STIM1 overexpression in hypoxia microenvironment contributes to pancreatic carcinoma progression

Abstract

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 ( r s = 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.

Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

“…The authors usually used immunohistochemical staining on large cohorts and Kaplan-Meier survival analysis, to observe a correlation between high channel expression and short patient survival. This is the case for KCa3.1 (Jiang et al, 2017), STIM1 (Wang et al, 2019), TRPM8 (Liu et al, 2018), TRPV6 (Song et al, 2018), TMEM16J (Jun et al, 2017), CLIC1 (Lu et al, 2015;Jia et al, 2016), and AQP1/AQP3 (Zou et al, 2019). The same correlation was obtained on gene expression using qPCR for TRPM8 (Du et al, 2018) or TCGA for TRPM2 (Lin et al, 2018) and TMEM16A (Crottes et al, 2019).…”

“…Even though, Ecadherin levels have shown to be upregulated, in contrary to what is usually seen in cells undergoing EMT where E-cadherin decrease in favor of N-cadherin (Gheldof and Berx, 2013). Furthermore, tissue microarray analysis showed that the STIM1 expression positively correlated with HIF-1a (Wang et al, 2019). It was further shown that similar protein expression levels of STIM1 and HIF-1a were expressed in different PDAC cell lines.…”

“…The co-upregulation of both proteins and the downregulation of STIM1 upon knockdown of HIF-1a indicate that STIM1 is regulated by HIF-1a on the transcriptional level. STIM1 promoter activity was tested in PANC-1 cells upon normoxia or hypoxia, where HIF-1a binding sites, under hypoxic conditions reduced STIM1 promoter activity (Wang et al, 2019). These results indicate that HIF-1a probably regulates STIM1 transcription and that STIM1 overexpression, in a hypoxic environment, can promote PDAC progression and invasion (Wang et al, 2019).…”

“…Different studies have investigated ion channels as potential biomarkers of PDAC development and progression. Using immunohistochemical analysis, high KCa3.1 expression in PDAC tissue was correlated with TNM stages III and IV (Jiang et al, 2017), and high expression of STIM1 was correlated with tumor grade (Wang et al, 2019). Upregulation of Kv11.1 expression was associated with advanced tumor grade and high expression of Ki67 proliferative marker (Lastraioli et al, 2015b), whereas TRPV6, TRPM8 and AQP1/AQP3 channels were positively correlated with tumor stages III and IV and large tumor size (Yee et al, 2014;Du et al, 2018;Liu et al, 2018;Song et al, 2018;Zou et al, 2019).…”

“…A recent study has been investigating the role of STIM1 in PDAC progression (Wang et al, 2019). shRNA knockdown of STIM1 showed decreased proliferation, invasion, and upregulation of E-cadherin protein levels and downregulation of vimentin levels, suggesting that STIM1 is involved in carcinogenesis of PDAC and in some way involved in Epithelial-Mesenchymal transition (EMT).…”