於鐵依賴性細胞死亡。

關鍵字

食道鱗狀上皮細胞癌；脂質生合成；中心粒結合蛋白 55 ；鐵依賴性細胞死亡

並列摘要

Esophageal cancer is one of the most aggressive cancers, with a low survival rate and poor prognosis. The five-year survival rate of ESCC patient is only 10% to 20%. Esophageal squamous cell carcinoma (ESCC) is one of the pathological subtypes of esophageal cancer. In Taiwan, more than 90% of esophageal cancers patients belong to the ESCC subtype. Previous studies have showed that cancer cells need to absorb a large amount of nutrients when they rapidly expand. Lipogenesis is also one of the metabolic pathways for cancer cells to quickly obtain energy for tumor growth. However, the relationship between lipogenesis and ESCC development is still obscure. Centrosomal associated protein 55 (CEP55), also known as c10orf3 or FLJ10540, is a member of the centrosomal associated protein family and is mainly involved in cell growth and division. Currently, many studies indicate that CEP55 is widely expressed in various cancers, including esophageal cancer. However, the further mechanisms of CEP55 in the growth of ESCC and its expression correlation with lipogenesis have not yet been discovered. In the current study, according to GEPIA database, the mRNA expression levels of lipogenic-related genes, such as SREBP1, FASN, and SCD1 are positively correlated with CEP55 mRNA expression. Moreover, we also found that CEP55 increased the proteins expressions of lipogenic-related molecules for accumulating intracellular lipid droplets. Advanced researches indicated that CEP55 bound to EGFR to increase the protein stability of EGFR and induced the protein expressions of FASN and SCD1 through enhancing the SREBP1 protein expression, causing the accumulation of intracellular lipid droplets, and promoted the growth of ESCC cells. Finally, we demonstrated that the inhibition of CEP55 induced the accumulation of intracellular ROS and caused ferroptosis through the inhibition of GPX4. In summary, CEP55 could enhance the ability of cell growth in ESCC cells by promoting lipogenesis, and prevent cell ferroptosis by decreasing intracellular ROS.