E2F家族转录因子在肿瘤发生中的作用
收稿日期: 2023-02-10
修回日期: 2023-05-01
网络出版日期: 2023-05-15
基金资助
国家自然科学基金项目(42207336);河北省自然科学基金生物农业联合基金项目(C202204227);河北大学研究生创新项目(HBU2022ss016)
E2F family play important roles in tumorigenesis
Received date: 2023-02-10
Revised date: 2023-05-01
Online published: 2023-05-15
Supported by
National Natural Science Foundation of China(42207336);Hebei Province Natural Science Foundation Joint Fund for Bioagriculture Project(C202204227);Post-graduates Innovation Fund Project of Hebei University(HBU2022ss016)
肿瘤严重威胁人类健康，转录因子是肿瘤治疗的潜在靶点。作为重要的转录因子家族，E2F在细胞增殖与调控进程中发挥重要作用。然而，E2F家族转录因子在肿瘤发生进程中的表达规律、基因功能和分子互作等关键信息尚不清晰。基于此，本研究对TCGA数据库中我国10种高发肿瘤的转录组测序数据、突变数据和蛋白质互作数据进行整合分析，探究E2F家族转录因子的表达、结构、功能、突变和系统发生特征。结果显示，E2F家族转录因子中的E2F1和E2F7基因在多种肿瘤样本中规律性上调表达，参与调控细胞周期、细胞衰老等信号通路；其中，E2F1作为重要的调控因子与其他蛋白的相互作用最多。值得指出的是，E2F家族转录因子的基因突变类型在肿瘤类型和患者性别中均存在差异，基因扩增占比最大。系统发生分析显示，E2F家族转录因子的结构在包括果蝇、线虫和人类在内41个物种中保守，并且它们在物种演化过程中表现出基因扩张倾向。综上所述，本研究阐明了E2F家族转录因子在我国高发肿瘤中的表达规律、突变特征和演化规律，提示E2F家族转录因子是相关肿瘤疾病的新型分子诊断标志物，为抗肿瘤靶向药物研发提供理论依据。
李飞飞, 王韵, 顾冀海, 张玉明, 柳峰松, 倪志华 . E2F家族转录因子在肿瘤发生中的作用[J]. 遗传, 2023 , 45(7) : 580 -592 . DOI: 10.16288/j.yczz.23-029
Tumors are serious threats to human health. The transcription factors are regarded as the potential targets for tumor treatment. As an important family of transcription factors, E2F family transcription factors (E2Fs) play vital roles in cell proliferation and regulation. However, the expression feature, gene functions, and molecular interactions of E2Fs in tumorigenesis are not clear. In this study, the transcriptome data, mutation data, and protein-protein interaction data of 10 high-incidence tumors in China from the TCGA database were integrated and analyzed to explore the expression, structure, function, mutation, and phylogenetic characteristics of E2Fs. The results showed that E2F1 and E2F7 were regularly upregulated in the tumor samples. Moreover, E2Fs participated in the regulation of the cell cycle, cell aging, and other signaling pathways. As an important regulator, E2F1 interacted with more proteins than other E2Fs. At the same time, the genetic mutation types of E2Fs varied in tumor type and patient sex, of which gene amplification accounts for the largest proportion. Phylogenetic analysis showed that E2Fs were conserved in 41 species, including fruit flies, nematodes, and humans. Meanwhile, E2Fs had a tendency for gene expansion during evolution. In conclusion, this study clarified the expression pattern, mutation characteristics, and evolutionary trend of E2Fs in high-incidence tumors in China, and suggested that E2F family transcription factors could be novel diagnostic markers for tumor diseases. Furthermore, this work can provide a theoretical basis for the development of anti-tumor-targeted drugs.
Key words： E2F1; E2F7; gene family
| [1] | Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249. |
| [2] | Siegel RL, Miller KD, Fuchs HE, Jemal A.Cancer statistics, 2022. CA Cancer J Clin, 2022, 72(1): 7-33. |
| [3] | Levrero M, De Laurenzi V, Costanzo A, Gong J, Wang JY, Melino G. The p53/p63/p73 family of transcription factors: overlapping and distinct functions. J Cell Sci, 2000, 113(Pt 10): 1661-1670. |
| [4] | Van Nostrand JL, Bowen ME, Vogel H, Barna M, Attardi LD. The p53 family members have distinct roles during mammalian embryonic development. Cell Death Differ, 2017, 24(4): 575-579. |
| [5] | Zhou DB, Xia Z, Xie MX, Gao Y, Yu Q, He BM.Exosomal long non-coding RNA SOX2 overlapping transcript enhances the resistance to EGFR-TKIs in non-small cell lung cancer cell line H1975. Hum Cell, 2021, 34(5): 1478-1489. |
| [6] | Nacarino-Palma A, Rejano-Gordillo CM, González-Rico FJ, Ordiales-Talavero A, Román áC, Cuadrado M, Bustelo XR, Merino JM, Fernández-Salguero PM. Loss of aryl hydrocarbon receptor favors K-RasG12D-driven non- small cell lung cancer. Cancers (Basel), 2021, 13(16): 4071. |
| [7] | Lei CG, Jia XY, Sun WJ. Establish six-gene prognostic model for glioblastoma based on multi-omics data of TCGA database. Hereditas (Beijing), 2021, 43(7): 665-689. |
| [7] | 雷常贵, 贾学渊, 孙文靖. 基于癌症基因组图谱计划多组学数据构建胶质母细胞瘤六基因预后模型. 遗传, 2021, 43(7): 665-689. |
| [8] | Paul D. The systemic hallmarks of cancer. J Cancer Metastasis Treat, 2020, 6(8): 69-99. |
| [9] | Jiramongkol Y, Lam EW. FOXO transcription factor family in cancer and metastasis. Cancer Metastasis Rev, 2020, 39(3): 681-709. |
| [10] | Kuo MH, Lee AC, Hsiao SH, Lin SE, Chiu YF, Yang LH, Yu CC, Chiou SH, Huang HN, Ko JC, Chou YT. Cross-talk between SOX2 and TGFβ signaling regulates EGFR-TKI tolerance and lung cancer dissemination. Cancer Res, 2020, 80(20): 4426-4438. |
| [11] | Lee CS, Siprashvili Z, Mah A, Bencomo T, Elcavage LE, Che YL, Shenoy RM, Aasi SZ, Khavari PA. Mutant collagen COL11A1 enhances cancerous invasion. Oncogene, 2021, 40(44): 6299-6307. |
| [12] | Bado IL, Zhang WJ, Hu JY, Xu Z, Wang H, Sarkar P, Li LC, Wan YW, Liu J, Wu W, Lo HC, Kim IS, Singh S, Janghorban M, Muscarella AM, Goldstein A, Singh P, Jeong HH, Liu CZ, Schiff R, Huang SX, Ellis MJ, Gaber MW, Gugala Z, Liu ZD, Zhang XHF. The bone microenvironment increases phenotypic plasticity of ER+ breast cancer cells. Dev Cell, 2021, 56(8): 1100-1117. |
| [13] | Park JH, Pyun WY, Park HW. Cancer metabolism: phenotype, signaling and therapeutic targets. Cells, 2020, 9(10): 2308. |
| [14] | Masciale V, Grisendi G, Banchelli F, D'Amico R, Maiorana A, Sighinolfi P, Brugioni L, Stefani A, Morandi U, Dominici M, Aramini B. Cancer stem-like cells in a case of an inflammatory myofibroblastic tumor of the lung. Front Oncol, 2020, 10: 673. |
| [15] | Bodor JN, Boumber Y, Borghaei H. Biomarkers for immune checkpoint inhibition in non-small cell lung cancer (NSCLC). Cancer, 2020, 126(2): 260-270. |
| [16] | Chen HH, Tarn WY. uORF-mediated translational control: recently elucidated mechanisms and implications in cancer. RNA Biol, 2019, 16(10): 1327-1338. |
| [17] | Yordy JS, Muise-Helmericks RC. Signal transduction and the ETS family of transcription factors. Oncogene, 2000, 19(55): 6503-6513. |
| [18] | He XW, Lindsay-Mosher N, Li Y, Molinaro AM, Pellettieri J, Pearson BJ. FOX and ETS family transcription factors regulate the pigment cell lineage in planarians. Development, 2017, 144(24): 4540-4551. |
| [19] | Rajagopal C, Lankadasari MB, Aranjani JM, Harikumar KB. Targeting oncogenic transcription factors by polyphenols: a novel approach for cancer therapy. Pharmacol Res, 2018, 130: 273-291. |
| [20] | Tsigelny IF, Kouznetsova VL, Pingle SC, Kesari S. bHLH transcription factors inhibitors for cancer therapy: general features for in silico drug design. Curr Med Chem, 2014, 21(28): 3227-3243. |
| [21] | Yeh JE, Toniolo PA, Frank DA. Targeting transcription factors: promising new strategies for cancer therapy. Curr Opin Oncol, 2013, 25(6): 652-658. |
| [22] | Redell MS, Tweardy DJ. Targeting transcription factors for cancer therapy. Curr Pharm Des, 2005, 11(22): 2873-2887. |
| [23] | Oikawa T. ETS transcription factors: possible targets for cancer therapy. Cancer Sci, 2004, 95(8): 626-633. |
| [24] | Darnell JE Jr. Transcription factors as targets for cancer therapy. Nat Rev Cancer, 2002, 2(10): 740-749. |
| [25] | Mitra P. Targeting transcription factors in cancer drug discovery. Explor Target Antitumor Ther, 2020, 1(6): 401-412. |
| [26] | Zhang WW, Yang SF, Chen DT, Yuwen DL, Zhang J, Wei XW, Han X, Guan XX. SOX2-OT induced by PAI-1 promotes triple-negative breast cancer cells metastasis by sponging miR-942-5p and activating PI3K/Akt signaling. Cell Mol Life Sci, 2022, 79(1): 59. |
| [27] | Wei YY, Hou J, Tang WR, Luo Y. The cooperation between p53 and Ras in tumorigenesis. Hereditas (Beijing), 2012, 34(12): 1513-1521. |
| [27] | 魏永永, 侯静, 唐文如, 罗瑛. p53与Ras协同及其在肿瘤发生中的作用. 遗传, 2012, 34(12): 1513-1521. |
| [28] | Bushweller JH. Targeting transcription factors in cancer- from undruggable to reality. Nat Rev Cancer, 2019, 19(11): 611-624. |
| [29] | Lambert SA, Jolma A, Campitelli LF, Das PK, Yin YM, Albu M, Chen XT, Taipale J, Hughes TR, Weirauch MT. The human transcription factors. Cell, 2018, 172(4): 650-665. |
| [30] | Lambert M, Jambon S, Depauw S, David-Cordonnier MH. Targeting transcription factors for cancer treatment. Molecules, 2018, 23(6): 1479. |
| [31] | Xanthoulis A, Tiniakos DG. E2F transcription factors and digestive system malignancies: how much do we know? World J Gastroenterol, 2013, 19(21): 3189-3198. |
| [32] | Fischer M, Schade AE, Branigan TB, Müller GA, DeCaprio JA. Coordinating gene expression during the cell cycle. Trends Biochem Sci, 2022, 47(12): 1009-1022. |
| [33] | Müller H, Helin K. The E2F transcription factors: key regulators of cell proliferation. Biochim Biophys Acta, 2000, 1470(1): M1-12. |
| [34] | Wang QX, Liu JP, Cheang I, Li JH, Chen TZ, Li YX, Yu B. Comprehensive analysis of the E2F transcription factor family in human lung adenocarcinoma. Int J Gen Med, 2022, 15: 5973-5984. |
| [35] | Sun CC, Zhou Q, Hu W, Li SJ, Zhang F, Chen ZL, Li G, Bi ZY, Bi YY, Gong FY, Bo T, Yuan ZP, Hu WD, Zhan BT, Zhang Q, Tang QZ, Li DJ. Transcriptional E2F1/2/5/8 as potential targets and transcriptional E2F3/6/7 as new biomarkers for the prognosis of human lung carcinoma. Aging (Albany NY), 2018, 10(5): 973-987. |
| [36] | Wang YY, Li M, Zhang L, Chen YT, Zhang SD. m6A demethylase FTO induces NELL2 expression by inhibiting E2F1 m6A modification leading to metastasis of non- small cell lung cancer. Mol Ther Oncolytics, 2021, 21: 367-376. |
| [37] | El-Khattouti A, Sheehan NT, Monico J, Drummond HA, Haikel Y, Brodell RT, Megahed M, Hassan M. Cd133(+) melanoma subpopulation acquired resistance to caffeic acid phenethyl ester-induced apoptosis is attributed to the elevated expression of abcb5: significance for melanoma treatment. Cancer Lett, 2015, 357(1): 83-104. |
| [38] | Carvajal LA, Hamard PJ, Tonnessen C, Manfredi JJ. E2F7, a novel target, is up-regulated by p53 and mediates DNA damage-dependent transcriptional repression. Genes Dev, 2012, 26(14): 1533-1545. |
| [39] | Li JX, Wang H, Cao FL, Cheng YF. A bioinformatics analysis for diagnostic roles of the E2F family in esophageal cancer. J Gastrointest Oncol, 2022, 13(5): 2115-2131. |
| [40] | Toolabi N, Daliri FS, Mokhlesi A, Talkhabi M. Identification of key regulators associated with colon cancer prognosis and pathogenesis. J Cell Commun Signal, 2022, 16(1): 115-127. |
| [41] | Liu XS, Gao Y, Liu C, Chen XQ, Zhou LM, Yang JW, Kui XY, Pei ZJ. Comprehensive analysis of prognostic and immune infiltrates for E2F transcription factors in human pancreatic adenocarcinoma. Front Oncol, 2020, 10: 606735. |
| [42] | Shen C, Chen XM, Xiao K, Che GW. New relationship of E2F1 and BNIP3 with caveolin-1 in lung cancer- associated fibroblasts. Thorac Cancer, 2020, 11(6): 1369-1371. |
| [43] | Xu ZH, Qu H, Ren YY, Gong ZZ, Ri HJ, Zhang F, Shao S, Chen XL, Chen X. Systematic analysis of E2F expression and its relation in colorectal cancer prognosis. Int J Gen Med, 2022, 15: 4849-4870. |
| [44] | Weng JZ, Wu AX, Ying JW. Chemosensitivity of gastric cancer: analysis of key pathogenic transcription factors. J Gastrointest Oncol, 2022, 13(3): 977-984. |
| [45] | Hu H, Miao YR, Jia LH, Yu QY, Zhang Q, Guo AY. Animaltfdb 3.0: a comprehensive resource for annotation and prediction of animal transcription factors. Nucleic Acids Res, 2019, 47(D1): D33-D38. |
| [46] | Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics, 2010, 26(1): 139-140. |
| [47] | Yu GC, Wang LG, Han YY, He QY. Clusterprofiler: an R package for comparing biological themes among gene clusters. Omics, 2012, 16(5): 284-287. |
| [48] | Mendes FK, Vanderpool D, Fulton B, Hahn MW. CAFé5 models variation in evolutionary rates among gene families. Bioinformatics, 2020, 36(22-23): 5516-5518. |
| [49] | Gaubatz S, Lindeman GJ, Ishida S, Jakoi L, Nevins JR, Livingston DM, Rempel RE. E2F4 and E2F5 play an essential role in pocket protein-mediated G1 control. Mol Cell, 2000, 6(3): 729-735. |
| [50] | Shiah JV, Johnson DE, Grandis JR. Transcription factors and cancer: approaches to targeting. Cancer J, 2023, 29(1): 38-46. |
| [51] | Shen C, Li J, Chang S, Che GW. Advancement of E2F1 in common tumors. Chin J Lung Cancer, 2020, 23(10): 921-926. |
| [51] | 沈诚, 李珏, 常帅, 车国卫. E2F1在常见肿瘤中的最新研究进展. 中国肺癌杂志, 2020, 23(10): 921-926. |
| [52] | Cam H, Dynlacht BD. Emerging roles for E2F: beyond the G1/S transition and DNA replication. Cancer Cell, 2003, 3(4): 311-316. |
| [53] | Xie D, Pei Q, Li JY, Wan X, Ye T. Emerging role of E2F family in cancer stem cells. Front Oncol, 2021, 11: 723137. |
| [54] | Jin X, Ding DL, Yan YQ, Li H, Wang B, Ma LL, Ye ZQ, Ma T, Wu Q, Rodrigues DN, Kohli M, Jimenez R, Wang LG, Goodrich DW, de Bono J, Dong HD, Wu HS, Zhu RZ, Huang HJ. Phosphorylated RB promotes cancer immunity by inhibiting NF-κb activation and PD-L1 expression. Mol Cell, 2019, 73(1): 22-35.e26. |
| [55] | Gulluni F, Prever L, Li HY, Krafcikova P, Corrado I, Lo WT, Margaria JP, Chen A, De Santis MC, Cnudde SJ, Fogerty J, Yuan A, Massarotti A, Sarijalo NT, Vadas O, Williams RL, Thelen M, Powell DR, Schueler M, Wiesener MS, Balla T, Baris HN, Tiosano D, McDermott BM Jr, Perkins BD, Ghigo A, Martini M, Haucke V, Boura E, Merlo GR, Buchner DA, Hirsch E. PI(3,4)P2- mediated cytokinetic abscission prevents early senescence and cataract formation. Science, 2021, 374(6573): eabk0410. |
| [56] | Segeren HA, Westendorp B. Mechanisms used by cancer cells to tolerate drug-induced replication stress. Cancer Lett, 2022, 544: 215804. |
| [57] | Guo AY, Hu JL, Li YY, Li P. Association of a low-frequency missense variant in E2F transcription factor 7 with colorectal cancer risk. Chin J Health Lab Technol, 2018, 28(17): 2118-2122. |
| [57] | 郭爱叶, 胡金龙, 李颖颖, 李泮. E2F转录因子7低频错义突变与结直肠癌风险的相关性研究. 中国卫生检验杂志, 2018, 28(17): 2118-2122. |
/
| 〈 |
|
〉 |
www.chinagene.cn
备案号：京ICP备09063187号-4
总访问:,今日访问:,当前在线:
