严俊实验室

严俊，理学博士，中科院上海生物化学与细胞生物学研究所博士毕业。曾在美国贝勒医学院和美国哥伦比亚大学从事博士后研究。2009年起任南京大学副教授，组建肿瘤表观遗传实验室。目前主要研究方向是利用基因组改造小鼠和临床样本，揭示肿瘤耐药和转移的表观遗传分子机制，建立新的分子药物靶点以及相应的临床前验证。至今共主持3项国家基金委面上项目，1项江苏省面上项目，1项教育部博士点新进教师类项目并参与2项973计划、1项国家支撑计划和1项国家重点研发计划和课题。共发表38篇论文，2篇综述和1篇论著，引用次数1100多次。

研究方向：

实验室的研究方向是肿瘤耐药复发和转移的分子机制。肿瘤复发和转移一直威胁着肿瘤病患的生命。因此对于这两个临床现象的深入认识将会对于肿瘤病患的生存和死亡率带来实际的改变。由于肿瘤组织存在非常显著的异质性，而不同的肿瘤细胞亚群在所处不同微环境或药物选择压力的情况下，筛选出最为适应环境的不同肿瘤亚群。治疗过程中，即使少量的肿瘤干性细胞残留于病患体内，它们仍可以重建整个肿瘤，从而导致肿瘤的复发和转移。现有的实验数据显示这些肿瘤干性细胞亚群具有上皮向间充质转变（EMT）和表达乙醛脱氢酶系等共同特性，但是还存在着很多未解之谜。譬如，肿瘤细胞干性维持的分子机制以及药物靶点的验证。以下是我们实验室的主要研究方向：

1. 耐药和转移的分子靶点发现和鉴定：

       我们利用小鼠模型及组学的手段分析鉴定耐药和转移的驱动基因。我们发现了组蛋白 H3K27甲基转移酶EZH2 表达量可以预测非小细胞肺癌的耐药性和无疾病进展生存。同时，我们在前列腺癌和膀胱癌中也发现重要参与耐药复发的非编码RNA，它们通过调控肿瘤干细胞群体的干性增加肿瘤的恶性程度。

2. 肿瘤微环境对于肿瘤细胞的耐药和转移的调控机制：

       肿瘤的微环境是一个与肿瘤细胞相互作用的重要场所，起到了维持肿瘤恶性的重要作用。我们实验证明在肌肉侵润型的膀胱癌组织中，肿瘤相关成纤维细胞（CAF）通过旁分泌TGFβ1促进膀胱癌细胞中 lncRNA-ZEB2NAT的表达，提高ZEB2蛋白水平，进而产生EMT。肿瘤微环境中CAF对于实体瘤细胞的调控网络将是一个重要的研究对象。

3. 新型耐药和转移的小鼠模型构建及其在小分子药物的前期临床验证：

       我们利用小鼠的优势，构建并鉴定了多种重现临床前列腺癌和膀胱癌的小鼠模型。同时我们利用天然产物和小分子单体鉴定了它们对于肿瘤的耐药及转移的有效性。其中包括Zyflamend、和厚朴酚和生育三烯酚等体内外的作用效果和机理。通过这些研究，将完成针对耐药和转移的小分子抑制剂的开发。

A. 代表性研究论文 (^*Correspondence author; ^‡First author)

1.    Xu PW, Chen C, Liu JK, Song YT, Zhou F*, Yan J*, Zhou J*. One-pot Sequential [3+3] Dipolar Cycloaddition of aldehyde or ketone, hydroxylamine with spirocyclopropyl oxindole. J. Org. Chem. 2018;83(20):12763-12774.

2.    Fang T‡, Liu D‡, Ning HM‡, Liu D, Sun JY, Huang XJ, Dong Y, Geng M, Yun SF*, Yan J*, Huang R*. Modified citrus pectin inhibited bladder tumor growth through downregulation of galectin-3. Acta Pharmacol Sin. 2018 May 16. doi: 10.1038/s41401- 018-0004-z.

3.    Huang X‡, Zhu H‡, Gao Z, Li J, Zhuang J, Dong Y, Shen B, Li M, Zhou H, Guo H*, Huang R*, Yan J*. Wnt7a activates canonical Wnt signaling, promotes bladder cancer cell invasion, and is suppressed by miR-370-3p. J Biol Chem. 2018;293(18): 6693. 

4.    Chang C, Liu J, He W, Qu M, Huang X, Deng Y, Shen L, Zhao X, Guo H, Jiang J, Fu XY, Huang R, Zhang D, Yan J*. A regulatory circuit HP1γ/miR-451a/c-Myc promotes prostate cancer progression. Oncogene 2018 Jan 25; 37(4):415-426.

5.    Xu P, Liu J, Shen L, Cao ZY, Zhao XL, Yan J*, Zhou J*. Diastereo- and enantioselective [3 + 3] cycloaddition of spirocyclopropyl oxindoles using both aldonitrones and ketonitrones.  Nat Commun. 2017;8:1619.

6.    Zhuang J‡, Shen L‡, Yang L, Huang X, Lu Q, Cui Y, Zheng X, Zhao X, Zhang D, Huang R, Guo H*, Yan J*. TGFβ1 promotes gemcitabine resistance regulating the lncRNA-LET/NF90/miR-145 signaling axis in bladder cancer. Theranostics 2017;7(12):3053-3067.

7.    Kong F, Wang M, Huang X, Yue Q, Wei X, Dou X, Peng X, Jia Y, Wu X, Zheng K, Wu T*, Yan J*, Li J*. Differential regulation of spermatogenic process by Lkb1 isoforms in mouse testis. Cell Death Dis 2017;8(10):e3121.    

8.    Yang L, Xue Y, Liu J, Zhuang J, Shen L, Shen B, Yan J*, Guo H*. Long noncoding RNA ASAP-IT promotes cancer stemness and predicts a poor prognosis in patients with bladder cancer. Neoplasma 2017;64(6):847-855.

9.    Shen L, Zhang F, Huang R, Yan J*, Shen B*. Honokiol inhibits bladder cancer cell invasion through repressing SRC-3 expression and epithelial-mesenchymal transition. Oncol Lett 2017;14:4294-4300.

10.   Han Y‡, Huang W‡, Liu J, Liu D, Cui Y, Huang R, Yan J*, Lei M*. Triptolide inhibits the AR signaling pathway to suppress the proliferation of enzalutamide-resistant prostate cancer cells. Theranostics 2017;7(7):1914-1927..

11.   Zhang Q^‡, Zhao W^‡, Ye C^‡, Zhuang J^‡, Chang C, Li Y, Huang X, Shen L, Li Y, Cui Y, Song J, Shen B, Eliaz I, Huang R, Ying H, Guo H, Yan J*. Honokiol inhibits bladder tumor growth by suppressing EZH2/miR-143 axis. Oncotarget2015; 6(35):37335-48.

12.   An J^‡, Ren S^‡, Murphy SJ^‡, Dalangood S^‡, Chang C, Pang X, Cui Y, Wang L, Pan Y, Zhang X, Zhu Y, Halling GC, Cheng L, Sukov WR, Karnes RJ, Vasmatzis G, Zhang Q, Zhang J, Cheville JC, Yan J^#, Sun Y^*,#, Huang H*^,#. Oncogenic truncated ERG proteins from TMPRSS2-ERG fusions are resistant to SPOP-mediated proteasome degradation. Mol Cell 2015;59(6):904-16. (^# Co-senior author; Highlighted by Mol Cell and Cancer Discov.)

13.   Zhuang J^‡, Lu Q^‡, Shen B^‡, Huang X, Shen L, Huang R, Yan J*, Guo H*. TGFβ1 secreted by cancer-associated fibroblasts induces epithelial-mesenchymal transition of bladder cancer cells through lncRNA-ZEB2NAT. Sci Rep2015;5:11924

14.   Li L, Zhang D, Wang X, Yao X, Ye C, Zhang S, Wang H, Xia H, Wang Y, Fang J, Yan J*, Ying H*. Hypoxia-inducible miR-182 enhances HIF1α signaling via targeting PHD2 and FIH1 inprostate cancer. Sci Rep 2015;5:12495.

15.   Ye C^‡, Zhao W^‡, Li M^‡, Zhuang J, Yan X, Lu Q, Chang C, Huang X, Zhou J, Xie B, Zhang Z, Yao X, Yan J*, Guo H*. δ-Tocotrienol induces human bladder cancer cell growth arrest, apoptosis and chemosensitization through inhibition of STAT3 pathway. PLoS One 2015;10(4):e0122712.

16.   Hou Z, Zhao W, Zhou J, Shen L, Zhan P, Xu C, Chang C, Bi H, Zou J, Yao X, Huang R, Yu L*, Yan J*. A long noncoding RNA Sox2ot regulates lung cancer cell proliferation and is a prognostic indicator of poor survival. Int J Biochem Cell Biol. 2014; 53: 380-388.

17.   Zhou J^‡, Bi H^‡, Zhan P^‡, Chang C, Xu C, Huang X, Yu L, Yao X*, Yan J*. Overexpression of HP1g is associated with poor prognosis in non-small cell lung cancer cell through promoting cell survival. Tumor Biol. 2014; 35(10):9777-9785.

18.   Zhao W, Chang C, Cui Y, Zhao X, Yang J, Shen L, Zhou J, Hou Z, Zhang Z, Ye C, Hasenmayer D, Perkins R, Huang X, Yao X, Yu L, Huang R, Zhang D, Guo H*, Yan J*. Steroid receptor coactivator-3 regulates glucose metabolism in bladder cancer cells through coactivation of hypoxia inducible-factor 1α. J Biol Chem. 2014;289(16):11219- 11229.

19.   Yan J*, Xie B, Capodice JL, Katz AE*. Zyflamend inhibits the expression and function of androgen receptor and acts synergistically with bicalutimide to inhibit prostate cancer cell growth. Prostate. 2012;72(3):244-252.

20.   Ayala G, Yan J, Rile Li, Deng Y, Thompson TC, Mims M, Hayes T, MacDonnell V, Lynch G, Frolov A, Miles B, Wheeler T, Harper W, Tsai MJ, Ittmann M, Kadmon D. Bortezomib mediated inhibition of SRC-3 degradation leads to activated AKT. Clin. Cancer Res. 2008; 14(22):7511-7518.

21.   Kinkade CW, Castillo-Martin M, Puzio-Kuter A, Yan J, Foster TH, Gao H, Sun Y, Ouyang X, Gerald WL, Cordon-Cardo C, Abate-Shen C. Targeting Akt/mTor and MEK/Erk MAP kinase signaling inhibits hormone-refractory prostate cancer in a pre-clinical mouse model. J Clin. Invest. 2008; 118(9):3051-3064.

22.   Yan J, Erdem H, Li R, Cai Y, Ayala G, Ittmann M, Yu-Lee L, Tsai SY, Tsai MJ. SRC-3/AIB1 promotes cell migration and invasiveness through focal adhesion turnover and matrix metalloproteinase expression. Cancer Res. 2008; 68(13):5460-5468.

23.   Yan J, Yu CT, Ozen M, Ittmann M, Tsai SY, Tsai MJ. Steroid receptor coactivator-3 and AP-1 coordinately regulates the transcription of components of the IGF/AKT signaling pathway. Cancer Res. 2006; 66(22): 11039-11046.

24.   Zhou HJ, Yan J, Luo W, Ayala G, Lin SH, Erdem H, Ittmann M, Tsai SY, Tsai MJ. SRC-3 is required for prostate cancer cell proliferation and survival. Cancer Res. 2005; 65: 7976-7983.

25.   Yan J^‡, Yu Y^‡, Wang N, Chang Y, Ying H, Liu W, He J, Li S, Jiang W, Li Y, Liu H, Wang H, Xu Y. LFIRE-1/HFREP-1, a liver-specific gene, is frequently downregulated and has growth suppressor activity in hepatocellular carcinoma.Oncogene. 2004; 23: 1939-1949.

B. 论著和综述:

1.    Liu W, Cao H, Yan J, Huang R, Ying H. ‘Micro-managers’ of hepatic lipid metabolism and NAFLD. Wiley Interdiscip Rev RNA. 2015;6(5):581-93.

2.    Yan J, Tsai SY, Tsai MJ. A central role of SRC-3/AIB1 intumorigenesis. In: Kumar R and O’Malley BW, eds. Nuclear receptor coregulators and human diseases. Singapore: World Scientific; 2008. p.219-241.

3.    Yan J, Tsai SY, Tsai MJ. SRC-3/AIB1: Transcriptional coactivator in oncogenesis. Acta Pharmacol. Sin. 2006; 27(4): 387-394. (Invited Review).