IL-37/STAT3/HIF-1α negative feedback signaling drives gemcitabine resistance in pancreatic cancer
IL-37/STAT3/HIF-1α negative feedback signaling drives gemcitabine resistance in pancreatic cancer
复制标题
IL-37/ STAT3/ HIF-1α 负反馈信号驱动胰腺癌吉西他滨耐药
DOI：
10.7150/thno.42416
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Hao, Jihui
中科院分区：
文献类型：
--
作者：
Zhao, Tiansuo;Jin, Fanjie;Hao, Jihui
人白细胞介素（IL）-37是IL-1家族的成员，具有有效的抗炎和免疫抑制特性。此前，已经报道IL-37抑制肿瘤生长和进展。方法：采用免疫组化方法检测胰腺导管腺癌（PDAC）组织中IL-37的表达，分析其与临床病理特征的关系。采用Western-blot和RT-PCR检测IL-37与缺氧诱导因子（HIF）-1 α的相关性。我们进行了染色质免疫沉淀和荧光素酶测定来验证HIF-1 α对IL-37表达的抑制。此外，在体外和体内的增益和功能丧失的研究被用来证明IL-37对PDAC的发展和chemicalresistance.Results的生物学功能：我们的研究结果表明，IL-37的表达显着降低PDAC组织相比，相邻的正常胰腺组织。PDAC中IL-37表达减少与PDAC组织学分级、肿瘤大小、淋巴结转移和血管浸润增加相关。IL-37低水平患者的无复发生存期和总生存期也显著缩短。重要的是，IL-37表达与吉西他滨疗效呈正相关。HIF-1 α通过与IL-37启动子中的缺氧反应元件（HRE）结合而减弱IL-37的转录。相反，IL-37通过抑制STAT 3抑制HIF-1 α表达。在功能上，PDAC细胞中IL-37的下调促进了体内和体外的化疗抗性、迁移和进展。结论：总的来说，我们的数据揭示了IL-37/STAT 3/HIF-1 α负反馈信号驱动PDAC中的吉西他滨抗性。
Human interleukin (IL)-37 is a member of the IL-1 family with potent anti-inflammatory and immunosuppressive properties. Previously, it has been reported that IL-37 suppresses tumor growth and progression. However, the roles of IL-37 in pancreatic cancer development and chemo-resistance remain unknown.Methods: Immunohistochemistry was used to analyze the correlation between IL-37 expression and clinicopathological features of pancreatic ductal adenocarcinoma (PDAC). Western-blot and RT-PCR was used to verify the correlation between IL-37 and hypoxia-inducible factor (HIF)-1 alpha. We performed chromatin immunoprecipitation and luciferase assays to validate HIF-1 alpha suppression of IL-37 expression. Moreover, gain- and loss-of-function studies in vitro and in vivo were used to demonstrate the biological function of IL-37 on PDAC development and chemo-resistance.Results: Our results showed that IL-37 expression was remarkably decreased in PDAC tissues when compared to adjacent normal pancreatic tissues. Reduced IL-37 expression in PDACs was associated with increased PDAC histological grade, tumor size, lymph node metastasis and vessel invasion. IL-37 low patients also have remarkably shorter relapse-free and overall survival. Importantly, IL-37 expression was positively correlated with Gemcitabine efficacy. Mechanistically, HIF-1 alpha attenuated IL-37 transcription by binding to the hypoxia response elements (HREs) in IL-37 promoter. Conversely, IL-37 suppressed HIF-1 alpha expression through STAT3 inhibition. Functionally, downregulation of IL-37 in PDAC cells promoted chemo-resistance, migration and progression in vivo and in vitro.Conclusions: Collectively, our data uncovered IL-37/STAT3/HIF-1 alpha negative feedback signaling drives Gemcitabine resistance in PDAC.