IGF2BP3 facilitates cell proliferation and tumorigenesis via modulation of JAK/STAT signalling pathway in human bladder cancer

Insulin‐like growth factor‐2 messenger RNA‐binding protein 3 (IGF2BP3) has been reported to contribute to tumorigenesis in several human cancers. However, the biological functions of IGF2BP3 in bladder cancer are poorly understood. We investigated the relation between IGF2BP3 expression and prognosis of bladder cancer patients. Cell proliferation, cell cycle and cell apoptosis assays were performed to assess IGF2BP3 functions. The results showed that IGF2BP3 was overexpressed in bladder cancer tissues compared with that in normal bladder tissues, and its higher expression was closely correlated with poor prognosis in bladder cancer patients. Overexpression of IGF2BP3 markedly promoted cell proliferation and cell cycle progression and inhibited cell apoptosis, while knockdown of IGF2BP3 notably suppressed the proliferation, promoted cell apoptosis and induced cell cycle arrest at the G0/G1 phase. Mechanistically, we revealed that IGF2BP3 promotes the activation of the JAK/STAT pathway in bladder cancer cells. Moreover, the JAK/STAT inhibitor dramatically blocked the tumour‐promoting activity of IGF2BP3. Tumour growth in vivo was also suppressed by knocking down of IGF2BP3. Hence, IGF2BP3 facilitated bladder cancer cell proliferation by activating the JAK/STAT signalling pathway. These findings suggest that IGF2BP3 exhibits an oncogenic effect in human bladder cancer progression.     

新型抗癌药物分子靶标STAT3的研究进展

信号转导与转录激活因子(STATs)是一类发挥信号转导和转录因子调节作用的蛋白质家族,它们可以作为信号转导分子和转录调节因子参与到细胞因子和生长因子对于正常细胞的调控作用中。STATs的异常激活,特别是STAT3激活,和多种人类恶性肿瘤相关联。相关的分子生物学和药理学模型的研究也已确认STAT3在肿瘤发生中的重要作用,这些工作为抗癌药物研发和治疗癌症提供了新的靶标。此外,结构性活化的STAT3突变体就足以诱导瘤原细胞的转化,并且进一步在体内形成肿瘤。结构性激活的STAT3信号通路常常伴随着一些基因如cyclinD1,c-Myc和Bcl-x的上调,同时也会破坏正常细胞生长与生存的调控机制。体外和体内的实验研究结果也证明,对于STAT3信号通路结构性的阻断可以导致STAT3高表达肿瘤类型中的细胞生长抑制和凋亡。这种已被证实了的肿瘤细胞内的结构性激活和生长存活之间的相互联系,为癌症治疗提供了广阔的应用前景。近年来针对STAT3抑制剂的研究逐渐成为热点,本文就此作一综述。     

信号转导与转录活化蛋白STAT3在肿瘤发生中的作用

STAT3是信号转导与转录活化蛋白（STAT）家族的一个重要成员,也是一个可以被多种调控细胞增殖、分化、发育、存活和炎症的细胞因子、生长因子及肿瘤蛋白所激活的关键信号转导蛋白。在多种肿瘤细胞、细胞性状转化过程和肿瘤形成过程中可以检测到组成性激活的STAT3。我们从STAT3在肿瘤细胞中组成性激活的机制、STAT3作为转录因子对肿瘤细胞调控的机制等方面对STAT3在肿瘤发生中的作用进行简要综述。     

STAT3基因沉默降低小鼠乳腺癌细胞的体外迁移能力

信号转导子与转录活化子3(STAT3)是一个具有信号转导和转录调控双重功能的转录因子,有文献报道STAT3在乳腺癌中的表达显著升高,并能促进乳腺癌的转移。为了深入探索STAT3在肿瘤发生发展中的作用和影响乳腺癌转移的分子机制,采用RNA干扰技术在小鼠乳腺癌细胞株4T1中沉默STAT3的表达。MTT实验结果显示STAT3沉默对4T1细胞的增殖能力没有影响;细胞迁移实验结果表明STAT3表达被沉默后4T1细胞的迁移能力明显被抑制;定量PCR结果显示,STAT3基因沉默后4T1细胞中VEGF和IL-6的mRNA水平下降,E-cadherin表达上升,mosin表达下降;信号通路检测显示STAT3基因表达沉默后MAPK的活化明显降低。研究表明STAT3在小鼠乳腺癌细胞的迁移过程中发挥重要作用,为以STAT3基因为靶向的治疗提供了一定的实验依据。