circRNA对miRNA的调控在致癌物MNNG诱发胃细胞恶变中的作用

Chemical carcinogen is an important cause for gastric cancer, and non-coding RNA regulation is a new epigenetic mechanism of malignant transformation of cells. Following miRNA and lncRNA, the importance of circular RNA (circRNA) has been manifested in the field of life sciences. But the reports about functional role of circRNA in medical field including toxicology and oncology still very scarcity. We have explored the mechanisms of chemical carcinogenesis on miRNA and lncRNA for many years, and published several SCI papers. We have found that circRNAs have a major impact on the biological characteristics in gastric cells transformed by carcinogen in our preliminary experiment. In this project, low dose typical gastric carcinogen MNNG will be applied to induce malignant transformation of gastric epithelial cell line and gastric carcinogenesis of rat. We further screen and identify the functional circRNAs in cell malignant transformation, explore the interaction between circRNA and miRNA. And we will finally study the effect and significance of regulation of circRNA on miRNA in the malignant transformation of cells induced by MNNG based on the perspective of the etiology. This project intends to reveal a new mechanism of chemical carcinogen induced-gastric cancer in a new epigenetic regulation level of circRNA, and provide new markers for cancer prevention and early diagnosis.

化学致癌物是胃癌重要病因，非编码RNA调控是细胞恶变的表观遗传新机制。继miRNA和lncRNA之后，环状RNA(circRNA)在生命科学领域的重要性已被关注，但包括毒理学和肿瘤学在内的医学领域circRNA功能研究报道仍相当匮缺。我们在化学致癌miRNA和lncRNA机制上已有多年研究，发表了多篇SCI论文。预实验已发现化学物诱变的胃细胞中，circRNA对细胞生物学特征有重要影响。本申请项目拟以低剂量代表性胃致癌物MNNG，诱导胃上皮细胞株恶性转化及大鼠胃癌，筛选和鉴定在细胞恶变发生中具有功能的circRNA，探索circRNA与miRNA的相互作用，并从病因学的角度，研究circRNA对miRNA的调控在MNNG诱导细胞恶性转化发生时的作用和意义。项目的开展将从circRNA这一新表观遗传调控层面，揭示化学致癌物诱发胃癌发生新机制，为肿瘤预防和早期诊断提供新标志物。

项目背景：化学致癌物是胃癌重要病因，非编码RNA调控是细胞恶变的表观遗传新机制。继miRNA和lncRNA之后，环状RNA(circRNA)在生命科学领域的重要性已被关注，但包括毒理学和肿瘤学在内的医学领域circRNA功能研究报道仍相当匮缺。我们在化学致癌miRNA和lncRNA机制上已有多年研究，发表了多篇SCI论文。预实验已发现化学物诱变的胃细胞中，circRNA对细胞生物学特征有重要影响。.主要研究内容：我们以circRNA为切入点探讨胃癌侵袭转移的机制，并最终为靶向药物的设计及肿瘤分子治疗提供新的靶点、开辟新的路径。本研究首先利用前期构建的MNNG诱导的胃上皮细胞恶性转化细胞模型，运用全转录组高通量测序技术分别检测了MNNG诱导恶性转化的胃上皮细胞株GES-1-T和未恶变的正常对照细胞株GES-1-N中全转录组表达谱，筛选出二者差异表达的环状RNA，在胃癌组织中应用荧光定量Real-time PCR实验进行组织验证，结合临床病理学特征分析表达改变的环状RNA是否参与胃癌的发生发展，并进一步深入探索其机制。.重要结果和关键数据：研究发现hsa_circ_006100、hsa_circ_0000592和hsa_circ_00014262等多个环状RNA通过促进胃癌增殖、侵袭和转移来影响胃癌发生发展。.科学意义：本研究假说的证实，将有助于人类深入了解MNNG诱导胃上皮细胞恶性转化的作用机理和调控机制。通过研究环状RNA发生发展机制，确立MNNG诱导胃上皮细胞恶性转化的分子靶点。这既是对胃癌发生发展分子机制的理论补充，也可以为胃癌的诊断和治疗提供新的分子靶点和治疗策略。