m6A甲基转移酶METTL3调控TXNIP对结直肠癌生物学特征的影响和机制研究

Epigenetic alterations immensely contributed to human carcinogenesis. Studies confirmed that the reversible RNA modifications N6-methyadenosine (m6A) represents a new layer of epigenetic deregulation in cancer progression. However, the underlying mechanism between m6A and colorectal cancer (CRC) is still unclear. In our previous work, we discovered that the expression of METTL3 (methyltransferase like 3), a major RNA N6-adenosine methyltransferase, and the level of m6A modification were significantly up-regulated in human CRC tissues. Knock down of METTL3 substantially abolished the CRC growth and invasion in vitro. However, the expression of TXNIP, a tumor suppressor gene in cancer, was increased in CRC cells. In this project, we propose to identify the roles of m6A modification and CRC. This study will delineate the mechanism of METTL3 in regulating TXNIP m6A modification and the effects of METTL3 in CRC progression. Our findings will provide a potential target for prevention and treatment of cancer proliferation and invasion.

表观遗传调控在结直肠癌的发生发展过程中发挥重要作用。研究证实发生在mRNA转录后水平的m6A修饰参与恶性肿瘤的进展，但是有关m6A修饰与结直肠癌发病的机制研究尚不清楚。我们前期研究发现，结直肠癌组织中m6A的修饰水平及m6A甲基转移酶METTL3的表达水平均显著升高；干扰METTL3表达后上调了抑癌基因TXNIP的表达并抑制了结肠癌细胞的增殖和侵袭，但其分子机制有待深入研究。本项目将以m6A修饰与结直肠癌进展为切入点，通过分子、细胞和动物模型实验探讨m6A甲基转移酶METTL3调控TXNIP对结直肠癌生物学特征的影响和机制，剖析m6A修饰对结直肠癌进展的调控作用。我们的研究将为结直肠肿瘤的发病机制和靶向治疗提供新的理论依据。

表观遗传调控在结直肠癌的发生发展过程中发挥重要作用。研究证实发生在mRNA转录后水平的m6A修饰参与恶性肿瘤的进展，但是有关m6A修饰与结直肠癌发病的机制研究尚不清楚。我们前期研究发现，结直肠癌组织中m6A的修饰水平及m6A甲基转移酶METTL3的表达水平均显著升高；干扰METTL3表达后上调了抑癌基因TXNIP的表达并抑制了结肠癌细胞的增殖和侵袭。本项目以m6A甲基转移酶METTL3与结直肠癌进展为切入点，通过分子、细胞和动物模型实验探讨了m6A甲基转移酶METTL3结直肠癌生物学特征的影响和及负性调控抑癌基因TXNIP的分子机制。我们通过成功构建肠道条件性敲除Mettl3基因的杂合子小鼠，证实了肠道条件性敲除Mettl3基因的杂合子肠道黏膜发育无异常的结果，揭示了肠道条件性敲除Mettl3基因能缓解AOM/DSS诱导的溃疡性结肠炎相关性结直肠癌模型小鼠的临床症状及肠道肿瘤形成的功能作用，并进一步证实了小鼠肠道条件性敲除Mettl3能促进Txnip表达的分子机制。我们的研究将为结直肠肿瘤的发病机制和靶向治疗提供新的理论依据。