Omrane Inés, Benammar-Elgaaied Amel
Laboratoire de Génétique Immunologie et Pathologie Humaine, Faculté des Sciences de Tunis, Université de Tunis EL MANAR, Tunisia.
Laboratoire de Génétique Immunologie et Pathologie Humaine, Faculté des Sciences de Tunis, Université de Tunis EL MANAR, Tunisia.
Biochim Biophys Acta. 2015 Aug;1856(1):28-38. doi: 10.1016/j.bbcan.2015.04.001. Epub 2015 Apr 21.
Colorectal cancer is a complex and multifactorial disease. Various factors such as genetic, immunological, epigenetic and environmental constitute minor risk factors with their additive effects contributing to the advent of colorectal cancer. In order to evaluate the role of innate and adaptive immunity in the susceptibility, the presentation and the development of colorectal cancer, we considered an immunogenetic approach on polymorphisms in the TLR4 gene and NOD2/CARD15 gene (receptors of innate immunity) as well as in cytokine genes of the TH17 pathway IL17A, IL17F and cytokine receptor IL23R. Then, we evaluated the expression of microRNAs regulated by TLR4 and NOD2/CARD15 or targeting TLR4, IL17 and proinflammatory cytokines (IL-6, TNF) induced by IL17. Through a case-control study, we showed that the polymorphism of IL17A is associated with its susceptibility to colorectal cancer. Considering the tumor location, we found that the mutated alleles of IL17A, IL17F and IL23R are rather associated with colon cancer and not with rectum cancer. This result confirms that the colon and rectum are two different physiological entities. This study shows that TLR4, IL17A/F and IL23R polymorphisms are involved in the presentation of the disease with regard to tumor architecture, histology, and differentiation, advanced stage of the disease and lymph node and metastasis. Overall, these polymorphisms are associated with a poor prognosis of the disease. Furthermore, in order to evaluate the involvement of epigenetic mechanisms in the occurrence of colorectal cancer, we aimed at analyzing the tumor compared to a normal adjacent tissue and the expression of miRNAs (miR21, miR146a, miR135a, miR147b and miR155) that regulate immunity genes especially the cytokines of the TH17 pathway. This research has shown that microRNAs 21, 135a and 146a are associated with colorectal cancer. Indeed, these three miRs are overexpressed in cancer tissue compared to healthy tissue. These results clearly confirm the involvement of epigenetics in colorectal cancer. In other words, this study reveals the importance of immunity and specifically the TH17 pathway in the development and presentation of colorectal cancer. These results suggest that TLR4, IL17A, IL17F and IL23R polymorphisms as well as the expression of microRNAs that regulate inflammation and the TH17 pathway are associated with the evolution and progression of the colorectal tumor that could be considered as biomarkers in colorectal cancer.
结直肠癌是一种复杂的多因素疾病。遗传、免疫、表观遗传和环境等多种因素构成了次要风险因素，它们的累加效应促使结直肠癌的发生。为了评估先天性免疫和适应性免疫在结直肠癌易感性、表现及发展中的作用，我们采用免疫遗传学方法研究了Toll样受体4（TLR4）基因和核苷酸结合寡聚化结构域2/胱天蛋白酶激活募集结构域15（NOD2/CARD15）基因（先天性免疫受体）以及辅助性T细胞17（TH17）通路的白细胞介素17A（IL17A）、白细胞介素17F（IL17F）细胞因子基因和细胞因子受体白细胞介素23受体（IL23R）的多态性。然后，我们评估了受TLR4和NOD2/CARD15调控或靶向TLR4、IL17及IL17诱导的促炎细胞因子（白细胞介素6、肿瘤坏死因子）的微小RNA的表达。通过病例对照研究，我们发现IL17A的多态性与其对结直肠癌的易感性相关。考虑到肿瘤位置，我们发现IL17A、IL17F和IL23R的突变等位基因与结肠癌相关，而与直肠癌无关。这一结果证实结肠和直肠是两个不同的生理实体。本研究表明，TLR4、IL17A/F和IL23R的多态性与疾病在肿瘤结构、组织学、分化、疾病晚期以及淋巴结和转移方面的表现有关。总体而言，这些多态性与疾病的不良预后相关。此外，为了评估表观遗传机制在结直肠癌发生中的作用，我们旨在分析肿瘤组织与相邻正常组织，并检测调控免疫基因尤其是TH17通路细胞因子的微小RNA（miR21、miR146a、miR135a、miR147b和miR155）的表达。这项研究表明，微小RNA 21、135a和146a与结直肠癌相关。事实上，与健康组织相比，这三种微小RNA在癌组织中均过度表达。这些结果明确证实了表观遗传学在结直肠癌中的作用。换句话说，本研究揭示了免疫尤其是TH17通路在结直肠癌发生和表现中的重要性。这些结果表明，TLR4、IL17A、IL17F和IL23R的多态性以及调控炎症和TH17通路的微小RNA的表达与结直肠癌肿瘤的演变和进展相关，可被视为结直肠癌的生物标志物。
