AKIP1通过调控自噬促进结直肠癌化疗抵抗的分子机制研究

Chemoresistance is the major cause of recurrence and poor prognosis in colorectal cancer patients. To identify the key molecular factors in regulating chemoresistance would be great value for prevention and therapy of tumor recurrence. Previously, we reported that PTOV1 promoted cancer stem cell self-renewal as well as recurrence through activating Wnt/β-catenin signaling (Journal of pathology. 2016). Moreover, we found that PTOV1 could upregulate AKIP1 expression, which is highly expressed in recurrent colorectal cancer. Our previously preliminary data indicated that AKIP1 promoted chemoresistance to colorectal cancer by modulating autophagy. Furthermore, immunoprecipitation assay showed that AKIP1, on one hand, could bind with and activate ULK1, on the other hand, could transcriptionally upregulate ATG7 expression, thus activating autophagy signaling pathway. In our current project, we will combine in vitro and in vivo experiments with clinical samples to deeply investigate the molecular mechanisms of AKIP1-induced autophagy in chemoresistance of colorectal cancer. Our work may help provide new predictors and therapeutic targets for colorectal cancer recurrence.

化疗抵抗是结直肠癌病人复发和预后不良的主要原因。因此寻找调控结直肠癌化疗抵抗的关键分子对肿瘤复发的预防和治疗具有重要的意义。前期我们已发表文章报道PTOV1能够通过激活Wnt/β-catenin信号通路调控肿瘤干细胞特性并促进乳腺癌复发(Journal of pathology. 2016)。进一步实验我们发现PTOV1能够上调AKIP1的表达，且AKIP1在复发性的结直肠癌中表达异常升高。近期的预实验结果显示：AKIP1能够激活自噬信号通路并诱导结直肠癌细胞化疗抵抗。通过进一步的免疫共沉淀实验我们发现AKIP1不仅能够结合并激活ULK1，同时又能转录上调ATG7的表达，共同促进自噬通路的激活。因此本项目承前启后，将深层次解析AKIP1激活自噬诱导结直肠癌化疗抵抗的分子机制，并与临床相结合，有望为结直肠癌复发提供新的预测标记物及治疗靶点。

肿瘤的化疗抵抗是肿瘤复发和病人预后不良的主要原因。阐明肿瘤化疗抵抗的分子机制，开发能克服化疗耐受的新型药物，实现化疗与分子靶向治疗的高效结合是目前治疗肿瘤的关键思路。本项目我们发现激酶结合蛋白AKIP1在复发性结直肠癌组织中表达显著升高，AKIP1高表达肿瘤细胞自噬信号通路激活且表现出更强的化疗药物耐受。深入的分子机制研究表明，AKIP1一方面通过与ULK1结合上调ULK1的磷酸化水平，另一方面通过与ATG7的启动子结合上调ATG7的表达，从而激活自噬信号通路。更重要的是，体内实验显示，在高表达AKIP1的肿瘤中使用自噬通路抑制剂CQ能显著增强结直肠癌细胞对化疗药物的敏感性。此外，我们还进一步拓展研究了靶向AKIP1在治疗肝癌中的潜能，我们发现用纳米载体携带AKIP1特异性的shRNAs能在体内有效地抑制肝癌的转移。这些结果为靶向AKIP1提高肿瘤化疗敏感性、抑制肿瘤转移提供了有力的科学证据，具有一定的临床转化应用潜能。