lnc-CRCMSL介导结直肠癌细胞脂质代谢失衡抑制肿瘤转移的机制研究

The main cause of death for colorectal cancer (CRC) patients is metastasis. The reprogramming process of lipid metabolism is one of the most important hallmarks of malignant tumors，but the underlying molecular mechanisms are still unclear. Lipid metabolism includes fatty acid oxidation and fatty acid synthesis, and inhibiting one of key enzymes in which could suppress tumor metastasis. lnc-CRCMSL （colorectal cancer metastasis suppressing lncRNA）is a novel long noncoding RNA which was screened out by gene chip with cis-regulation. We confirmed that lnc-CRCMSL could significantly suppress the migration, invasion and metastasis of colorectal cancer cells. lnc-CRCMSL could affect the activity of its cis-regulate gene MAP2K6 and then affect the activity of P38 and up-regulate the expression of PPARa . AS p38-PPARa signaling pathway could participate in fatty acid β-oxidation, we suspect lnc-CRCMSL could affect the fatty acid β oxidation of colorectal cancer cells by MAP2K6-p38-PPARa signal axis. Meanwhile, we found that lnc-CRCMSL could specifically combine with ACC1, a key enzyme in fatty acid synthesis. ACC1 has been reported highly expressed in many malignant tumors, and ACC1 has been an important target for treatment. lnc-CRCMSL could down-regulate the expression of ACC1 to suppress fatty acid synthesis in colorectal cancer. In conclusion, we propose a hypothesis: lnc-CRCMSL inhibits fatty acid synthesis and promotes fatty acid β-oxidation so that lipid metabolism in CRC loses balance ,which suppresses colorectal cancer cells metastasis.

结直肠癌最主要的死亡原因是转移。脂质代谢重编程是恶性肿瘤重要特征之一，但其具体机制尚未阐明清楚。脂质代谢包括脂肪酸合成与氧化，二者保持动态平衡，抑制脂肪酸合成或氧化的任何一个关键酶均能抑制肿瘤转移。lnc-CRCMSL是我们通过基因芯片结合cis调控筛选出与结直肠癌转移相关的新的长链非编码RNA，能显著抑制结直肠癌细胞迁移、侵袭和转移。CRCMSL能抑制MAP2K6的活性从而抑制P38活性，上调PPARa及下游靶基因CPT1A和ACOX1表达，推测CRCMSL能通过MAP2K6-P38-PPARa信号轴促进结直肠癌细胞脂肪酸β氧化。同时CRCMSL能特异性结合脂肪酸合成关键酶ACC1并下调其表达，推测CRCMSL能抑制结直肠癌细胞脂肪酸合成。综上，我们提出假设：CRCMSL促进结直肠癌细胞脂肪酸β氧化的同时抑制其合成导致脂质代谢失衡抑制肿瘤转移。

结直肠癌患者最主要的死亡原因是肿瘤转移。我们在前期研究中已证实ENSG00000267194是与结直肠癌患者不良预后相关的抑癌基因，并将其命名为结直肠癌转移抑制长链非编码RNA（ColoRectal Cancer Metastasis-Suppressed LncRNA，CRCMSL），CRCMSL可以直接结合高迁移率族蛋白B2（high mobility group box-2 protein,HMGB2），通过抑制HMGB2入核从而抑制OCT4介导的EMT的发生，抑制结直肠癌侵袭转移 （文章已于2018年12月在Oncogene上发表，IF：6.853，JCR1区，本人为共同一作）。为了进一步探索CRCMSL抑制结直肠癌侵袭转移的分子机制，我们通过生物信息学分析了CRCMSL的生物学功能，提示CRCMSL可能影响脂肪酸代谢，已有文献报道，结直肠癌中脂质代谢异常，抑制癌细胞的脂质代谢成为治疗结直肠癌的新策略。为探究CRCMSL与脂质代谢的关系，我们进行脂质组学检测，发现敲低CRCMSL导致SW620细胞内脂质代谢物含量普遍升高，且差异脂质以磷脂为主。乙酰辅酶A羧化酶1（ACC1）是脂肪酸合成过程的关键酶，在多种恶性肿瘤中呈高表达，如肝癌、乳腺癌、前列腺癌、小细胞肺癌等，通过抑制 ACC1干扰癌细胞的脂质代谢成为治疗恶性肿瘤的新靶点。我们发现，CRCMSL能有效富集ACC1并能抑制其活性，并与ACC抑制剂ND630起协同作用。体内外生物学功能实验发现CRCMSL与ND630均能抑制结直肠癌细胞的侵袭转移，体外结果显示二者有明确的协同作用，但体内实验二者协同作用需要进一步验证。本课题阐明了CRCMSL通过抑制ACC的活性影响结直肠癌细胞脂肪酸合成从而抑制其侵袭转移，与代谢新药ND630有协同作用，为结直肠癌患者临床治疗提供新的理论基础和科学依据。