Numb基因及其可变剪接在胰腺癌中的研究进展

李鹏昊; 郑楷炼; 许熊飞; 金钢

doi:10.3969/j.issn.1001-5256.2022.12.042

Numb基因及其可变剪接在胰腺癌中的研究进展

DOI: 10.3969/j.issn.1001-5256.2022.12.042

海军军医大学长海医院肝胆胰脾外科, 上海 200433

基金项目:

上海市2020年度“科技创新行动计划”自然科学基金项目 (20ZR1457300)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：李鹏昊负责拟定写作思路，检索文献和论文撰写；许熊飞、金钢、郑楷炼负责课题设计；郑楷炼负责指导、修改论文并最终定稿。

详细信息

通信作者:
郑楷炼, zhengkl828@126.com

计量
- 文章访问数: 1295
- HTML全文浏览量: 963
- PDF下载量: 29
- 被引次数: 0
出版历程
- 收稿日期: 2022-06-01
- 录用日期: 2022-07-22
- 出版日期: 2022-12-20

Numb and its alternative splicing in pancreatic cancer

Department of Hepatobiliary Pancreatic and Splenic Surgery, Changhai Hospital, Naval Medical University, Shanghai 200433, China

Research funding:

Natural Science Fund project of Shanghai 2020 "Science and Technology Innovation Action Plan" (20ZR1457300)

More Information

Corresponding author: ZHENG Kailian, zhengkl828@126.com (ORCID: 0000-0002-7341-0639)

摘要

摘要: 胰腺癌是一种常见的消化道肿瘤，恶性程度高，预后极差。目前针对胰腺癌有多种治疗方案，但效果均不太理想。阐明胰腺癌发病机制仍是临床亟需解决的重要难题。可变剪接是真核生物基因表达调控的重要手段，同一基因的剪接异构体介导产生不同生物学表型，其异常可导致诸多疾病的产生。Numb，一种重要的细胞命运决定蛋白，其可变剪接近年来被发现与癌症的发生密切相关。在胰腺癌中Numb的选择性剪接可产生多种不同亚型的Numb蛋白，对癌症相关通路的活化以及肿瘤细胞生物学行为具有不同的调节作用，探索Numb的剪接异构体在胰腺癌中不同功能有利于解释胰腺癌发病机理和新疗法的开发。本文就Numb蛋白在胰腺癌中研究进展进行综述，着重探讨其剪接异构体功能特点以及不同亚型对胰腺癌各方面的调节作用。
- 胰腺肿瘤 /
- Numb /
- 剪接体
Abstract: Pancreatic cancer, a common digestive system tumor with high malignancy and a poor prognosis, has several treatment options. However, none of them are particularly effective because understanding the pathogenesis of pancreatic cancer remains a significant clinical challenge. Splicing isoforms mediate various biological phenotypes as an important means of regulating gene expression in eukaryotes, and their abnormalities can lead to a variety of diseases. Numb is an important cell fate determining protein whose alternative splicing has been linked to the development of various cancers. In pancreatic cancer, selective splicing of Numb can result in a variety of Numb protein subtypes, each with a different regulatory effect on the activation of various cancer-related signal pathways and tumor cell biology. This paper reviews the recent progress of Numb protein research in pancreatic cancer, with a focus on the regulatory role of its different isoforms in pathogenesis.
- Pancreatic Neoplasms /
- Numb /
- Spliceosomes

HTML全文

参考文献(43)

[1]	MIZRAHI JD, SURANA R, VALLE JW, et al. Pancreatic cancer[J]. Lancet, 2020, 395(10242): 2008-2020. DOI: 10.1016/S0140-6736(20)30974-0.
[2]	SIEGEL RL, MILLER KD, JEMAL A. Cancer statistics, 2018[J]. CA Cancer J Clin, 2018, 68(1): 7-30. DOI: 10.3322/caac.21442.
[3]	GULINO A, DI MARCOTULLIO L, SCREPANTI I. The multiple functions of Numb[J]. Exp Cell Res, 2010, 316(6): 900-906. DOI: 10.1016/j.yexcr.2009.11.017.
[4]	WESTHOFF B, COLALUCA IN, D'ARIO G, et al. Alterations of the Notch pathway in lung cancer[J]. Proc Natl Acad Sci U S A, 2009, 106(52): 22293-22298. DOI: 10.1073/pnas.0907781106.
[5]	LU Y, XU W, JI J, et al. Alternative splicing of the cell fate determinant Numb in hepatocellular carcinoma[J]. Hepatology, 2015, 62(4): 1122-1131. DOI: 10.1002/hep.27923.
[6]	PECE S, SERRESI M, SANTOLINI E, et al. Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis[J]. J Cell Biol, 2004, 167(2): 215-221. DOI: 10.1083/jcb.200406140.
[7]	ZHENG KL, HE TL, JI WP, et al. Alternative splicing of NUMB, APP and VEGFA as the features of pancreatic ductal carcinoma[J]. Int J Clin Exp Pathol, 2015, 8(6): 6181-6191.
[8]	SHENG W, DONG M, ZHOU J, et al. Cooperation among Numb, MDM2 and p53 in the development and progression of pancreatic cancer[J]. Cell Tissue Res, 2013, 354(2): 521-532. DOI: 10.1007/s00441-013-1679-6.
[9]	BECHARA EG, SEBESTYÉN E, BERNARDIS I, et al. RBM5, 6, and 10 differentially regulate NUMB alternative splicing to control cancer cell proliferation[J]. Mol Cell, 2013, 52(5): 720-733. DOI: 10.1016/j.molcel.2013.11.010.
[10]	CHOI HY, SEOK J, KANG GH, et al. The role of NUMB/NUMB isoforms in cancer stem cells[J]. BMB Rep, 2021, 54(7): 335-343. DOI: 10.5483/BMBRep.
[11]	MCGILL MA, DHO SE, WEINMASTER G, et al. Numb regulates post-endocytic trafficking and degradation of Notch1[J]. J Biol Chem, 2009, 284(39): 26427-26438. DOI: 10.1074/jbc.M109.014845.
[12]	WANG C, NING K, HU HH, et al. Research progress in tumor microenvironment of pancreatic cancer[J]. Chin J Dig Surg, 2020, 19(1): 109-112. DOI: 10.3760/cma.j.issn.1673-9752.2020.01.018. 王超, 宁克, 胡欢欢, 等. 胰腺癌肿瘤微环境的研究进展[J]. 中华消化外科杂志, 2020, 19(1): 109-112. DOI: 10.3760/cma.j.issn.1673-9752.2020.01.018.
[13]	NATSUIZAKA M, WHELAN KA, KAGAWA S, et al. Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma[J]. Nat Commun, 2017, 8(1): 1758. DOI: 10.1038/s41467-017-01500-9.
[14]	COUTURIER L, MAZOUNI K, SCHWEISGUTH F. Numb localizes at endosomes and controls the endosomal sorting of notch after asymmetric division in Drosophila[J]. Curr Biol, 2013, 23(7): 588-593. DOI: 10.1016/j.cub.2013.03.002.
[15]	COUTURIER L, MAZOUNI K, SCHWEISGUTH F. Inhibition of Notch recycling by Numb: relevance and mechanism(s)[J]. Cell Cycle, 2013, 12(11): 1647-1648. DOI: 10.4161/cc.24983.
[16]	FRISE E, KNOBLICH JA, YOUNGER-SHEPHERD S, et al. The Drosophila Numb protein inhibits signaling of the Notch receptor during cell-cell interaction in sensory organ lineage[J]. Proc Natl Acad Sci U S A, 1996, 93(21): 11925-11932. DOI: 10.1073/pnas.93.21.11925.
[17]	MCGILL MA, MCGLADE CJ. Mammalian numb proteins promote Notch1 receptor ubiquitination and degradation of the Notch1 intracellular domain[J]. J Biol Chem, 2003, 278(25): 23196-23203. DOI: 10.1074/jbc.M302827200.
[18]	MISQUITTA-ALI CM, CHENG E, O'HANLON D, et al. Global profiling and molecular characterization of alternative splicing events misregulated in lung cancer[J]. Mol Cell Biol, 2011, 31(1): 138-150. DOI: 10.1128/MCB.00709-10.
[19]	GVNGÖR C, HOFMANN BT, WOLTERS-EISFELD G, et al. Pancreatic cancer[J]. Br J Pharmacol, 2014, 171(4): 849-858. DOI: 10.1111/bph.12401.
[20]	BARMAN S, FATIMA I, SINGH AB, et al. Pancreatic cancer and therapy: Role and regulation of cancer stem cells[J]. Int J Mol Sci, 2021, 22(9): 4765. DOI: 10.3390/ijms22094765
[21]	TRUONG LH, PAUKLIN S. Pancreatic cancer microenvironment and cellular composition: Current understandings and therapeutic approaches[J]. Cancers (Basel), 2021, 13(19): 5028. DOI: 10.3390/cancers13195028.
[22]	YANG L, SHI P, ZHAO G, et al. Targeting cancer stem cell pathways for cancer therapy[J]. Signal Transduct Target Ther, 2020, 5(1): 8. DOI: 10.1038/s41392-020-0110-5.
[23]	NWAEBURU CC, ABUKIWAN A, ZHAO Z, et al. Quercetin-induced miR-200b-3p regulates the mode of self-renewing divisions in pancreatic cancer[J]. Mol Cancer, 2017, 16(1): 23. DOI: 10.1186/s12943-017-0589-8.
[24]	LUU T. Epithelial-mesenchymal transition and its regulation mechanisms in pancreatic cancer[J]. Front Oncol, 2021, 11: 646399. DOI: 10.3389/fonc.2021.646399.
[25]	DONGRE A, WEINBERG RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer[J]. Nat Rev Mol Cell Biol, 2019, 20(2): 69-84. DOI: 10.1038/s41580-018-0080-4.
[26]	GAIANIGO N, MELISI D, CARBONE C. EMT and treatment resistance in pancreatic cancer[J]. Cancers (Basel), 2017, 9(9): 122. DOI: 10.3390/cancers9090122.
[27]	PAN G, LIU Y, SHANG L, et al. EMT-associated microRNAs and their roles in cancer stemness and drug resistance[J]. Cancer Commun (Lond), 2021, 41(3): 199-217. DOI: 10.1002/cac2.12138.
[28]	SHENG WW, DONG M, LIU ZR, et al. Relationship and clinicopathological significance of Numb and epithelial-mesenchymal transition related proteins in human pancreatic cancer[J]. Chin J Surg, 2016, 54(12): 929-934. DOI: 10.3760/cma.j.issn.0529-5815.2016.12.011. 盛伟伟, 董明, 刘峥嵘, 等. Numb与上皮细胞间质转分化相关蛋白在胰腺癌中表达的相关性及其临床病理学意义[J]. 中华外科杂志, 2016, 54(12): 929-934. DOI: 10.3760/cma.j.issn.0529-5815.2016.12.011.
[29]	SHENG W, TANG J, CAO R, et al. Numb-PRRL promotes TGF-β1- and EGF-induced epithelial-to-mesenchymal transition in pancreatic cancer[J]. Cell Death Dis, 2022, 13(2): 173. DOI: 10.1038/s41419-022-04609-y.
[30]	KRUSE JP, GU W. Modes of p53 regulation[J]. Cell, 2009, 137(4): 609-622. DOI: 10.1016/j.cell.2009.04.050.
[31]	HU J, CAO J, TOPATANA W, et al. Targeting mutant p53 for cancer therapy: direct and indirect strategies[J]. J Hematol Oncol, 2021, 14(1): 157. DOI: 10.1186/s13045-021-01169-0.
[32]	BYKOV V, ERIKSSON SE, BIANCHI J, et al. Targeting mutant p53 for efficient cancer therapy[J]. Nat Rev Cancer, 2018, 18(2): 89-102. DOI: 10.1038/nrc.2017.109.
[33]	TOSONI D, ZECCHINI S, COAZZOLI M, et al. The Numb/p53 circuitry couples replicative self-renewal and tumor suppression in mammary epithelial cells[J]. J Cell Biol, 2015, 211(4): 845-862. DOI: 10.1083/jcb.201505037.
[34]	CONFALONIERI S, COLALUCA IN, BASILE A, et al. Exon 3 of the NUMB gene emerged in the chordate lineage coopting the NUMB protein to the regulation of MDM2[J]. G3 (Bethesda), 2019, 9(10): 3359-3367. DOI: 10.1534/g3.119.400494.
[35]	COLALUCA IN, BASILE A, FREIBURGER L, et al. A Numb-Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer[J]. J Cell Biol, 2018, 217(2): 745-762. DOI: 10.1083/jcb.201709092.
[36]	NEOPTOLEMOS JP, KLEEFF J, MICHL P, et al. Therapeutic developments in pancreatic cancer: current and future perspectives[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(6): 333-348. DOI: 10.1038/s41575-018-0005-x.
[37]	ZHANG TP, LIU RZ, REN B. Current status and challenges of total neoadjuvant therapy for pancreatic cancer[J]. Chin J Dig Surg, 2022, 21(4): 461-464. DOI: 10.3760/cma.j.cn115610-20220320-00141. 张太平, 刘悦泽, 任博. 胰腺癌全程新辅助治疗的现状及挑战[J]. 中华消化外科杂志, 2022, 21(4): 461-464. DOI: 10.3760/cma.j.cn115610-20220320-00141.
[38]	HO WJ, JAFFEE EM, ZHENG L. The tumour microenvironment in pancreatic cancer-clinical challenges and opportunities[J]. Nat Rev Clin Oncol, 2020, 17(9): 527-540. DOI: 10.1038/s41571-020-0363-5.
[39]	ZENG S, PÖTTLER M, LAN B, et al. Chemoresistance in pancreatic cancer[J]. Int J Mol Sci, 2019, 20(18): 4504. DOI: 10.3390/ijms20184504.
[40]	HENG W, DONG M, CHEN C, et al. Cooperation of Musashi-2, Numb, MDM2, and P53 in drug resistance and malignant biology of pancreatic cancer[J]. FASEB J, 2017, 31(6): 2429-2438. DOI: 10.1096/fj.201601240R.
[41]	SESHACHARYULU P, BAINE MJ, SOUCHEK JJ, et al. Biological determinants of radioresistance and their remediation in pancreatic cancer[J]. Biochim Biophys Acta Rev Cancer, 2017, 1868(1): 69-92. DOI: 10.1016/j.bbcan.2017.02.003.
[42]	RAJASEKAR P, O'NEILL CL, EELES L, et al. Epigenetic changes in endothelial progenitors as a possible cellular basis for glycemic memory in diabetic vascular complications[J]. J Diabetes Res, 2015, 2015: 436879. DOI: 10.1155/2015/436879.
[43]	ZHU D, XIA J, LIU C, et al. Numb/Notch/PLK1 signaling pathway mediated hyperglycemic memory in pancreatic cancer cell radioresistance and the therapeutic effects of metformin[J]. Cell Signal, 2022, 93: 110268. DOI: 10.1016/j.cellsig.2022.110268.