Hypoxia induced ferritin light chain (FTL) promoted epithelia mesenchymal transition and chemoresistance of glioma

Abstract

Background Hypoxia, a fundamental characteristic of glioma, is considered to promote tumor malignancy by inducing process of epithelial mesenchymal transition (EMT). Ferritin Light Chain (FTL) is one of the iron metabolism regulators and is overexpressed in glioma. However, relationship between hypoxia and FTL expression and its role in regulating EMT remains unclear. Methods Immunohistochemistry (IHC), western blot and public datasets were used to evaluate FTL level in glioma. Wound healing, transwell assays, CCK8, annexin V staining assay were used to measure migration, invasion, proliferation and apoptosis of glioma cells in vitro. Interaction between HIF1A and FTL was assessed by luciferase reporter and Chromatin immunoprecipitation (ChIP) assays. Subcutaneous xenograft model was established to investigate in vivo growth. Results FTL expression was enriched in high grade glioma (HGG) and its expression significantly associated with IDH1/2 wildtype and unfavorable prognosis of glioma patients. FTL expression positively correlated with HIF1A in glioma tissues and obviously increased in U87 and U251 cells under hypoxia in a time-dependent manner. Mechanistically, HIF-1α regulates FTL expression by directly binding to HRE-3 in FTL promoter region. Furthermore, we found that knockdown FTL dramatically repressed EMT and reduced migration and invasion of glioma by regulating AKT/GSK3β/ β-catenin signaling both in vitro and in vivo. Moreover, our study found downregulation FTL decreased the survival rate and increased the apoptosis of glioma cells treated with temozolomide (TMZ). FTL expression segregated glioma patients who were treated with TMZ or with high MGMT promoter methylation into survival groups in TCGA dataset. Patients with methylated MGMT who had high FTL expression presented similar prognosis with patients with unmethylated MGMT. Conclusion Our study strongly suggested that hypoxia-inducible FTL was a regulator of EMT and acted not only as a prognostic marker but also a novel biomarker of response to TMZ in glioma.

Comprehensive analysis of ferritin subunits expression and positive correlations with tumor-associated macrophages and T regulatory cells infiltration in most solid tumors

“…Ferritin, the most important iron storage form in humans, is an essential nutrient that plays crucial roles in diverse cellular physiopathological processes, including regulation of the tumor microenvironment and immunometabolism [ 1 , 2 ]. Ferritin is composed of two subunits: a light chain (FTL, 19 kDa) and a heavy chain (FTH, 21 kDa) [ 3 ]. We previously showed that FTH1 and FTL have positive linear correlation and the protein expression levels of both were higher in head and neck squamous cell carcinoma (HNSC) tumor tissues compared with normal tissues, and that elevated FTH1 was related to poorer prognosis [ 4 ].…”

Hypoxia-Induced miR-137 Inhibition Increased Glioblastoma Multiforme Growth and Chemoresistance Through LRP6

“…Correlation analysis of clinical samples shown that miR-137 was positively correlated with E-cadherin, and contrary to Vimentin, indicating that miR-137 may promote TMZ sensitivity by affecting EMT-related factors. Accumulating evidence showed that Wnt/bcatenin pathway played crucial role in regulating EMT (35)(36)(37). Wnt/b-catenin pathway involves the stabilization of b-catenin through the binding of Wnt ligand to cell surface receptors such as LRP6.…”

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

“…It is well documented that hypoxic tumors have a poor vascularization that limits drug bioavailability [ 91 ]. In addition, the low O 2 tension reduces the possibility of inducing oxidative stress that is often a mechanism of killing exerted by chemotherapeutic drugs [ 36 ], such as cisplatin [ 92 ], doxorubicin, etoposide [ 93 ], gemcitabine [ 94 ]. Moreover, by creating an unfavorable environment, hypoxia selects aggressive and metastatic clones, as well as clones rich of anti-apoptotic proteins such as IAP3 and Bcl-2: this selection is independent on HIF-1ɑ activation [ 95 ], but it contributes to counteract the apoptosis induced by anti-cancer agents.…”

“…Finally, HIF-1α increases resistance to chemotherapy by promoting EMT [ 36 ], which induces cell proliferation and migration, as demontstrated by the down-regulation of E-cadherin and the up-regulation of vimentin in hypoxic PC cells. Propofol, recently identified as a HIF-1α inhibitor, not only reduces EMT but also sensitizes cells to docetaxel [ 146 ].…”

“…Both HIF-1ɑ and HIF-2ɑ promote a more invasive phenotype [33], by activating the epithelial-mesenchymal transition (EMT) program [34][35][36] or cooperating with other strong pro-invasive factors such as Met receptor and soluble hepatocyte growth factor (HGF) [37], or VEGF receptor (VEGFR)/VEGF [38]. Notably, in triple negative breast cancer (TNBC) HIF-1ɑ stimulates the relase of the typical pro-inflammatory cytokine IL-1β that induces a metastatic attitude in both tumor cells and cancer associated fibroblasts (CAFs), creating a TME that strongly favors metastatization [39].…”