结肠癌演进中LIN28B非Let-7依赖的作用新机制—作为ceRNA的研究

Malignant colorectal cancer has high morbidity and mortality rates among all the cancers worldwide, its molecular mechanisms underlying occurrence, progression, metastasis and relapse remain to be under clear. LIN28A is a reprogramming factor and conserved RNA-binding protein. LIN28B is the only homolog of LIN28 in humans. LIN28B has been identified to be overexpressed in a wide range of solid tumors and hematological malignancies, and recognized as an oncogene. Blockage of let-7 miRNA biogensis and subsequent derepression of let-7 miRNA target genes by LIN28B play important roles in cancer progression and metastasis. Based on the research progress, this project proposes LIN28B mRNA as a ceRNA (competitive endogenous RNA) hypothesis. .By the bioinformatics, cell molecular biology technolgies and animal tumor models, the project aims to confirm that LIN28B does not depend on its protein coding function but its mRNA molecule as a ceRNA to participate in the regulation of colon cancer progression. In this study, we will screen and verify the target mRNAs of LIN28B transcript products and the candidate miRNAs that mediate the interaction between LIN28B, and identify the LIN28B-centered ceRNA network in the process. The successful implementation of this project will explain the mechanism of classical proto-oncogene from a new perspective. The establishment of LIN28B-centred ceRNA hypothesis will promote us understand of the function and molecular mechanism of Lin28 in tumor malignant transformation and stem cell induction.

恶性结肠癌发病率、死亡率居高不下，究其原因是其发生发展和转移复发等分子机制不很清楚。重编程因子LIN28A的人类同源物—LIN28B作为癌基因被广泛关注。传统认识认为Lin28B蛋白以Let-7依赖途径控制肿瘤的演进。基于研究进展，本项目申请提出LIN28B的mRNA分子作为竞争性内源RNA （ceRNA）的假说。本项目拟借助生物信息学、细胞分子生物学和动物肿瘤模型等证实LIN28B可不依赖于其蛋白编码功能而是以其mRNA分子作为ceRNA来参与调控结肠癌的演进过程的新的作用机制。并且，通过对LIN28B的mRNA的靶mRNA和介导二者相互作用的miRNA的筛选与验证，揭示结肠癌演进过程中的以LIN28B为核心的ceRNA调控网络。本项目的成功实施将从全新视角阐释经典原癌基因的作用机制；LIN28B分子ceRNA假说的建立将会促进理解Lin28在肿瘤恶性转化和干细胞诱导上的功能和分子机理。

肿瘤转移是造成结直肠癌患者死亡的主要原因。长非编码RNA（lncRNAs）对肿瘤的进展和转移至关重要，重编程因子LIN28A的人类同源物—LIN28B作为癌基因被广泛关注。然而，LIN28B在结直肠癌转移中的具体作用尚不清楚。本研究应用生物信息学、细胞分子生物学和动物肿瘤模型等证实LIN28B可不依赖于其蛋白编码功能而是以其mRNA分子作为ceRNA来激活上皮间质转化（EMT）促进结直肠癌肿瘤细胞的迁移和侵袭。并且，通过对LIN28B的mRNA的靶mRNA和介导二者相互作用的miRNA的筛选与验证，揭示结肠癌演进过程中的miR-557对LIN28B的重要调控作用。本研究对结直肠癌转移的分子机制有了新的认识，为结直肠癌的治疗提供了新的思路。

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