HIF1 Contributes to Hypoxia-Induced Pancreatic Cancer Cells Invasion via Promoting QSOX1 Expression

Abstract

Background: Quiescin sulfhydryl oxidase 1 (QSOX1), which oxidizes sulfhydryl groups to form disulfide bonds in proteins, is found to be over-expressed in various pancreatic cancer cell lines and patients. QSOX1 promotes invasion of pancreatic cancer cells by activating MMP-2 and MMP-9. However, its regulatory mechanism remains largely undefined. Methods: Real-time PCR and Western blot were employed to detect the expression of QSOX1 in human pancreatic cancer cell lines under hypoxic condition. Luciferase reporter and ChIP assays were used to assess the regulation of QSOX1 by hypoxia-inducible factor 1 (HIF-1). Small interfering RNA (siRNA) was applied to knock down endogenous expression of QSOX1. Matrigel-coated invasion chamber essays were conducted to detect the invasion capacity of QSOX1-depleted cells. Results: Both hypoxia and hypoxia mimicking reagent up-regulated the expression of QSOX1 in human pancreatic cancer cell lines. Knockdown of HIF-1α eliminated hypoxia induced QSOX1 expression. HIF-1α was found directly bound to two hypoxia-response elements (HRE) of QSOX1 gene, both of which were required for HIF-1 induced QSOX1 expression. Moreover, QSOX1 silencing blocked hypoxia-induced pancreatic cancer cells invasion. Conclusion: QSOX1 is a direct target of HIF-1 and may contribute to hypoxia-induced pancreatic cancer cells invasion.

Thymus vulgaris (Thyme) Inhibits Proliferation, Adhesion, Migration, and Invasion of Human Colorectal Cancer Cells

“…42,43 As is well known, increased levels of MMP are positively and directly correlated with increased invasiveness and metastasis of different types of cancer cells, including CRCs. [44][45][46][47] Although the molecular mechanisms for the TVE-suppressed adhesion were not investigated in this study, it is possible that TVE modulates cell integrin adhesion. Integrins can be regulated at three different levels: affinity, avidity, or expression of integrins.…”

Sevoflurane suppresses hypoxia-induced growth and metastasis of lung cancer cells via inhibiting hypoxia-inducible factor-1α

“…A549 cells in the exponential growth phase were inoculated in plates, and were cultured in CO 2 for 24 h. According to the experimental protocol as described previously [12,14], cell culture plates were placed into an airtight glass chamber with inlet and outlet connectors. The inlet port of the chamber was connected to an anesthesia machine (Cicero-EM, Dräger, Germany).…”

Tumor-initiating cells of breast and prostate origin show alterations in the expression of genes related to iron metabolism

“…These changes were then subsequently confirmed on protein level in MCF7 sphere model (Figure 6B). Thus, HIF2α could be responsible for metabolic adaptations of TICs and might also be responsible for the observed upregulation of several iron metabolism-related genes such as CYBRD1 or QSOX1 [11, 12]. …”

“…QSOX1 is a HIF target gene, connected to cellular quiescence and extracellular matrix remodelling [12]. Physiological role of this enzyme includes generation of disulphide bonds accompanied by generation of hydrogen peroxide and it contains the essential for respiratory and vegetative growth (ERV) domain homologous to the yeast Erv1p that is required for maturation of the cytosolic FeS clusters [101–105].…”

“…Furthermore, there is a tight crosstalk between the hypoxic response of the cell and cellular iron metabolism as low iron levels elicit activation of the hypoxia inducible factors (HIF) encoded by the HIF1A and endothelial Per-ARNT-Sim Domain Protein 1 ( EPAS1 ) genes [10]. Activation of these genes is connected with higher iron uptake through CYBRD1 in the enterocytes [11] and in the non-physiological setting it is connected with activation of tissue remodelling factors such as quiescin sulfhydryl oxidase1 (coded by QSOX1) [12]. Other important regulators of iron metabolism represent proteins involved in iron export such as hephaestin encoded by the HEPH gene and ferroportin ecoded by the solute carrier family 40 member 1 ( SLC40A1 ) gene [13, 14].…”