童强松 博士/教授（华中科技大学同济医学院附属协和医院）
报告主题：环状RNA与蛋白质相互作用调控肿瘤驱动基因转录及侵袭转移
嘉宾简介：
国家教育部新世纪优秀人才，华中学者。美国约翰.霍普金斯大学博士后，美国外科学会会员，国家自然科学基金、教育部留学回国基金、教育部博士点基金评委。长期致力于小儿各种泌尿生殖系畸形、肿瘤的微创及重建手术。主持国家自然科学基金7项，教育部新世纪人才支持计划1项、教育部留学回国基金资助课题1项，湖北省自然科学创新群体基金1项，华中科技大学自主创新基金2项，在Nature Commun, Cancer Res, Cell Death Differ, Oncogene等国际期刊发表SCI论文50余篇，他引1800余次，H指数28。为J Natl Cancer Inst, Trends Biochem Sci, Theranostics, Oncogene等杂志特约审稿人。
代表性成果介绍：
Cancer Research：circ-CTNNB1的顺式调控作用
2019年2月1日，Cancer Research杂志发表了华中科技大学同济医学院附属协和医院童强松教授和郑丽端教授为共同通讯作者的文章，报道发现circ-CTNNB1通过顺式作用调控YY1的转录活性，进而促进Wnt/β-catenin通路相关的基因表达。
circ-CTNNB1来源于CTNNB1的10号内含子，定位在细胞核中。很多肿瘤细胞中circ-CTNNB1表现为高表达，干扰circ-CTNNB1抑制增殖，过表达则促进增殖。RNA Pull-down实验捕获与circ-CTNNB1相互作用的蛋白，发现了DDX3。进一步的验证和功能分析表明circ-CTNNB1可以通过与DDX3相互作用，结合YY1并促进其转录活性，进而激活下游包括Wnt/β-catenin通路相关的基因表达。（参考文献[2]）
推荐阅读：揭秘cis-asting circ-CTNNB1调控β-Catenin活化的机制
circ-CTNNB1的顺式调控作用模型（参考文献[2]）
Cell Death & Differentiation：circAGO2结合HuR调控AGO2与靶基因的结合
2018年10月19日，Cell Death & Differentiation在线发表了华中科技大学同济医学院附属协和医院童强松教授和郑丽端教授为共同通讯作者的文章，报道circAGO2结合HuR并促进其结合只靶基因的3’UTR，阻碍AGO2与miRNAs复合物的结合，调控下游基因的活性，进而促进肿瘤发展。
AGO2是RISC复合物中唯一具有内切核酸酶活性的亚基成分，发现在多种肿瘤中呈现异常高表达的状态。在这篇文章中作者发现了来自AGO2内含子的一种circRNA（circAGO2），多数肿瘤中circAGO2表达增高，功能分析表明circAGO2具有促癌作用。基于RNA Pull-down分析，发现了circAGO2可以与HuR结合。机制方面，circAGO2通过结合HuR蛋白，促进HuR在靶基因的3’UTR富集，阻止AGO2的结合，调控靶基因的稳定性。（参考文献[4]）
推荐阅读：Cell Death & Differentiation连发两篇circRNA研究论文
circAGO2结合HuR调控AGO2与靶基因的结合（参考文献[4]）
Nature Communications：ARMC12结合RBBP4抑制抑癌基因表达
2018年7月19日，Nature Communications杂志在线发表了华中科技大学同济医学院附属协和医院童强松教授和郑丽端教授为共同通讯作者的文章，报道神经母细胞瘤中ARMC12可以结合RBBP4抑制下游一些抑癌基因的表达。ARMC12可以结合RBBP4，进一步促进PRC2复合物和EZH2，抑制下游一些抑癌基因的表达。（参考文献[5]）
ARMC12结合RBBP4抑制抑癌基因表达（参考文献[5]）
Oncogene：胃癌中lncRNA pancEts-1调控Ets-1基因表达
2018年8月，Oncogene杂志发表了华中科技大学同济医学院附属协和医院童强松教授和郑丽端教授为共同通讯作者的文章，报道发现一种Ets-1基因启动子相关的非编码RNA（pancEts-1）在胃癌中调控Ets-1表达。作者通过UCSC基因组浏览器发现位于Ets-1基因上游的一个包含4个外显子的非编码RNA，pancEts-1。RNA pull-down，RIP，EMSA及体外结合实验表明pancEts-1可以与NONO蛋白结合。pancEts-1与NONO结合后促进后者与ERG的结合，增强下游基因的转录。（参考文献[6]）
pancEts-1调控Est-1基因转录机制（参考文献[6]）
Oncogene：HPSE增强子RNA作用机制
2018年5月，Oncogene杂志发表了华中科技大学同济医学院附属协和医院童强松教授和郑丽端教授为共同通讯作者的文章，报道一种增强子RNA（eRNA）在肿瘤中可增强HPSE的表达。作者通过FANTOM5和4DGenome的染色质相互作用数据的分析，预测到一种潜在的eRNA，功能分析表明该分析可促进细胞增殖和侵袭。机制方便， 该分子通过与hnRNPU的结合，促进与p300的结合并进而促进形成超级增强子，进而促进相关靶基因的表达。（参考文献[7]）
HPSE增强子RNA作用机制（参考文献[7]）
Cancer Research：在神经母细胞瘤中pancEts-1调控β-Catenin稳定性及入核
2018年1月8日，Cancer Research杂志在线发表了华中科技大学同济医学院附属协和医院童强松教授和郑丽端教授为共同通讯作者的文章，报道Ets-1基因启动子相关的非编码RNA pancEts-1在神经母细胞瘤中调控β-Catenin稳定性的机制。神经母细胞瘤中pancEts-1可在胞质中结合hnRNPK，结合并保护β-Catenin，促进其稳定性和入核，进而促进下游相关基因的表达。（参考文献[9]）
pancEts-1调控β-Catenin稳定性及入核（参考文献[9]）
代表性研究成果列表
1. Tao X, Hu Y, Li L, Xu R, Fu J, Tong Q*, Fu Q*. Genetic deletion of β2 adrenergic receptors exacerbates hepatocellular lipid accumulation in high-fat diet mice. Biochem Biophys Res Commun. 2019 Mar 26;511(1):73-78. doi: 10.1016/j.bbrc.2019.02.037
2. Yang F, Fang E, Mei H, Chen Y, Li H, Li D, Song H, Wang J, Hong M, Xiao W, Wang X, Huang K, Zheng L*, Tong Q*. Cis-Acting circ-CTNNB1 Promotes β-Catenin Signaling and Cancer Progression via DDX3-Mediated Transactivation of YY1. Cancer Res. 2019 Feb 1;79(3):557-571. doi: 10.1158/0008-5472.CAN-18-1559
3. Fang E, Wang J, Hong M, Zheng L, Tong Q*. Valproic acid suppresses Warburg effect and tumor progression in neuroblastoma. Biochem Biophys Res Commun. 2019 Jan 1;508(1):9-16. doi: 10.1016/j.bbrc.2018.11.103
4. Chen Y, Yang F, Fang E, Xiao W, Mei H, Li H, Li D, Song H, Wang J, Hong M, Wang X, Huang K, Zheng L*, Tong Q*. Circular RNA circAGO2 drives cancer progression through facilitating HuR-repressed functions of AGO2-miRNA complexes. Cell Death Differ. 2019 Jul;26(7):1346-1364. doi: 10.1038/s41418-018-0220-6
5. Li D, Song H, Mei H, Fang E, Wang X, Yang F, Li H, Chen Y, Huang K, Zheng L*, Tong Q*. Armadillo repeat containing 12 promotes neuroblastoma progression through interaction with retinoblastoma binding protein 4. Nat Commun. 2018 Jul 19;9(1):2829. doi: 10.1038/s41467-018-05286-2
6. Li D, Chen Y, Mei H, Jiao W, Song H, Ye L, Fang E, Wang X, Yang F, Huang K, Zheng L*, Tong Q*. Ets-1 promoter-associated noncoding RNA regulates the NONO/ERG/Ets-1 axis to drive gastric cancer progression. Oncogene. 2018 Aug;37(35):4871-4886. doi: 10.1038/s41388-018-0302-4
7. Li D, Chen Y, Mei H, Jiao W, Song H, Ye L, Fang E, Wang X, Yang F, Huang K, Zheng L*, Tong Q*. HPSE enhancer RNA promotes cancer progression through driving chromatin looping and regulating hnRNPU/p300/EGR1/HPSE axis. Oncogene. 2018 Aug;37(35):4871-4886. doi: 10.1038/s41388-018-0302-4.
8. Zhao X, Li D, Huang D, Song H, Mei H, Fang E, Wang X, Yang F, Zheng L*, Huang K*, Tong Q*. Risk-Associated Long Noncoding RNA FOXD3-AS1 Inhibits Neuroblastoma Progression by Repressing PARP1-Mediated Activation of CTCF. Mol Ther. 2018 Mar 7;26(3):755-773. doi: 10.1016/j.ymthe.2017.12.017
9. Li D, Wang X, Mei H, Fang E, Ye L, Song H, Yang F, Li H, Huang K, Zheng L, Tong Q*. Long Noncoding RNA pancEts-1 Promotes Neuroblastoma Progression through hnRNPK-Mediated β-Catenin Stabilization. Cancer Res. 2018 Mar 1;78(5):1169-1183. doi: 10.1158/0008-5472.CAN-17-2295.
10. Zheng L, Chen Y, Ye L, Jiao W, Song H, Mei H, Li D, Yang F, Li H, Huang K, Tong Q*. miRNA-584-3p inhibits gastric cancer progression by repressing Yin Yang 1- facilitated MMP-14 expression. Sci Rep. 2017 Aug 21;7(1):8967. doi: 10.1038/s41598-017-09271-5.
11. Pu J, Tang S*, Tong Q*, Wang G, Jia H, Jia Q, Li K, Li D, Yang D, Yang J, Li H, Li S, Mei H. Neuregulin 1 is involved in enteric nervous system development in zebrafish. J Pediatr Surg. 2017 Jul;52(7):1182-1187. doi: 10.1016/j.jpedsurg.2017.01.005
12. Zheng L, Jiao W, Mei H, Song H, Li D, Xiang X, Chen Y, Yang F, Li H, Huang K, Tong Q*. miRNA-337-3p inhibits gastric cancer progression through repressing myeloid zinc finger 1-facilitated expression of matrix metalloproteinase 14. Oncotarget. 2016 Jun 28;7(26):40314-40328. doi: 10.18632/oncotarget.9739
13. Qu H, Zheng L, Song H, Jiao W, Li D, Fang E, Wang X, Mei H, Pu J, Huang K, Tong Q*. microRNA-558 facilitates the expression of hypoxia-inducible factor 2 alpha through binding to 5′-untranslated region in neuroblastoma. Oncotarget. 2016 Jun 28;7(26):40657-40673. doi: 10.18632/oncotarget.9813
14. Zheng L, Jiao W, Song H, Qu H, Li D, Mei H, Chen Y, Yang F, Li H, Huang K, Tong Q*. miRNA-558 promotes gastric cancer progression through attenuating Smad4-mediated repression of heparanase expression. Cell Death Dis. 2016 Sep 29;7(9):e2382. doi: 10.1038/cddis.2016.293
15. Mei H, Zhao X, Li D, Fang E, Wang X, Song H, Pu J, Zheng L, Tong Q*. Comparison of transumbilical multiport and standard laparoscopic pyeloplasty in children: Mid-term results at a single center. J Pediatr Surg. 2017 Mar;52(3):473-477. doi: 10.1016/j.jpedsurg.2016.08.013
16. Qu H, Zheng L, Jiao W, Mei H, Li D, Song H, Fang E, Wang X, Li S, Huang K, Tong Q*. Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase. Sci Rep. 2016 Sep 6;6:32628. doi: 10.1038/srep32628
17. Xiang X, Mei H, Zhao X, Pu J, Li D, Qu H, Jiao W, Zhao J, Huang K, Zheng L*, Tong Q*. miRNA-337-3p suppresses neuroblastoma progression by repressing the transcription of matrix metalloproteinase 14. Oncotarget. 2015 Sep 8;6(26):22452-66
18. Xiang X, Mei H, Qu H, Zhao X, Li D, Song H, Jiao W, Pu J, Huang K, Zheng L, Tong Q*. miRNA-584-5p exerts tumor suppressive functions in human neuroblastoma through repressing transcription of matrix metalloproteinase 14. Biochim Biophys Acta. 2015 Sep;1852(9):1743-54. doi: 10.1016/j.bbadis.2015.06.002
19. Li D, Zhao X, Xiao Y, Mei H, Pu J, Xiang X, Jiao W, Song H, Qu H, Huang K, Zheng L*, Tong Q*. Intelectin 1 suppresses tumor progression and is associated with improved survival in gastric cancer. Oncotarget. 2015 Jun 30;6(18):16168-82.
20. Li D, Mei H, Pu J, Xiang X, Zhao X, Qu H, Huang K, Zheng L, Tong Q*. Intelectin 1 suppresses the growth, invasion and metastasis of neuroblastoma cells through up-regulation of N-myc downstream regulated gene 2. Mol Cancer. 2015 Feb 21;14:47. doi: 10.1186/s12943-015-0320-6
21. Qu H, Zheng L, Pu J, Mei H, Xiang X, Zhao X, Li D, Li S, Mao L, Huang K, Tong Q*. miRNA-558 promotes tumorigenesis and aggressiveness of neuroblastoma cells through activating the transcription of heparanase. Hum Mol Genet. 2015 May 1;24(9):2539-51. doi: 10.1093/hmg/ddv018
22. Xiang X, Zhao X, Qu H, Li D, Yang D, Pu J, Mei H, Zhao J, Huang K, Zheng L*, Tong Q*. Hepatocyte nuclear factor 4 alpha promotes the invasion, metastasis and angiogenesis of neuroblastoma cells via targeting matrix metalloproteinase 14. Cancer Lett. 2015 Apr 10;359(2):187-97. doi: 10.1016/j.canlet.2015.01.008
23. Mei H, Qi T, Li S, Pu J, Cao G, Tang S, Zheng L, Tong Q*. Transumbilical multiport laparoscopic nephroureterectomy for congenital renal dysplasia in children: midterm follow-up from a single institution. Front Pediatr. 2013 Dec 13;1:46. doi: 10.3389/fped.2013.00046
24. Li D, Mei H, Qi M, Yang D, Zhao X, Xiang X, Pu J, Huang K, Zheng L*, Tong Q*. FOXD3 is a novel tumor suppressor that affects growth, invasion, metastasis and angiogenesis of neuroblastoma. Oncotarget. 2013 Nov;4(11):2021-44.
25. Zheng L, Li D, Xiang X, Tong L, Qi M, Pu J, Huang K, Tong Q*. Methyl jasmonate abolishes the migration, invasion and angiogenesis of gastric cancer cells through down-regulation of matrix metalloproteinase 14. BMC Cancer. 2013 Feb 10;13:74. doi: 10.1186/1471-2407-13-74
26. Zheng L, Qi T, Yang D, Qi M, Li D, Xiang X, Huang K, Tong Q*. microRNA-9 suppresses the proliferation, invasion and metastasis of gastric cancer cells through targeting cyclin D1 and Ets1. PLoS One. 2013;8(1):e55719. doi: 10.1371/journal.pone.0055719
27. Zheng L, Pu J, Qi T, Qi M, Li D, Xiang X, Huang K, Tong Q*. miRNA-145 targets v-ets erythroblastosis virus E26 oncogene homolog 1 to suppress the invasion, metastasis, and angiogenesis of gastric cancer cells. Mol Cancer Res. 2013 Feb;11(2):182-93. doi: 10.1158/1541-7786.MCR-12-0534
28. Mei H, Pu J, Qi T, Qi M, Li D, Tang S, Zheng L, Tong Q*. Transumbilical multiport laparoscopic orchiopexy in children: comparison with standard laparoscopic orchiopexy. Urology. 2012 Dec;80(6):1345-9. doi: 10.1016/j.urology.2012.07.076
29. Zhang H, Qi M, Li S, Qi T, Mei H, Huang K, Zheng L*, Tong Q*. microRNA-9 targets matrix metalloproteinase 14 to inhibit invasion, metastasis, and angiogenesis of neuroblastoma cells. Mol Cancer Ther. 2012 Jul;11(7):1454-66. doi: 10.1158/1535-7163.MCT-12-0001
30. Jiang G, Zheng L, Pu J, Mei H, Zhao J, Huang K, Zeng F*, Tong Q*. Small RNAs targeting transcription start site induce heparanase silencing through interference with transcription initiation in human cancer cells. PLoS One. 2012;7(2):e31379. doi: 10.1371/journal.pone.0031379
31. Zheng L, Weng M, Qi M, Qi T, Tong L, Hou X, Tong Q*. Aberrant expression of intelectin-1 in gastric cancer: its relationship with clinicopathological features and prognosis. J Cancer Res Clin Oncol. 2012 Jan;138(1):163-72. doi: 10.1007/s00432-011-1088-8
32. Yang C, Zhang H, Pu J, Mei H, Zheng L, Tong Q*. Laparoscopic vs open herniorrhaphy in the management of pediatric inguinal hernia: a systemic review and meta-analysis. J Pediatr Surg. 2011 Sep;46(9):1824-34. doi: 10.1016/j.jpedsurg.2011.04.001
33. Mei H, Pu J, Yang C, Zhang H, Zheng L, Tong Q*. Laparoscopic versus open pyeloplasty for ureteropelvic junction obstruction in children: a systematic review and meta-analysis. J Endourol. 2011 May;25(5):727-36. doi: 10.1089/end.2010.0544
34. Guo J, Liang Z, Zhang H, Yang C, Pu J, Mei H, Zheng L, Zeng F, Tong Q*. Laparoscopic versus open orchiopexy for non-palpable undescended testes in children: a systemic review and meta-analysis. Pediatr Surg Int. 2011 Sep;27(9):943-52. doi: 10.1007/s00383-011-2889-1
35. Mei H, Zheng L, Zhou C, Tong Q*. Metanephric adenoma in a 2-year-old child: case report and immunohistochemical observations. J Pediatr Hematol Oncol. 2010 Aug;32(6):489-93. doi: 10.1097/MPH.0b013e3181e34de1
36. Hu T, Wang Z, Zeng F, Chen X, Gu Z, Zheng L, Tong Q*. Expression pattern of testis-specific expressed gene 2 in cryptorchidism model and its role in apoptosis of spermatogenic cells. J Huazhong Univ Sci Technolog Med Sci. 2010 Apr;30(2):193-7. doi: 10.1007/s11596-010-0212-3
37. Zheng L, Pu J, Jiang G, Weng M, He J, Mei H, Hou X, Tong Q*. Abnormal expression of early growth response 1 in gastric cancer: association with tumor invasion, metastasis and heparanase transcription. Pathol Int. 2010 Apr;60(4):268-77. doi: 10.1111/j.1440-1827.2010.02512.x
38. Zheng L, Jiang G, Mei H, Pu J, Dong J, Hou X, Tong Q*. Small RNA interference-mediated gene silencing of heparanase abolishes the invasion, metastasis and angiogenesis of gastric cancer cells. BMC Cancer. 2010 Feb 5;10:33. doi: 10.1186/1471-2407-10-33
39. Tong Q*, Zheng L, Tang S, Du Z, Wu Z, Mei H, Ruan Q. Lymphatic sparing laparoscopic Palomo varicocelectomy for varicoceles in children: intermediate results. J Pediatr Surg. 2009 Aug;44(8):1509-13. doi: 10.1016/j.jpedsurg.2008.10.049.
40. Tong Q*, Zheng L, Tang S, Zeng F, Du Z, Mei H, Wu Z, Pu J, Ruan Q. Comparison of laparoscopic-assisted versus open dismembered pyeloplasty for ureteropelvic junction obstruction in infants: intermediate results. Urology. 2009 Oct;74(4):889-93. doi: 10.1016/j.urology.2009.03.053
41. Tong Q*, Zheng L, Tang S, Mao Y, Wang Y, Liu Y, Cai J, Ruan Q. Laparoscopy-assisted orchiopexy for recurrent undescended testes in children. J Pediatr Surg. 2009 Apr;44(4):806-10. doi: 10.1016/j.jpedsurg.2008.07.024
42. Zheng L, Tong Q*, Weng M, He J, Lv Q, Wu Z, Du Z, Mei H, Hou X. Expression of resistin-like molecule beta in Barrett’s esophagus: a novel biomarker for metaplastic epithelium. Dig Dis Sci. 2010 Jan;55(1):32-9. doi: 10.1007/s10620-009-0719-2
43. Tong Q#, Zheng L, Li B, Wang D, Huang C, Matuschak GM, Li D*. Hypoxia-induced mitogenic factor enhances angiogenesis by promoting proliferation and migration of endothelial cells. Exp Cell Res. 2006 Nov 1;312(18):3559-69
44. Tong Q#, Zheng L, Lin L, Li B, Wang D, Huang C, Matuschak GM, Li D*. Participation of the PI-3K/Akt-NF-kappa B signaling pathways in hypoxia-induced mitogenic factor-stimulated Flk-1 expression in endothelial cells. Respir Res. 2006 Jul 27;7:101.
45. Tong Q#, Zheng L, Lin L, Li B, Wang D, Li D*. Hypoxia-induced mitogenic factor promotes vascular adhesion molecule-1 expression via the PI-3K/Akt-NF-kappaB signaling pathway. Am J Respir Cell Mol Biol. 2006 Oct;35(4):444-56
46. Tong Q#, Zheng L, Kang Q, Dodd-O J, Langer J, Li B, Wang D, Li D*. Upregulation of hypoxia-induced mitogenic factor in bacterial lipopolysaccharide-induced acute lung injury. FEBS Lett. 2006 Apr 17;580(9):2207-15.
47. Tong Q#, Zheng L, Lin L, Li B, Wang D, Huang C, Li D*. VEGF is upregulated by hypoxia-induced mitogenic factor via the PI-3K/Akt-NF-kappaB signaling pathway. Respir Res. 2006 Mar 2;7:37
48. Tong Q#, Zheng L, Dodd-o J, Langer J, Wang D, Li D*. Hypoxia-induced mitogenic factor modulates surfactant protein B and C expression in mouse lung. Am J Respir Cell Mol Biol. 2006 Jan;34(1):28-38