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

Publisher: BioMed Central Country of Publication: England NLM ID: 8308647 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-9966 (Electronic) Linking ISSN: 03929078 NLM ISO Abbreviation: J Exp Clin Cancer Res Subsets: MEDLINE

Publication: 2009- : London : BioMed Central
Original Publication: [Roma] : APSIT,

Drug Resistance, Neoplasm* ; Epithelial-Mesenchymal Transition*; Apoferritins/*metabolism ; Biomarkers, Tumor/*metabolism ; Glioma/*drug therapy ; Hypoxia/*physiopathology ; Temozolomide/*pharmacology; Animals ; Antineoplastic Agents, Alkylating/pharmacology ; Apoferritins/genetics ; Apoptosis ; Biomarkers, Tumor/genetics ; Cell Movement ; Cell Proliferation ; Female ; Gene Expression Regulation, Neoplastic ; Glioma/genetics ; Glioma/metabolism ; Glioma/pathology ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Middle Aged ; Prognosis ; Survival Rate ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays

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.

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No. 81572489 National Natural Science Foundation of China

Keywords: Chemoresistance; Epithelial mesenchymal transition; Ferritin light chain; Glioblastoma; Hypoxia; Prognosis

0 (Antineoplastic Agents, Alkylating)
0 (Biomarkers, Tumor)
0 (FTL protein, human)
9013-31-4 (Apoferritins)
YF1K15M17Y (Temozolomide)

Date Created: 20200718 Date Completed: 20210329 Latest Revision: 20210329

20231215

PMC7364815

10.1186/s13046-020-01641-8

32677981