Serine-arginine protein kinase 1 promotes a cancer stem cell-like phenotype through activation of Wnt/β-catenin signalling in NSCLC
Serine-arginine protein kinase 1 promotes a cancer stem cell-like phenotype through activation of Wnt/β-catenin signalling in NSCLC
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丝氨酸-精氨酸蛋白激酶 1 通过激活 NSCLC 中的 Wnt/β-连环蛋白信号传导促进癌症干细胞样表型。
DOI：
10.1002/path.4767
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发表时间：
2016-10-01
影响因子：
7.3
通讯作者：
Song, Libing
中科院分区：
文献类型：
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作者：
Gong, Liyun;Song, Junwei;Song, Libing
肿瘤干细胞(CSCs)通常与癌症复发和转移有关，高达30-55%的非小细胞肺癌(NSCLC)患者会发生癌症复发和转移。在此，我们发现丝氨酸-精氨酸蛋白激酶1(SRPK1)在人NCSLC的mRNA和蛋白水平上都有高表达。SRPK1与非小细胞肺癌的临床分期(p<；0.001)、T(p=0.001)、N(p=0.007)和M(p=0.001)分型有关。在体外培养的人非小细胞肺癌细胞系中，SRPK1异位过表达促进了干细胞样表型的获得。SRPK1的过表达增加了球体的形成和不包括Hoechst染料的侧群细胞的比例。相反，SRPK1沉默减少了球体的数量和侧群细胞的比例。小鼠研究表明，SRPK1促进了NSCLC细胞系的肿瘤生长，并且SRPK1的过表达减少了体内启动肿瘤发生所需的肿瘤细胞数量。从机制上讲，基因集浓缩分析表明，Wnt/β-catenin信号与SRPK1的mRNA水平相关，并且这一信号通路被异位表达的SRPK1在NSCLC细胞系中过度激活。免疫荧光显示，SRPK1促进了β-连环蛋白在NSCLC细胞核中的积聚，抑制β-连环蛋白信号转导抑制了SRPK1诱导的干细胞样表型。综上所述，我们的发现表明，SRPK1通过Wnt/β-catenin信号转导促进非小细胞肺癌干细胞样表型。此外，SRPK1可能成为非小细胞肺癌诊断和治疗的新靶点。版权所有(C)2016年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Cancer stem cells (CSCs) are commonly associated with cancer recurrence and metastasis that occurs in up to 30-55% of non-small-cell lung carcinoma (NSCLC) patients. Herein, we showed that serine-arginine protein kinase 1 (SRPK1) was highly expressed at both the mRNA and the protein levels in human NCSLC. SRPK1 was associated with the clinical features of human NSCLC, including clinical stage (p < 0.001) and T (p = 0.001), N (p = 0.007), and M (p = 0.001) classifications. Ectopic overexpression of SRPK1 promoted the acquisition of a stem cell-like phenotype in human NSCLC cell lines cultured in vitro. Overexpression of SRPK1 increased sphere formation and the proportion of side-population cells that exclude Hoechst dye. Conversely, SRPK1 silencing reduced the number of spheres and the proportion of side-population cells. Mouse studies indicated that SRPK1 promoted NSCLC cell line tumour growth and SRPK1 overexpression reduced the number of tumour cells required to initiate tumourigenesis in vivo. Mechanistically, gene set enrichment analysis showed that Wnt/beta-catenin signalling correlated with SRPK1 mRNA levels and this signalling pathway was hyperactivated by ectopic SRPK1 expression in NSCLC cell lines. Immunofluorescence demonstrated that SRPK1 enhanced beta-catenin accumulation in the nuclei of NSCLC cell lines, and inhibition of beta-catenin signalling abrogated the SRPK1-induced stem cell-like phenotype. Together, our findings suggest that SRPK1 promotes a stem cell-like phenotype in NSCLC via Wnt/beta-catenin signalling. Moreover, SRPK1 may represent a novel target for human NSCLC diagnosis and therapy. Copyright (C) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.