张苏杰;殷华奇;叶雄俊;徐涛;
ZHANG Su-jie;YIN Hua-qi;YE Xiong-jun;XU Tao;Department of Urology,Peking University People's Hospital;

• 1:北京大学人民医院泌尿外科

摘要(Abstract)：

Musashi-2(Msi-2)蛋白自发现以来,有关其在干细胞未分化状态和自我更新能力中发挥的作用一直是研究的热点,而近年来也证实Msi-2在恶性肿瘤的发生、发展中起到关键性作用,现有研究不仅仅局限于Msi-2促进恶性肿瘤发生发展的机制,Msi-2应用于恶性肿瘤诊断和个体化治疗的价值也日益凸显。本文将对Msi-2在恶性肿瘤发生发展中的作用及其作为诊断及治疗靶点的最新研究进展进行综述。
The role that Musashi-2( Msi-2) protein plays in maintaining the undifferentiated status and self-renewal ability of stem cells has been a hot issue since its discovery. In recent years,it has been confirmed that Msi-2 plays a key role in the development and progression of malignant tumors. The existing study is not limited to Msi-2's function in promoting the development of malignant tumor. The use of Msi-2 in the diagnosis of malignant tumors,and its value in individual treatment have become increasingly prominent. We will review the role of Msi-2 in the development of malignant tumors and its latest research progress as a diagnostic and therapeutic target.

关键词(KeyWords)： Musashi-2;恶性肿瘤;干细胞;靶向治疗
Musashi-2;cancer;stem cell;targeted therapy

Abstract:

Keywords:

基金项目(Foundation):

作者(Author): 张苏杰;殷华奇;叶雄俊;徐涛;
ZHANG Su-jie;YIN Hua-qi;YE Xiong-jun;XU Tao;Department of Urology,Peking University People's Hospital;

Email:

DOI:

参考文献(References)：

• [1]Okano H,Imai T,Okabe M.Musashi:a translational regulator of cell fate[J].J Cell Sci,2002,115:1355-1359.
• [2]Nakamura M,Okano H,Blendy JA,et al.Musashi,a neural RNA-binding protein required for Drosophila adult external sensory organ development[J].Neuron,1994,13:67-81.
• [3]Sakakibara S,Nakamura Y,Satoh H,et al.Rna-binding protein Musashi2:developmentally regulated expression in neural precursor cells and subpopulations of neurons in mammalian CNS[J].J Neurosci,2001,21:8091-8107.
• [4]Hope KJ,Cellot S,Ting SB,et al.An RNAi screen identifies Msi2 and Prox1 as having opposite roles in the regulation of hematopoietic stem cell activity[J].Cell Stem Cell,2010,7:101-113.
• [5]Hattori E,Shu HJ,Saito T,et al.Expression of the RNAbinding protein Musashi1 in adult liver stem-like cells[J].Hepatol Res,2010,40:432-437.
• [6]Samuel S,Walsh R,Webb J,et al.Characterization of putative stem cells in isolated human colonic crypt epithelial cells and their interactions with myofibroblasts[J].Am J Physiol Cell Physiol,2009,296:C296-C305.
• [7]Clarke RB,Spence K,Anderson E,et al.A putative human breast stem cell population is enriched for steroid receptorpositive cells[J].Dev Biol,2005,277:443-456.
• [8]Han SP,Tang YH,Smith R.Functional diversity of the hnRNPs:past,present and perspectives[J].Biochem J,2010,430:379-392.
• [9]Barbouti A,Hoglund M,Johansson B,et al.A novel gene,MSI2,encoding a putative RNA-binding protein is recurrently rearranged at disease progression of chronic myeloid leukemia and forms a fusion gene with HOXA9 as a result of the cryptic t(7;17)(p15;q23)[J].Cancer Res,2003,63:1202-1206.
• [10]Sakakibara S,Nakamura Y,Yoshida T,et al.RNA-binding protein Musashi family:roles for CNS stem cells and a subpopulation of ependymal cells revealed by targeted disruption and antisense ablation[J].Proc Natl Acad Sci USA,2002,99:15194-15199.
• [11]Ito T,Kwon HY,Zimdahl B,et al.Regulation of myeloid leukaemia by the cell-fate determinant Musashi[J].Nature,2010,466:765-768.
• [12]Kharas MG,Lengner CJ,Al-Shahrour F,et al.Musashi-2regulates normal hematopoiesis and promotes aggressive myeloid leukemia[J].Nat Med,2010,16:903-908.
• [13]Pattabiraman DR,Weinberg RA.Tackling the cancer stem cells-what challenges do they pose?[J].Nat Rev Drug Discov,2014,13:497-512.
• [14]Wang S,Li N,Yousefi M,et al.Transformation of the intestinal epithelium by the MSI2 RNA-binding protein[J].Nat Commun,2015,6:6517.
• [15]Guo K,Cui J,Quan M,et al.The novel KLF4/MSI2 signaling pathway regulates growth and metastasis of pancreatic cancer[J].Clin Cancer Res,2017,23:687-696.
• [16]Choi YM,Kim KB,Lee JH,et al.DBC2/Rho BTB2 functions as a tumor suppressor protein via Musashi-2 ubiquitination in breast cancer[J].Oncogene,2017,36:2802-2812.
• [17]Fujiwara T,Zhou J,Ye S,et al.RNA-binding protein Musashi2 induced by RANKL is critical for osteoclast survival[J].Cell Death Dis,2016,7:e2300.
• [18]Kwon HY,Bajaj J,Ito T,et al.Tetraspanin 3 is required for the development and propagation of acute myelogenous leukemia[J].Cell Stem Cell,2015,17:152-164.
• [19]Kaeda J,Ringel F,Oberender C,et al.Longitudinal study to assess the clinical significance of MSI2 expression in chronic myeloid leukemia patients[J].Acta Haematol,2016,136:62-64.
• [20]Park SM,Gonen M,Vu L,et al.Musashi2 sustains the mixed-lineage leukemia-driven stem cell regulatory program[J].J Clin Invest,2015,125:1286-1298.
• [21]Byers RJ,Currie T,Tholouli E,et al.MSI2 protein expression predicts unfavorable outcome in acute myeloid leukemia[J].Blood,2011,118:2857-2867.
• [22]Hattori A,Mcskimming D,Kannan N,et al.RNA binding protein MSI2 positively regulates FLT3 expression in myeloid leukemia[J].Leuk Res,2017,54:47-54.
• [23]Zhao HZ,Jia M,Luo ZB,et al.Prognostic significance of the Musashi-2(MSI2)gene in childhood acute lymphoblastic leukemia[J].Neoplasma,2016,63:150-157.
• [24]Mu Q,Wang Y,Chen B,et al.High expression of Musashi-2indicates poor prognosis in adult B-cell acute lymphoblastic leukemia[J].Leuk Res,2013,37:922-927.
• [25]Taggart J,Ho T C,Amin E,et al.MSI2 is required for maintaining activated myelodysplastic syndrome stem cells[J].Nat Commun,2016,7:10739.
• [26]He L,Zhou X,Qu C,et al.Musashi2 predicts poor prognosis and invasion in hepatocellular carcinoma by driving epithelialmesenchymal transition[J].J Cell Mol Med,2014,18:49-58.
• [27]Wang MH,Qin SY,Zhang SG,et al.Musashi-2 promotes hepatitis Bvirus related hepatocellular carcinoma progression via the Wnt/beta-catenin pathway[J].Am J Cancer Res,2015,5:1089-1100.
• [28]Li N,Yousefi M,Nakauka-Ddamba A,et al.The Msi Family of RNA-Binding Proteins Function Redundantly as Intestinal Oncoproteins[J].Cell Rep,2015,13:2440-2455.
• [29]Zong Z,Zhou T,Rao L,et al.Musashi2 as a novel predictive biomarker for liver metastasis and poor prognosis in colorectal cancer[J].Cancer Med,2016,5:623-630.
• [30]Kudinov AE,Deneka A,Nikonova AS,et al.Musashi-2(MSI2)supports TGF-beta signaling and inhibits claudins to promote non-small cell lung cancer(NSCLC)metastasis[J].Proc Natl Acad Sci U S A,2016,113:6955-6960.
• [31]Katz Y,Li F,Lambert NJ,et al.Musashi proteins are posttranscriptional regulators of the epithelial-luminal cell state[J].Elife,2014,3:e3915.
• [32]Kang MH,Jeong KJ,Kim WY,et al.Musashi RNA-binding protein 2 regulates estrogen receptor 1 function in breast cancer[J].Oncogene,2017,36:1745-1752.
• [33]Nahas GR,Murthy RG,Patel SA,et al.The RNA-binding protein Musashi 1 stabilizes the oncotachykinin 1 mRNA in breast cancer cells to promote cell growth[J].FASEB J,2016,30:149-159.
• [34]Yang C,Zhang W,Wang L,et al.Musashi-2 promotes migration and invasion in bladder cancer via activation of the JAK2/STAT3 pathway[J].Lab Invest,2016,96:950-958.
• [35]Cox JL,Wilder PJ,Gilmore JM,et al.The SOX2-interactome in brain cancer cells identifies the requirement of MSI2 and USP9X for the growth of brain tumor cells[J].PLo S One,2013,8:e62857.
• [36]Emadi-Baygi M,Nikpour P,Mohammad-Hashem F,et al.MSI2 expression is decreased in grade II of gastric carcinoma[J].Pathol Res Pract,2013,209:689-691.
• [37]Minuesa G,Antczak C,Shum D,et al.A 1536-well fluorescence polarization assay to screen for modulators of the MUSASHI family of RNA-binding proteins[J].Comb Chem High Throughput Screen,2014,17:596-609.
• [38]Lan L,Appelman C,Smith AR,et al.Natural product(-)-gossypol inhibits colon cancer cell growth by targeting RNAbinding protein Musashi-1[J].Mol Oncol,2015,9:1406-1420.
• [39]Han Y,Ye A,Zhang Y,et al.Musashi-2 silencing exerts potent activity against acute myeloid leukemia and enhances chemosensitivity to daunorubicin[J].PLo S One,2015,10:e136484.
• [40]Lee J,An S,Choi YM,et al.Musashi-2 is a novel regulator of paclitaxel sensitivity in ovarian cancer cells[J].Int J Oncol,2016,49:1945-1952.