RAB14 activates MAPK signaling to promote bladder tumorigenesis
RAB14 activates MAPK signaling to promote bladder tumorigenesis
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RAB14激活MAPK信号促进膀胱肿瘤发生
DOI：
10.1093/carcin/bgz039
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发表时间：
2019-11-01
期刊：
影响因子：
4.7
通讯作者：
Zeng, Tao
中科院分区：
文献类型：
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作者：
Chao, Haichao;Deng, Leihong;Zeng, Tao
膀胱癌（BC）是一种致命的侵袭性恶性肿瘤，约占人类所有癌症死亡的5%;然而，BC患者的潜在分子机制和潜在靶向治疗仍不清楚。我们在此报告，RAB 14在具有高转移潜能的BC组织和细胞中过表达，并且其丰度与BC患者的淋巴结转移（P = 0.001）、高级别肿瘤分期（P = 0.009）、低分化（P < 0.001）和不利的预后（P = 0.003，log-rank检验）显著相关。RAB 14的干预可降低TWIST 1蛋白的表达，抑制细胞的迁移和侵袭（P < 0.05）。此外，沉默RAB 14在体外减少细胞增殖并诱导细胞凋亡，并在小鼠异种移植模型中抑制肿瘤发生。我们证明，RAB 14促进的BC癌的发生和进展与丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶信号的激活有关，通过上调MAPK 1/MAPK 8和下调双特异性蛋白磷酸酶6/Src同源2结构域包含的转化蛋白/Fos原癌基因，AP-1转录因子亚基（FOS）。我们提供的证据表明，RAB 14作为一种肿瘤促进剂，并通过激活MAPK途径调节BC细胞的侵袭和转移潜力。
Bladder cancer (BC) is a fatal invasive malignancy accounting for approximately 5% of all cancer deaths in humans; however, the underlying molecular mechanisms and potential targeted therapeutics for BC patients remain unclear. We report herein that RAB14 was overexpressed in BC tissues and cells with high metastatic potential and its abundance was significantly associated with lymph node metastasis (P = 0.001), a high-grade tumor stage (P = 0.009), poor differentiation (P < 0.001) and unfavorable prognoses of BC patients (P = 0.003, log-rank test). Interference by RAB14 mediated a reduction in the TWIST1 protein and inhibited cell migration and invasion (P < 0.05). Moreover, silencing RAB14 reduced cell proliferation and induced apoptosis in vitro and suppressed tumorigenesis in a mouse xenograft model. We demonstrated that RAB14-promoted BC cancer development and progression were associated with activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase signaling through upregulation of MAPK1/MAPK8 and downregulation of dual-specificity protein phosphatase 6/Src homology 2 domain containing transforming protein/Fos proto-oncogene, AP-1 transcription factor subunit (FOS). We provide evidence that RAB14 acts as a tumor promoter and modulates the invasion and metastatic potential of BC cells via activating the MAPK pathway.