STIM1 overexpression in hypoxia microenvironment contributes to pancreatic carcinoma progression
STIM1 overexpression in hypoxia microenvironment contributes to pancreatic carcinoma progression
复制标题
缺氧微环境中 STIM1 过度表达有助于胰腺癌进展
DOI：
10.20892/j.issn.2095-3941.2018.0304
复制
发表时间：
2019-02-01
影响因子：
5.5
通讯作者：
Sun, Jianwei
中科院分区：
文献类型：
--
作者：
Wang, Jian;Shen, Junling;Sun, Jianwei
据报道，基质相互作用分子1 （STIM1）过表达在多种癌症的进展中起重要作用。然而，胰腺导管腺癌（pancreatic ductal adencarcinoma， PDAC）中STIM1过表达的机制及其与缺氧的关系尚不清楚。方法采用免疫组化方法检测STIM1和HIF-1α在包括胰腺癌和匹配的正常胰腺组织中的表达，并统计分析其与临床病理参数的关系。采用q-PCR、Western blot、ChIP和荧光素酶法分析胰腺癌PANC-1细胞中HIF-1α和STIM1的转录调控。结果与正常组织相比，STIM1和HIF-1α在癌组织中阳性率和表达量均升高（P < 0.05）。Kaplan-Meier法显示HIF-1α和STIM1表达水平升高与无病生存率降低显著相关（P = 0.025和P = 0.029）。HIF-1α与STIM1在肿瘤组织和胰腺癌细胞系中的表达呈显著正相关（rs = 0.3343, P = 0.0011）。此外，ChIP和荧光素酶检测证实HIF-1α与STIM1启动子结合并调节其在PANC-1细胞中的表达。结论缺氧微环境下，HIF-1α介导的STIM1表达上调可促进PDAC的进展。HIF-1α和STIM1是PDAC治疗的潜在预后标志物和/或治疗靶点。
Objective Stromal interaction molecule 1 (STIM1) overexpression has been reported to play an important role in progression of several cancers. However, the mechanism of STIM1 overexpression and its relationship with hypoxia in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Methods STIM1 and HIF-1α expression was tested using immunohistochemistry in tissue microarray (TMA) including pancreatic cancer and matched normal pancreatic tissues, and their relationships with clinicopathological parameters were statistically analyzed. q-PCR, Western blot, ChIP, and luciferase assay were employed to 030 analyze transcriptional regulation between HIF-1α and STIM1 in pancreatic cancer PANC-1 cells. Results Both STIM1 and HIF-1α showed higher positive rates and up-regulated expression in cancer tissues compared to that of normal tissues (P < 0.05). The Kaplan–Meier method revealed that higher HIF-1α and STIM1 expression levels were significantly correlated with decreased disease-free survival ( P = 0.025 and P = 0.029, respectively). The expression of HIF-1α showed a significant positive correlation with that of STIM1 in cancer tissues (rs = 0.3343, P = 0.0011) and pancreatic cancer cell lines. Furthermore, ChIP and luciferase assays confirmed that HIF-1α bound to the STIM1 promoter and regulated its expression in PANC-1 cells. Conclusions In hypoxia microenvironment, up-regulated expression of STIM1 mediated by HIF-1α promotes PDAC progression. HIF-1α and STIM1 are potential prognostic markers and/or therapeutic targets for PDAC treatment.