Niu Zhengchuan, Xu Pingping, Zhu Dexiang, Tang Wentao, Ji Meiling, Lin Qi, Liu Tianyu, Ren Li, Wei Ye, Xu Jianmin
Department of General Surgery, Zhongshan Hospital of Fudan University Shanghai 200032, China.
Int J Clin Exp Pathol. 2018 Oct 1;11(10):4771-4783. eCollection 2018.
In recent years, aberrant mRNA translational control has gained much attention as a critical player in the malignant process of tumors. Eukaryotic initiation factor 4E (eIF4E), by binding to the mRNA cap, can regulate specific protein synthesis, contributing to malignancy in human tumors. However, integrin β1 mediated chemoresistance under translational control remains unknown in colorectal cancer.
The expression relationship between eIF4E and Integrin β1, along with their clinical significance was investigated in colorectal cancerous tissues of 118 cases using immunohistochemistry. Cell transfection techniques of small interfering RNA (siRNA) and cDNA expression plasmid were applied to investigate the molecular relationship of integrin β1 and eIF4E and their biological effects on 5FU resistance in SW480 and LoVo cell lines.
The expression of eIF4E and integrin β1 was positively correlated in colorectal cancer, and patients with high expressions of both markers tended to have a worse prognosis according to a Kaplan-Meier survival analysis. Integrin β1 could contribute to 5-fluorouracil (5FU) resistance in colorectal cancer cell lines. Moreover, the protein expression of β1 could be regulated by eIF4E, interestingly, without any change of mRNA expression level. Significantly, Hoechst/PI double staining and an MTT assay proved integrin β1 could contribute to cellular survival and 5FU resistance under translational control of eIF4E in these cells.
We conclude that integrin β1 mediated 5FU chemo resistance in colorectal cancer could be translationally regulated by eIF4E. Promisingly, targeting key molecules of this translational apparatus may provide an innovative therapeutic strategy for colorectal cancer.
近年来，异常的mRNA翻译控制作为肿瘤恶性进展过程中的关键因素受到了广泛关注。真核生物起始因子4E（eIF4E）通过与mRNA帽结合，可调节特定蛋白质的合成，在人类肿瘤的恶性发展中发挥作用。然而，在结直肠癌中，整合素β1介导的翻译控制下的化疗耐药性仍不清楚。
采用免疫组织化学方法，对118例结直肠癌组织中eIF4E与整合素β1的表达关系及其临床意义进行研究。应用小干扰RNA（siRNA）和cDNA表达质粒的细胞转染技术，研究整合素β1与eIF4E的分子关系及其对SW480和LoVo细胞系5-氟尿嘧啶（5FU）耐药性的生物学影响。
在结直肠癌中，eIF4E与整合素β1的表达呈正相关。根据Kaplan-Meier生存分析，两种标志物高表达的患者预后往往较差。整合素β1可导致结直肠癌细胞系对5-氟尿嘧啶（5FU）耐药。此外，β1的蛋白表达可受eIF4E调节，有趣的是，mRNA表达水平无任何变化。重要的是，Hoechst/PI双染和MTT分析证明，在这些细胞中，整合素β1在eIF4E的翻译控制下可促进细胞存活和5FU耐药。
我们得出结论，整合素β1介导的结直肠癌5FU化疗耐药性可由eIF4E进行翻译调控。有望通过靶向这一翻译机制的关键分子为结直肠癌提供创新的治疗策略。
