研究myosin 1B調控食道鱗狀上皮細胞癌生長之分子機制

食道癌(esophageal cancer, EC)為一種上消化道腫瘤，每年診斷病例超過 50 萬例，依據病理組織型態可分為兩種類型:食道鱗狀上皮細胞癌(esophageal squamous cell carcinoma, ESCC)與食道腺癌(esophageal adenocarcinoma, EAC)，超過90%的食道癌病例為食道鱗狀細胞癌。儘管在治療方面取得了顯著的進步，但食道鱗狀細胞癌患者的預後極差，5年存活率僅為20%。因此，為食道鱗狀細胞癌患者建立新的治療策略以近一步改善預後不良的問題非常重要。Myosin 1B (MYO1B)為myosin家族的成員之一，與肌動蛋白組織和聚合有關。MYO1B在許多癌症中會有高度的表現促進腫瘤細胞的增殖、遷移、侵襲，如: 頭頸鱗狀細胞癌、子宮頸癌等，在實驗室先前研究證實，在食道鱗狀細胞癌中透過SNAI2 / cyclin D1訊號路徑參與腫瘤進展 。目前MYO1B 誘導食道鱗狀細胞癌發展的分子機制尚未清楚。 在研究中透過GEO數據庫分析發現在食道鱗狀細胞癌病患組織中MYO1B與SREBP1的mRNA表現之間呈正相關，進一步利用Western blot、Oil red O 染色、BODIPY染色證實MYO1B 高表現和敲低後能夠影響SREBP1、FASN和SCD1的表現、三酸甘油脂和膽固醇的生成以及脂滴的累積，同時也發現MYO1B透過SREBP1來調控脂質生合成相關蛋白的表現進而影響脂滴的累積與細胞生長。接著也觀察到MYO1B能夠調控並且結合RICTOR參與EGFR/AKT/RAPTOR路徑。此外，透過西方墨點法觀察到MYO1B 敲低後會減弱GPX4的蛋白表現從而增加細胞中活性氧化物(ROS)累積誘導細胞鐵死亡。從研究結果得知， MYO1B/SREBP路徑參與脂質合生成與調控鐵依賴性死亡，顯示MYO1B和SREBP1可作為診斷食道鱗狀細胞癌患者的潛在分子。

Esophageal cancer (EC) is an upper gastrointestinal tumor. It is a highly fatal disease, more than 500,000 deaths each year. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two main histological subtypes of EC, over 90% of EC cases are ESCC in Asia, including Taiwan. Despite improved in surgical techniques, the ESCC patients with a five-year survival rate are less than 20%. Therefore, it is important to explore novel biomolecules for improving the survival of ESCC patients. Myosin 1B (MYO1B), a member of the myosin family, is related to actin organization and polymerization in human cells. In human cancers, MYO1B overexpression is positively correlated with cell proliferation, migration, and invasion, such as head and neck squamous cell carcinoma, cervical cancer and pancreatic cancer. Our previous study shows that MYO1B is involved in tumor progression through SNAI2/cyclin D1 signaling pathway in ESCC. However, the molecular mechanisms of MYO1B-induced ESCC development remain unclear. In this current study, based on GEO database analysis, mRNA expression level of MYO1B had positively correlated with SREBP1 mRNA expression in tumor tissues of ESCC patients. The in vitro study showed that MYO1B overexpression enhanced lipogenic-related protein expressions such as SREBP1, FASN and SCD1 in ESCC cells, leading to promoting lipogenesis, triglycerides and cholesterol production, and accumulation of lipid droplet by Western blot, Oil red O staining, and BODIPY approaches. In contrast, knockdown MYO1B had an opposite effect. Mechanistically, we illustrated that MYO1B modulated SREBP1 protein expression to promote lipid droplet accumulation and cell growth. Moreover, MYO1B regulated and associated with RICTOR to participate in EGFR/AKT/RAPTOR pathway in ESCC cells. Importantly, inhibition of MYO1B induced ESCC cell ferroptosis by decreasing GPX4 protein expression and increasing ROS accumulation. Collectively, our finding demonstrate that MYO1B/SREBP1 signaling involves in lipogenesis and modulates ferroptosis in ESCC cells, indicating that MYO1B and SREBP1 might be potential molecules for diagnosis in ESCC patients.