Sipos Ferenc, Firneisz Gábor, Műzes Györgyi
Ferenc Sipos, Gábor Firneisz, Györgyi Műzes, 2 Department of Internal Medicine, Semmelweis University, H-1088 Budapest, Hungary.
World J Gastroenterol. 2016 Sep 21;22(35):7938-50. doi: 10.3748/wjg.v22.i35.7938.
Colonic inflammation is required to heal infections, wounds, and maintain tissue homeostasis. As the seventh hallmark of cancer, however, it may affect all phases of tumor development, including tumor initiation, promotion, invasion and metastatic dissemination, and also evasion immune surveillance. Inflammation acts as a cellular stressor and may trigger DNA damage or genetic instability, and, further, chronic inflammation can provoke genetic mutations and epigenetic mechanisms that promote malignant cell transformation. Both sporadical and colitis-associated colorectal carcinogenesis are multi-step, complex processes arising from the uncontrolled proliferation and spreading of malignantly transformed cell clones with the obvious ability to evade the host's protective immunity. In cells upon DNA damage several proto-oncogenes, including c-MYC are activated in parelell with the inactivation of tumor suppressor genes. The target genes of the c-MYC protein participate in different cellular functions, including cell cycle, survival, protein synthesis, cell adhesion, and micro-RNA expression. The transcriptional program regulated by c-MYC is context dependent, therefore the final cellular response to elevated c-MYC levels may range from increased proliferation to augmented apoptosis. Considering physiological intestinal homeostasis, c-MYC displays a fundamental role in the regulation of cell proliferation and crypt cell number. However, c-MYC gene is frequently deregulated in inflammation, and overexpressed in both sporadic and colitis-associated colon adenocarcinomas. Recent results demonstrated that endogenous c-MYC is essential for efficient induction of p53-dependent apoptosis following DNA damage, but c-MYC function is also involved in and regulated by autophagy-related mechanisms, while its expression is affected by DNA-methylation, or histone acetylation. Molecules directly targeting c-MYC, or agents acting on other genes involved in the c-MYC pathway could be selected for combined regiments. However, due to its context-dependent cellular function, it is clinically essential to consider which cytotoxic drugs are used in combination with c-MYC targeted agents in various tissues. Increasing our knowledge about MYC-dependent pathways might provide direction to novel anti-inflammatory and colorectal cancer therapies.
结肠炎症对于治愈感染、伤口以及维持组织内稳态是必需的。然而，作为癌症的第七个标志，它可能会影响肿瘤发展的各个阶段，包括肿瘤起始、促进、侵袭和转移扩散，还包括逃避免疫监视。炎症作为一种细胞应激源，可能引发DNA损伤或基因不稳定，此外，慢性炎症可诱发促进恶性细胞转化的基因突变和表观遗传机制。散发性和结肠炎相关的结直肠癌发生都是多步骤、复杂的过程，源于恶性转化细胞克隆的不受控制的增殖和扩散，这些细胞克隆具有明显的逃避免疫保护的能力。在DNA损伤的细胞中，包括c-MYC在内的几个原癌基因会与肿瘤抑制基因的失活同时被激活。c-MYC蛋白的靶基因参与不同的细胞功能，包括细胞周期、存活、蛋白质合成、细胞黏附以及微小RNA表达。由c-MYC调控的转录程序取决于具体情况，因此细胞对c-MYC水平升高的最终反应可能从增殖增加到凋亡增强不等。考虑到生理状态下的肠道内稳态，c-MYC在细胞增殖和隐窝细胞数量的调节中发挥着重要作用。然而，c-MYC基因在炎症中经常失调，并且在散发性和结肠炎相关的结肠腺癌中均过度表达。最近的研究结果表明，内源性c-MYC对于DNA损伤后有效诱导p53依赖性凋亡至关重要，但c-MYC的功能也参与自噬相关机制并受其调节，而其表达受DNA甲基化或组蛋白乙酰化的影响。可以选择直接靶向c-MYC的分子或作用于c-MYC途径中其他相关基因的药物用于联合治疗方案。然而，由于其细胞功能取决于具体情况，临床上至关重要的是要考虑在不同组织中哪些细胞毒性药物与c-MYC靶向药物联合使用。增加我们对MYC依赖性途径的了解可能为新型抗炎和结直肠癌治疗提供方向。
