人类恶性肿瘤相关基因结构与功能分析

一、研究概况

1978年,研究室开始了人类实体瘤的细胞遗传学研究工作。从最初实体瘤的细胞遗传学水平分析到20世纪90年开始的分子遗传学水平研究,研究室一直致力于人类恶性实体肿瘤相关基因结构与功能分析。2001年,《实体瘤细胞遗传学研究》获国家科技进步二等奖。

二、研究内容

1、实体肿瘤相关基因的鉴定与定位克隆。

2、实体肿瘤相关基因的生物学功能研究。

3、实体肿瘤相关基因的分子调节机制研究。

4、实体肿瘤相关基因参与信号转导通路的分子基础。

三、研究成果

(一)实体肿瘤资源库的建立

与哈尔滨医科大学附属第一、第二和附属肿瘤医院合作,按照知情同意的原则,通过采集北方地区常见实体瘤患者的血液及组织样本,建立了中国北方实体肿瘤遗传资源库,包括胃癌、结肠癌、肺癌和卵巢癌等。

(二)发表学术文章(*通讯作者)

1.         Zhao Y, Liang L, Fan Y, Sun S, An L, Shi Z, Cheng J, Jia W, Sun W, Mori-Akiyama Y, Zhang H, Fu S, Yang J*. (2012) PPM1B negatively regulates antiviral response via dephosphorylating TBK1. Cell Signal. 24(11):2197-204. PMID:22750291

2.         Sun W, Guo C, Meng X, Yu Y, Jin Y, Tong D, Geng J, Huang Q, Qi J, liu A, Guan R, Xu L, Sun D, Ji W, Liu P, Liu F, Sun H, Ji G, Fu S, Bai J*. (2012) Differential expression of PAI-RBP1, Clorf142 and COTL1 in NSCLC cell lines with different tumor metastatic potential. J Investig Med. 60(4):689-94. PMID:22373659

3.         Bai J, Guo C, Sun W, Li M, Meng X, Yu Y, Jin Y, Tong D, Geng J, Huang Q, Qi J, Fu S*. (2012) DJ-1 may contribute to metastasis of non-small cell lung cancer. Mol Biol Rep. 39(3):2697-703. PMID: 21670963

4.         Lee KY, Liu L, Jin Y, Fu SB, Rosales JL*. (2012) Cdk5 mediates vimentin Ser56 phosphorylation during GTP-induced secretion by neutrophils. J Cell Physiol. 227(2):739-50. PMID: 21465480

5.         Meng X, Wang G, Liu P, Hou J, Jin Y, Yu Y, Bai J, Chen F, Sun W, Fu S*. (2011) ATP-binding cassette B1 gene polymorphisms, mRNA expression and chemosensitivity to paclitaxel in non-small cell lung cancer cells. Respirology. 16(8):1228-34. PMID: 21883677

6.         Jung J, Lee MK, Jin Y, Fu SB, Rosales JL, Lee KY*. (2011) Clues for c-Yes involvement in the cell cycle and cytokinesis. Cell Cycle. 10(9):1502-3. PMID: 21566460

7.         Yu J, Liu P, Cui X, Sui Y, Ji G, Guan R, Sun D, Ji W, Liu F, Liu A, Zhao Y, Yu Y, Jin Y, Bai J, Geng J, Xue Y, Qi J, Lee KY, Fu S*. (2011) Identification of novel subregions of LOH in gastric cancer and analysis of the HIC1 and TOB1 tumor suppressor genes in these subregions. Mol Cells. 32(1):47-55. PMID: 21533545

8.         Kim T, Park JS, Lee P, Jin Y, Fu SB, Rosales JL, Lee KY*. (2011) Novel alternatively spliced variant form of human CDK5RAP2. Cell Cycle. 10(6). PMID: 21346412

9.         Fan YH, Yu Y, Mao RF, Tan XJ, Xu GF, Zhang H, Lu XB, Fu SB, Yang J*. (2011) USP4 targets TAK1 to downregulate TNFα-induced NF-κB activation. Cell Death Differ. 18(10):1547-60. PMID: 21331078

10.     Shi Z, Cai Z, Sanchez A, Zhang T, Wen S, Wang J, Yang J, Fu S*, Zhang D*. (2011) A novel Toll-like receptor that recognizes vesicular stomatitis virus. J Biol Chem. 286(6):4517-24. PMID: 21131352

11.     Mao R, Fan Y, Mou Y, Zhang H, Fu S, Yang J*. (2011) TAK1 lysine 158 is required for TGF-β-induced TRAF6-mediated Smad-independent IKK/NF-κB and JNK/AP-1 activation. Cell Signal. 23(1):222-7. PMID: 20837137

12.     Wang QS, Li M, Zhang LY*, Jin Y, Tong DD, Yu Y, Bai J, Huang Q, Liu FL, Liu A, Lee KY, Fu SB*. (2010) Down-regulation of ING4 is associated with initiation and progression of lung cancer. Histopathology. 57(2):271-81. PMID: 20716169

13.     Zhang W, Zhu J, Bai J, Jiang H, Liu F, Liu A, Liu P, Ji G, Guan R, Sun D, Ji W, Yu Y, Jin Y, Meng X, Fu S*. (2010) Comparison of the inhibitory effects of three transcriptional variants of CDKN2A in human lung cancer cell line A549. J Exp Clin Cancer Res. 29:74. PMID: 20565749

14.     Sun W, Wang H, Zhao X, Yu Y, Fan Y, Wang H, Wang X, Lu X, Zhang G, Fu S*, Yang J*. (2010) Protein phosphatase 2A acts as a mitogen-activated protein kinase kinase kinase 3 (MEKK3) phosphatase to inhibit lysophosphatidic acid-induced IkappaB kinase beta/nuclear factor-kappaB activation. J Biol Chem. 285(28):21341-8. PMID: 20448038

15.     Sun W, Ge N, Yu Y, Burlingame S, Li X, Zhang M, Ye S, Fu S, Yang J*. (2010) Phosphorylation of Thr-516 and Ser-520 in the kinase activation loop of MEKK3 is required for lysophosphatidic acid-mediated optimal IkappaB kinase beta (IKKbeta)/nuclear factor-kappaB (NF-kappaB) activation. J Biol Chem. 285(11):7911-8. PMID: 20068038

16.     Fan Y, Yu Y, Shi Y, Sun W, Xie M, Ge N, Mao R, Chang A, Xu G, Schneider MD, Zhang H, Fu S, Qin J, Yang J*. (2010) Lysine 63-linked polyubiquitination of TAK1 at lysine 158 is required for tumor necrosis factor alpha- and interleukin-1beta-induced IKK/NF-kappaB and JNK/AP-1 activation. J Biol Chem. 285(8):5347-60. PMID: 20038579

17.     Sun W, Tan X, Shi Y, Xu G, Mao R, Gu X, Fan Y, Yu Y, Burlingame S, Zhang H, Rednam SP, Lu X, Zhang T, Fu S, Cao G, Qin J, Yang J*. (2010) USP11 negatively regulates TNFalpha-induced NF-kappaB activation by targeting on IkappaBalpha. Cell Signal. 22(3):386-94. PMID: 19874889

18.     Liu F, Yu Y, Jin Y, Fu S*. (2010) TSG101, identified by screening a cancer cDNA library and soft agar assay, promotes cell proliferation in human lung cancer. Mol Biol Rep. 37(6):2829-38. PMID: 19787439

19.     Li C, Shi Z, Zhang L, Huang Y, Liu A, Jin Y, Yu Y, Bai J, Chen D, Gendron C, Liu X, Fu S*. (2010) Dynamic changes of territories 17 and 18 during EBV-infection of human lymphocytes. Mol Biol Rep. 37(5):2347-54. PMID: 19685159

20.     Fan Y, Mao R, Zhao Y, Yu Y, Sun W, Song P, Shi Z, Zhang D, Yvon E, Zhang H, Fu S, Yang J*. (2009) Tumor necrosis factor-alpha induces RelA degradation via ubiquitination at lysine 195 to prevent excessive nuclear factor-kappaB activation. J Biol Chem. 284(43):29290-7. PMID: 19706600

21.     Zhang C, Fu L, Fu J, Hu L, Yang H, Rong TH, Li Y, Liu H, Fu SB, Zeng YX, Guan XY*. (2009) Fibroblast growth factor receptor 2-positive fibroblasts provide a suitable microenvironment for tumor development and progression in esophageal carcinoma. Clin Cancer Res. 15(12):4017-27. PMID: 19509166

22.     Shi Z, Cai Z, Wen S, Chen C, Gendron C, Sanchez A, Patterson K, Fu S, Yang J, Wildman D, Finnell RH, Zhang D*. (2009) Transcriptional regulation of the novel Toll-like receptor Tlr13. J Biol Chem. 284(31):20540-7. PMID: 19487701

23.     Li M, Jin Y, Sun WJ, Yu Y, Bai J, Tong DD, Qi JP, Du JR, Geng JS, Huang Q, Huang XY, Huang Y, Han FF, Meng XN, Rosales JL, Lee KY, Fu SB*. (2009) Reduced expression and novel splice variants of ING4 in human gastric adenocarcinoma. J Pathol. 219(1):87-95. PMID: 19479822

24.     Meng XN, Jin Y, Yu Y, Bai J, Liu GY, Zhu J, Zhao YZ, Wang Z, Chen F, Lee KY, Fu SB*. (2009) Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion. Br J Cancer. 101(2):327-34. PMID: 19568240

25.     Sun W, Li H, Yu Y, Fan Y, Grabiner BC, Mao R, Ge N, Zhang H, Fu S, Lin X, Yang J*. (2009) MEKK3 is required for lysophosphatidic acid-induced NF-kappaB activation. Cell Signal. 21(10):1488-94. PMID: 19465115

26.     Sun W, Yu Y, Dotti G, Shen T, Tan X, Savoldo B, Pass AK, Chu M, Zhang D, Lu X, Fu S, Lin X, Yang J*. (2009) PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation. Cell Signal. 21(1):95-102. PMID: 18930133

27.     Tong DD, Jiang Y, Li M, Kong D, Meng XN, Zhao YZ, Jin Y, Bai J, Fu SB, Geng JS*. (2009) RUNX3 inhibits cell proliferation and induces apoptosis by TGF-beta-dependent and -independent mechanisms in human colon carcinoma cells. Pathobiology. 76(4):163-9. PMID: 19571605

28.     Wang X, Sun W, Bai J, Ma L, Yu Y, Geng J, Qi J, Shi Z, Fu S*. (2009) Growth inhibition induced by transforming growth factor-beta1 in human oral squamous cell carcinoma. Mol Biol Rep. 36(5):861-9. PMID: 18418730

29.     Yu J, Zhou H, Jin Y, Bai J, Yu Y, Geng J, Qi J, Fu S*. (2008) Three distinct regions of allelic deletion on chromosome 17 involved in sporadic gastric cancer. Hepatogastroenterology. 55(85):1487-91. PMID: 18795719

30.     Yu Y, Ge N, Xie M, Sun W, Burlingame S, Pass AK, Nuchtern JG, Zhang D, Fu S, Schneider MD, Fan J, Yang J*. (2008) Phosphorylation of Thr-178 and Thr-184 in the TAK1 T-loop is required for interleukin (IL)-1-mediated optimal NFkappaB and AP-1 activation as well as IL-6 gene expression. J Biol Chem. 283(36):24497-505. PMID: 18617512

31.     Liu G, Meng X, Jin Y, Bai J, Zhao Y, Cui X, Chen F, Fu S*. (2008) Inhibitory role of focal adhesion kinase on anoikis in the lung cancer cell A549. Cell Biol Int. 32(6):663-70. PMID: 18343694

32.     Yu JC, Zhou H, Bai J, Yu Y, Geng JS, Qi JP, Fu SB*. (2008) Human gastric adenocarcinoma allelotype on chromosomes 17 and 18. J Int Med Res. 36(2):279-88. PMID: 18380938

33.     Li X, Yue ZC, Zhang YY, Bai J, Meng XN, Geng JS, Fu SB*. (2008) Elevated serum level and gene polymorphisms of TGF-beta1 in gastric cancer. J Clin Lab Anal. 22(3):164-71. PMID: 18484655

34.     Huang Y, Jin Y, Yan CH, Yu Y, Bai J, Chen F, Zhao YZ, Fu SB*. (2008) Involvement of Annexin A2 in p53 induced apoptosis in lung cancer. Mol Cell Biochem. 309(1-2):117-23. PMID: 18008140

35.     Cui X, Gao L, Jin Y, Zhang Y, Bai J, Feng G, Gao W, Liu P, He L, Fu S*. (2007) The E233del mutation in BFSP2 causes a progressive autosomal dominant congenital cataract in a Chinese family. Mol Vis. 13:2023-9. PMID: 17982427

36.     Huang X, Shi Z, Wang W, Bai J, Chen Z, Xu J, Zhang D, Fu S*. (2007) Identification and characterization of a novel protein ISOC2 that interacts with p16INK4a. Biochem Biophys Res Commun. 361(2):287-93. PMID: 17658461

37.     Liu F, Li Y, Yu Y, Fu S, Li P*. (2007) Cloning of novel tumor metastasis-related genes from the highly metastatic human lung adenocarcinoma cell line Anip973. J Genet Genomics. 34(3):189-95. PMID: 17498616

38.     Zhang CY, Feng YX, Yu Y, Sun WJ, Bai J, Chen F, Fu SB*. (2006) The molecular mechanism of resistance to methotrexate in mouse methotrexate-resistant cells by cancer drug resistance and metabolism SuperArray. Basic Clin Pharmacol Toxicol. 99(2):141-5. PMID: 16918715

39.     Yan J, Yun H, Yang Y, Jing B, Feng C, Song-bin F*. (2006) Upregulation of BNIP3 promotes apoptosis of lung cancer cells that were induced by p53. Biochem Biophys Res Commun. 346(2):501-7. PMID: 16765911

40.     Ma LL, Sun WJ, Wang Zh, Zh GY, Li P, Fu SB*. (2006) Effects of silencing of mutant p53 gene in human lung adenocarcinoma cell line Anip973. J Exp Clin Cancer Res. 25(4):585-92. PMID: 17310850

41.     Shi ZC, Yu Y, Li Y, Fu SB*. (2005) The effect of RAB5A gene on rearrangement of microfilaments in human lung adenocarcinoma cells. Yi Chuan Xue Bao. 32(12):1227-34. PMID: 16459650

42.     Gao L, Qin W, Cui H, Feng G, Liu P, Gao W, Ma L, Li P, He L, Fu S*. (2005) A novel locus of coralliform cataract mapped to chromosome 2p24-pter. J Hum Genet. 50(6):305-10. PMID: 15933805

43.     Li X, Zhang YY, Wang Q, Fu SB*. (2005) Association between endogenous gene expression and growth regulation induced by TGF-beta1 in human gastric cancer cells. World J Gastroenterol. 11(1):61-8. PMID: 15609398

44.     Yu JC, Sun KL, Liu B, Fu SB*. (2004) Allelotyping for loss of heterozygosity on chromosome 18 in gastric cancer. World J Gastroenterol. 10(13):1964-6. PMID: 15222047

45.     Wang Q, Tsao SW, Fu S, Xue W, Meng X, Feng H, Wong YC, Wang X*. (2004) Overexpression of Id-1 in gastric adenocarcinoma: implication for a novel diagnostic marker. Anticancer Res. 24(2B):881-6. PMID: 15161041

46.     Wang Q, Wang B, Guan X, Gao H, Cheng H, Zhang Q, Huang C, Li P, Fu S*. (2003) Analysis of comparative genomic hybridization and loss of heterozygosity in 43 primary gastric carcinomas. Chin Med J (Engl). 116(4):517-23. PMID: 12875714

47.     Guan XY, Fu SB, Xia JC, Fang Y, Sham JS, Du BD, Zhou H, Lu S, Wang BQ, Lin YZ, Liang Q, Li XM, Du B, Ning XM, Du JR, Li P, (2000) Trent JM. Recurrent chromosome changes in 62 primary gastric carcinomas detected by comparative genomic hybridization. Cancer Genet Cytogenet. 123(1):27-34. PMID: 11120330

48.     Xia JC, Lu S, Geng JS, Fu SB, Li P, Liu QZ. (1998) Direct chromosome analysis of ten primary gastric cancers. Cancer Genet Cytogenet. 102(1):88-90. PMID: 9530349

49.     Fu SB*, Li P. (1997) Cytogenetic study of twenty-three primary squamous cell carcinomas of the lung. Cancer Genet Cytogenet. 99(1):54-8. PMID: 9352796

50.     Fu SB*, Wang BQ, Li P. (1997) Frequent somatic mutation of the MTS1/CDK4I gene in human non-small cell lung carcinomas. Chin Med Sci J. 12(4):251

51.     Fu SB*, Li P, Feng XL, Liu CX, Liu QZ. (1994) The origin of isochromosomes and their significance in tumorigenesis of human lung cancer. Cancer Genet Cytogenet. 74(2):120-2. PMID: 8019955

52.     Lu YJ, Xiao S, Yan YS, Fu SB, Liu QZ, Li P*. (1993) Direct chromosome analysis of 50 primary breast carcinomas. Cancer Genet Cytogenet. 69(2):91-9. PMID: 8402564