MACC1通过调控MCT1翻译起始影响胃癌化疗敏感性

Chemotherapeutic insensitivity was a main obstacle for effective treatment of gastric cancer (GC), the underlying mechanism has remained to be explored. Our previous study has indicated that Metastasis-associated in colon cancer-1(MACC1) plays a significant role in regulating drug sensitivity by upregulating Monocarboxylate transporter 1(MCT1) expression. However, their relation on chemotherapy sensitivity has not been clarified. It’s reported that the 3' non-coding region of MCT1 may be related with translation initiation control. Moreover, eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), a key molecule of translation initiation, can be phosphorylated by downstream pathways of MACC1. These suggested that MACC1 might upregulate MCT1 expression by initiating its translation. Our preliminary experiment on GC revealed that MCT1 expression was enhanced via overexpression of MACC1 while MCT1 mRNA level showed no significant change; MACC1 promoted phosphorylation of 4E-BP1. Accordingly, we hypothesize that MACC1 initiates MCT1 translation through phosphorylating 4E-BP1, which further increases MCT1 expression and leads to GC chemotherapeutic insensitivity. Current project will be carried out at molecular, cellular, animal, clinical and bioinformatic levels to clarify the mechanism how MACC1 regulating GC chemotherapeutic insensitivity by initiating MCT1 translation, which will provide new theoretical basis for signal transduction of GC chemotherapeutic insensitivity.

胃癌的化疗耐药是当前的研究热点。我们前期研究发现，MACC1可通过调控MCT1的蛋白表达影响胃癌细胞对5-FU的化疗敏感性，然而，MACC1调控MCT1的具体机制尚未见报道。通过文献检索、生物信息学分析和前期预实验结果，我们推测MACC1可能通过磷酸化激活4E-BP1，触发MCT1的翻译起始过程，上调MCT1的蛋白表达，进而降低胃癌细胞对5-FU化疗敏感性。因此，本项目旨在探讨MACC1通过调控MCT1翻译起始影响胃癌细胞化疗敏感性的具体机制，通过干扰胃癌细胞中MACC1的表达，观察MACC1对胃癌细胞5-FU化疗敏感性、MCT1的翻译活性、EIF-4F复核体各亚基磷酸化以及复合体装配等的调控作用，以4E-BP1为桥梁分子阐明MACC1触发MCT1翻译起始的具体机制，并在临床标本与动物模型就中予以验证，以期从基因转录后水平调控的角度为MACC1参与介导胃癌化疗耐药提供新的分子生物学依据。

背景：胃癌是最常见的恶性肿瘤之一，其发病率与死亡率在我国肿瘤中均高居前三位。目前晚期胃癌的治疗仍以化疗为主，化疗耐药是失败的主要原因。前期研究发现，MACC1可通过调控MCT1的蛋白表达影响胃癌细胞对5-FU的化疗敏感性。然而，MACC1调控MCT1的具体机制尚未见报道。我们推测MACC1可能通过磷酸化激活4E-BP1，触发MCT1的翻译起始过程，上调MCT1的蛋白表达，进而降低胃癌细胞对5-FU化疗敏感性。.研究内容及结果：(1)MACC1通过触发MCT1翻译起始过程上调MCT1蛋白表达影响胃癌化疗敏感性；(2)MACC1通过磷酸化激活4E-BP1触发MCT1翻译起始；(3)MACC1通过PI3K/AKT/mTOR通路促进4E-BP1磷酸化。细胞及动物实验提示，MACC1、MCT1可影响胃癌对顺铂、奥沙利铂、伊立替康等多种化疗药物的敏感性。MACC1对MCT1的调控是通过磷酸化激活4E-BP1，触发MCT1的翻译起始过程，上调MCT1的蛋白表达实现。本项目旨在探讨MACC1通过调控MCT1翻译起始影响胃癌细胞化疗敏感性的具体机制，通过干扰胃癌细胞中MACC1的表达，观察MACC1对胃癌细胞5-FU化疗敏感性、MCT1的翻译活性、EIF-4F复核体各亚基磷酸化以及复合体装配等的调控作用，以4E-BP1为桥梁分子阐明MACC1触发MCT1翻译起始的具体机制。.研究意义：从基因转录后水平调控的角度为MACC1参与介导胃癌化疗耐药提供新的分子生物学依据。