eIF4E promotes tumorigenesis and modulates chemosensitivity to cisplatin in esophageal squamous cell carcinoma.
eIF4E promotes tumorigenesis and modulates chemosensitivity to cisplatin in esophageal squamous cell carcinoma.
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eIF4E 促进食管鳞状细胞癌肿瘤发生并调节顺铂化疗敏感性
DOI：
10.18632/oncotarget.11694
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发表时间：
2016-10-11
期刊：
影响因子：
--
通讯作者：
Leng AM
中科院分区：
文献类型：
--
作者：
Liu T;Li R;Zhao H;Deng J;Long Y;Shuai MT;Li Q;Gu H;Chen YQ;Leng AM
食管鳞状细胞癌患者通常被诊断为晚期疾病，对化疗反应不佳。eIF 4 E的过表达导致增强关键恶性肿瘤相关蛋白的翻译，并使肿瘤生长和各种人类恶性肿瘤的化疗耐药性，但它是否在ESCC中发挥作用仍不清楚。我们假设eIF 4 E促进ESCC肿瘤发生，并促进对顺铂为基础的化疗获得性耐药的发展。在本研究中，我们发现eIF 4 E在临床ESCC组织和ESCC细胞系中表达显著增加，其表达水平与ESCC的淋巴结转移、TNM分期以及总生存期和无病生存期相关。我们还表明，在EC 9706中敲低eIF 4 E将显著降低体外和体内的细胞增殖、集落形成、迁移和侵袭、凋亡，反之亦然。此外，ESCC中的“弱mRNA”被证明受eIF 4 E的调控，这可能解释了上述功能。eIF 4 E的过表达降低了顺铂对食管鳞癌细胞系和移植瘤的生长抑制作用（P < 0.05）。通过shRNA敲低eIF 4 E增加了顺铂诱导的ESCC细胞系的细胞毒性，并增强了异种移植肿瘤模型对顺铂的化疗敏感性。此外，我们发现PI 3 K/AKT通路和Bcl-2/Bax比值可能与eIF 4 E诱导的ESCC顺铂耐药有关。我们的数据共同显示了eIF 4 E表达与ESCC化疗反应的相关性，并表明治疗靶向eIF 4 E可能是改善ESCC化疗反应的可行方法。
Patients with esophageal squamous cell cancer are often diagnosed with advanced diseases that respond poorly to chemotherapy. Overexpression of eIF4E leads to enhance the translation of key malignancy-related proteins and enabling tumor growth and chemoresistance in a variety of human malignancies, but whether it has a role in ESCC remains obscure. We hypothesized that eIF4E promoted ESCC tumorigenesis and facilitated the development of acquired resistance to the cisplatin-based chemotherapy. In this study, we showed that eIF4E expression was increased significantly in clinical ESCC tissues and and ESCC cell lines and its expression level was correlated with lymph node metastasis, TNM stage, as well as overall and disease-free survival of ESCC. We also showed here that knockdown of eIF4E in EC9706 would dramatically reduced cell proliferation, colony formation, migration and invasion, apoptosis in vitro as well as in vivo, and vice versa. Moreover, “weak mRNAs” were demonstrated to be regulated by eIF4E in ESCC, which might interpret the above function. Overexpression of eIF4E decreased the efficacy of cisplatin-induced cell growth inhibition in ESCC cell line and xenograft model (P < 0.05). eIF4E knockdown by shRNA increased cisplatin-induced cytotoxicity in ESCC cell lines, and enhanced chemosensitivity to cisplatin in xenograft tumor models. Furthermore, we found that the PI3K/AKT pathway and Bcl-2/Bax ratio might be responsible for the eIF4E-induced cisplatin resistance in ESCC. Our data collectively show association of eIF4E expression with chemotherapeutic response in ESCC, and suggest that therapeutically targeting eIF4E may be a viable means of improving chemotherapy response in ESCC.
影响因子：
7.4
作者：
Witton, CJ
通讯作者：
Witton, CJ