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Hypoxia-induced CXC chemokine ligand 14 expression drives protumorigenic effects through activation of insulin-like growth factor-1 receptor signaling in glioblastoma
Cancer Science ( IF 5.7 ) Pub Date : 2022-09-15 , DOI: 10.1111/cas.15587
Sung-Tai Wei, Jung-Ying Chiang, Hwai-Lee Wang, Fu-Ju Lei, Yen-Chih Huang, Chi-Chung Wang, Der-Yang Cho, Chia-Hung Hsieh

Hypoxic tumor microenvironment (HTM) promotes a more aggressive and malignant state in glioblastoma. However, little is known about the role and mechanism of CXC chemokine ligand 14 (CXCL14) in HTM-mediated glioblastoma progression. In this study, we report that CXCL14 expression correlated with poor outcomes, tumor grade, and hypoxia-inducible factor (HIF) expression in patients with glioblastoma. CXCL14 was upregulated in tumor cells within the hypoxic areas of glioblastoma. Hypoxia induced HIF-dependent expression of CXCL14, which promoted glioblastoma tumorigenicity and invasiveness in vitro and in vivo. Moreover, CXCL14 gain-of-function in glioblastoma cells activated insulin-like growth factor-1 receptor (IGF-1R) signal transduction to regulate the growth, invasiveness, and neurosphere formation of glioblastoma. Finally, systemic delivery of CXCL14 siRNA nanoparticles (NPs) with polysorbate 80 coating significantly suppressed tumor growth in vivo and extended the survival time in patient-derived glioblastoma xenografts. Together, these findings suggest that HIF-dependent CXCL14 expression contributes to HTM-promoted glioblastoma tumorigenicity and invasiveness through activation of the IGF-1R signaling pathway. CXCL14 siRNA NPs as an oligonucleotide drug can inhibit glioblastoma progression and constitute a translational path for the clinical treatment of glioblastoma patients.

中文翻译:

缺氧诱导的 CXC 趋化因子配体 14 表达通过激活胶质母细胞瘤中的胰岛素样生长因子-1 受体信号来驱动致癌作用

缺氧肿瘤微环境 (HTM) 促进胶质母细胞瘤更具侵袭性和恶性状态。然而,关于 CXC 趋化因子配体 14 (CXCL14) 在 HTM 介导的胶质母细胞瘤进展中的作用和机制知之甚少。在这项研究中,我们报告了 CXCL14 表达与胶质母细胞瘤患者的不良预后、肿瘤分级和缺氧诱导因子 (HIF) 表达相关。CXCL14 在胶质母细胞瘤缺氧区域内的肿瘤细胞中上调。缺氧诱导 CXCL14 的 HIF 依赖性表达,从而促进胶质母细胞瘤在体外和体内的致瘤性和侵袭性。此外,CXCL14 在胶质母细胞瘤细胞中的功能获得可激活胰岛素样生长因子-1 受体 (IGF-1R) 信号转导,从而调节胶质母细胞瘤的生长、侵袭性和神经球形成。最后,全身递送具有聚山梨醇酯 80 涂层的 CXCL14 siRNA 纳米颗粒 (NPs) 可显着抑制体内肿瘤生长并延长患者来源的胶质母细胞瘤异种移植物的存活时间。总之,这些发现表明 HIF 依赖性 CXCL14 表达通过激活 IGF-1R 信号通路促进 HTM 促进胶质母细胞瘤的致瘤性和侵袭性。CXCL14 siRNA NPs作为一种寡核苷酸药物可以抑制胶质母细胞瘤的进展,并构成胶质母细胞瘤患者临床治疗的转化途径。这些发现表明,HIF 依赖性 CXCL14 表达通过激活 IGF-1R 信号通路促进 HTM 促进的胶质母细胞瘤致瘤性和侵袭性。CXCL14 siRNA NPs作为一种寡核苷酸药物可以抑制胶质母细胞瘤的进展,并构成胶质母细胞瘤患者临床治疗的转化途径。这些发现表明,HIF 依赖性 CXCL14 表达通过激活 IGF-1R 信号通路促进 HTM 促进的胶质母细胞瘤致瘤性和侵袭性。CXCL14 siRNA NPs作为一种寡核苷酸药物可以抑制胶质母细胞瘤的进展,并构成胶质母细胞瘤患者临床治疗的转化途径。
更新日期:2022-09-15
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