1. RNA腺苷脱氨酶（ADAR）在发育、免疫调控与肿瘤发生中的平衡机制研究

RNA腺苷脱氨酶（ADAR）家族是介导A-to-I RNA编辑反应的核心酶类，在调控基因表达、维持免疫稳态及推动组织发育中发挥着关键作用。ADAR1在胚胎早期的造血与免疫系统建立中至关重要，而ADAR2则对神经系统的发育与神经元稳态维持不可或缺。ADAR在疾病发生中的角色同样不容忽视。我们团队发现，ADAR1在多种疾病中异常上调，在肿瘤发生中具备类致癌基因活性，而ADAR2具有明显的抑癌作用（Gut, 2014；Gastroenterology, 2016），两者在肿瘤微环境中形成动态“编辑平衡”，深刻影响下游基因表达及免疫逃逸机制。尽管ADAR的功能机制已获初步认识，其组织特异性调控、不同发育阶段的作用及编辑依赖性功能仍未明晰（Cell Reports, 2024）。我们计划结合肝脏特异性基因编辑模型与不同阶段的人类肝组织样本，深入分析RNA编辑在免疫调节中的作用及其对肝脏疾病发展的影响。这将为揭示慢性肝炎进展为肝癌的分子机制提供重要线索，也为RNA靶向治疗和肝脏干细胞干预策略的开发奠定理论基础。

2. ADAR介导RNA编辑在肿瘤中的功能解析与靶向干预

A-to-I RNA编辑是人类转录组中最常见的RNA修饰形式，由ADAR家族催化完成，约80%的基因可被其编辑。自1987年首次在非洲爪蟾中被发现以来，ADAR介导的RNA编辑逐渐被证实广泛发生于mRNA的编码区、非编码区及多种非编码RNA中，在癌症发生与进展中发挥关键调控作用，并通过影响RNA剪接、稳定性、翻译效率及免疫应答等方式，推动结直肠癌、肝癌、乳腺癌和黑色素瘤等多种肿瘤的发展。我们团队长期聚焦于ADAR介导的RNA编辑如何塑造肿瘤细胞命运，并系统鉴定了多个与肿瘤密切相关的编辑靶点，包括COPA、AZIN1、COG3、PDZD7、METTL7A等（Nat Med. 2013；J Hepatol. 2021；Blood. 2023；Sci Adv. 2020；NAR. 2017；PNAS. 2024等），揭示RNA编辑作为癌症驱动机制的核心地位。在此基础上，我们计划建立高灵敏度RNA编辑检测体系，结合高通量表型筛选与人工智能靶点预测，筛选高特异性RNA编辑抑制剂，并系统评估其在体内外模型中的抗肿瘤活性与作用机制。该研究有望推动RNA编辑抑制剂的药物开发，为RNA靶向治疗开辟新路径。

3. 基于结构-功能一体化筛选平台的RNA调控机制解析与精准干预

RNA在胚胎发育和肿瘤发生等生命关键过程中的调控功能愈发受到关注，越来越多证据表明，特定RNA分子的结构构象变化直接决定其调控潜能，影响基因表达、细胞命运决定及组织稳态。然而，目前缺乏针对RNA的有效调控手段，RNA结构本身高度动态、富含二级结构、多呈瞬时构象的特性，使得传统的“结构-功能”研究方法难以适用。同时，RNA缺乏类蛋白质的稳定结合口袋，导致目前在RNA结构识别与靶点开发上仍面临重大技术瓶颈，严重制约了RNA功能研究与临床转化的深入推进。本项目拟以RNA在胚胎发育与肿瘤调控中的关键作用为切入点，聚焦RNA结构解析与功能验证的核心问题，基于DEL（DNA编码化合物库）技术与高通量RNA结构分析平台，结合人工智能算法进行RNA结构口袋识别、功能位点预测与候选分子筛选，构建集“结构-功能-活性”于一体的新型RNA研究平台。该平台不仅将显著提升RNA靶点识别与调控效率，也有望建立RNA靶向调控的通用策略。最终，我们希望推动RNA功能调控研究从理论走向应用，在胚胎发育调控与抗肿瘤干预等重大生物医学问题中实现精准突破。

2022年，上海市领军人才项目（海外）

2024年，青年百人计划启动基金

2025年，同济大学附属普陀区人民医院柔性引进人才基金

2025年，上海市自然基金

1.  Han J*, SongY*, Xie J, Shen H, Gan WL, Ng L, Ng BYL, Ng VHE, Sui X, Tano V, Tang SJ,Chen L. Modulation of m6A RNA modification by DAP3 in cancer cells. Proceedingsof the National Academy of Sciences of the United States of America. 2024Oct;121(40):e2404509121. *Co-first author.

2.  Song Y, An O, Ren X,Chan TH, Tay DJ, Tang SJ, Han J, Hong HQ, Ng VHE, Ke X, Shen H, Pitcheshwar P,Lin SJ, Leong KW, Molias FB, Yang H, Kappei D, Chen L. RNA editing mediates thefunctional switch of COPA in a novelmechanism of hepatocarcinogenesis. Journal of Hepatology. 2021 Jan;74(1):135-147.

3.  Song Y#,*, Ke X*,Chen L#. Potential use of RNA-based therapeutics for breast cancertreatment. Current Medicinal Chemistry2021;28(25):5110-5136. *Co-first author, # Co-corresponding author.

4.  Qi L*, Song Y*, Chan TH, Lin CH, Yang H, HongHQ, Tay DJT, Lin JS, Maury JJP, Tenen DG, Chen L. An RNA editing/dsRNAbinding-independent gene regulatory mechanism of ADARs and its clinicalimplication in cancer. Nucleic Acids Research. 2017 Oct13;45(18):10436-10451. *Co-first author.

5.  Song Y, Chen L, Zeng T,Chan TH, Lian QZ, Chow R, Cai X, Li Y, Li Y, Liu M, Wong N, Yuan YF, Pei D,Guan XY. Loss of ATOH8 Increases StemCell Features of Hepatocellular Carcinoma Cells. Gastroenterology, 2015Oct;149(4):1068-81.e5.

6.  Gan WL, Ren X, Ng VHE, Song Y, Tano V, Han J,Ng L, An O, Xie J, BLY, Tay DJT, Tang SJ, Shen H, Khare S, Young DY, DasGuptaR, Chen L. Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis modulatesADAR1-mediated immunity in the liver. Cell Reports. 2024 Jul 23;43(7):114400.

7. Guo J, Chen S, Onishi Y, Shi Q, Song Y, Mei H,Chen L, Kool ET, Zhu RY. RNA Control via Redox-Responsive Acylation. AngewChem Int Ed Engl. 2024 May 21;63(21):e202402178.

7.  Guo M, Chan HMT, Zhou QL, An O, Li Y, Song Y,Tan ZH, Ng HEV, Peramangalam PS, Tan ZQ, Cao X, Iwanaga E, Matsuoka M, Ooi MG,Jen WY, Koh LP, Chan E, Tan LK, Goh Y, Wang W, Koh BTH, Chan MC, Fullwood MJ,Chng WJ, Osato M, Pulikkan JA, Yang H, Chen L, Tenen DG. Core binding factorfusion downregulation of ADAR2 RNA editing contributes to AML leukemogenesis.Blood. 2023 Jun 22;141(25):3078-3090

8.  Han J, An O, Ren X, Song Y, Tang SJ, Shen H,  KeXY, Ng VHE, Tay DJ, Tan HQ, Kappei D, Yang H, Chen L. Multilayered Control ofSplicing Regulatory Networks by DAP3 Leads to Widespread Alternative SplicingChanges in Cancer. Nature Communications. 2022 Apr 4;13(1):1793.

9.  Shen H, An O n, Ren X, Song Y, Tang SJ, Ke XY, Han J, Tay DJ, Ng VHE, Molias FB,Pitcheshwar P, Leong KW, Tan KK, Yang H, Chen L. ADARs act as potent regulatorsof circular transcriptome in cancer. Nature Communications. 2022 Mar21;13(1):1508.

10. Molias FB, Sim A, Leong KW, An O, Song Y, Ng VHE, Lim MWJ, Ying C, TeoJXJ, Göke J, Chen L. Antisense RNAs influence promoter usage of theircounterpart sense genes in cancer. Cancer Research. 2021 Dec1;81(23):5849-5861.

11. Tay DJ, Song Y,Peng B, Toh TB, Hooi L, Kaixin Toh DF, Hong H, Tang SJ, Han J, Gan WL, Man ChanTH, Krishna MS, Patil KM, Maraswami M, Loh TP, Dan YY, Zhou L, Bonney GK,Kah-Hoe Chow P, Chen G, Kai-Hua Chow E, Le MT, Chen L. Targeting RNA Editing ofAntizyme Inhibitor 1: a Potential Oligonucleotide-Based Antisense Therapy forCancer. Molecular Therapy. 2021 Nov 3;29(11):3258-3273.

12. An O, Song Y,Ke X, So J, Sundar R, Yang H, Rha SY, Lee MH, Tay ST, Ong X, Keng ATL, Ng M,Tantoso E, Chen L, Tan P, and Yong WP. "3G" Trial: An RNA EditingSignature to Guide Gastric Cancer Chemotherapy. Cancer Research. 2021 May15;81(10):2788-2798.

13. Han J, An O, Hong H, Chan TH, Song Y, Shen H, Tang SJ, Lin JS, Ng VHE, Tay DJ, Molias FB,Pitcheshwar P, Yang H, Chen L. Suppression of Adenosine-to-Inosine (A-to-I) RNAEditome by Death Associated Protein 3 (DAP3) Promotes Cancer Progression. ScienceAdvances, 2020 Jun 17;6(25):eaba5136.

14. Tang SJ, Shen H, An O, Hong HQ, Li J, Song Y, Han J, Tay DJ, Ng VHE, MoliasFB, Leong KW, Pitcheshwar P, Yang H, Chen L. Cis- andtrans-regulations of pre-mRNA splicing by RNA editing enzymes influence cancerdevelopment. Nature Communications. 2020 Feb 7;11(1):799.

15. Hong HQ, An O, Chan TH, Ng VHE, Kwok HS, Lin JS, QiL, Han J, Tay DJT, SJ, Yang H, Song Y,Molias FB, Tenen DG and Chen L. Bidirectional regulation ofadenosine-to-inosine (A-to-I) RNA editing by DEAH box helicase 9 (DHX9) incancer. Nucleic Acids Research, 2018 Sep 6;46(15):7953-7969.

16. Chan TH, Qamra A, Tan KT, Guo J, Yang H, Qi L, LinJS, Ng VH, Song Y, Hong H, Tay ST,Liu Y, Lee J, Rha SY, Feng Z, So JB, Bin Tean T, Guan YK, Rozen S, Tenen DG,Tan P, Chen L. ADAR-mediated RNA editing predicts progression and prognosis ofGastric Cancer. Gastroenterology.2016 Oct;151(4):637-650.e10.

17. Liu M, Chen L, Ma N, Chow R, Li Y, Song Y, Chan THM, Fang S, Yang X, Xi S,Jiang L, Li Y, Zeng T, Li Y, Yuan Y, and Guan XY. CHD1L Promotes LineageReversion of Hepatocellular Carcinoma through Opening Chromatin for KeyDevelopmental Transcription Factors. Hepatology 2016 May;63(5):1544-59.

18. Chow RK, Sin ST, Liu M, Li Y, Chan TH, Song Y, Chen L, Kwong DL, Guan XY. AKR7A3suppresses tumorigenicity and chemoresistance in hepatocellular carcinomathrough attenuation of ERK, c-Jun and NF-κB signaling pathways. Oncotarget.2016 Oct 18;8(48):83469-83479

19.  Liu M, Li Y, Chen L, Chan TH, Song Y, Fu L, Zeng T, Dai YD, Zhu YH, Li Y, Chen J, Yuan YF, GuanXY. Allele-specific imbalance of Oxidative Stress Induced Growth Inhibitor 1contributes to the progression of hepatocellular carcinoma. Gastroenterology,2014 Apr;146(4):1084-96.

20. Chan TH, Lin CH, Qi L, Fei J, Li Y, Yong KJ, Liu M, Song Y, Chow RK, Ng VH, Yuan YF, TenenDG, Guan XY, Chen L. A disrupted RNA editing balance mediated by ADARs(Adenosine DeAminases that act on RNA) in human hepatocellular carcinoma. Gut.2013 May;63(5):832-43.

21. Chen L, Li Y, Lin CH, Chan TH, Chow RK, Song Y, Liu M, Yuan YF, Fu L, Kong KL,Qi L, Li Y, Zhang N, Tong AH, Kwong DL, Man K, Lo CM, Lok S, Tenen DG, Guan XY.Recoding RNA editing of AZIN1 predisposes to hepatocellular carcinoma. NatureMedicine. 2013Feb;19(2):209-16.

22. Fan H, Chen L, Zhang F, Quan Y, Su X, Qiu X, Zhao Z,Kong KL, Dong S, Song Y, Chan TH,Guan XY. MTSS1, a novel target of DNA methyltransferase 3B, functions as atumor suppressor in hepatocellular carcinoma. Oncogene. 2012 May 3;31(18):2298-308.