Fibroblast growth factor 11 (FGF11) promotes non-small cell lung cancer (NSCLC) progression by regulating hypoxia signaling pathway

Abstract

Background Accumulating evidence highlights the critical roles of fibroblast growth factors (FGFs) in regulating the progression of multiple human cancers, including non-small cell lung cancer (NSCLC). In this study, we investigated the role of FGF11 in the progression of NSCLC. Methods Previously published transcriptomic data (GSE75037 and GSE81089) were used to compare FGF11 expression level between NSCLC tumor tissues and adjacent normal tissues. 100 cases of NSCLC tumor tissues and 30 cases of matched adjacent normal tissues were used to validate FGF11 expression at mRNA and protein level by qPCR and immunohistochemistry. Bioinformatics analysis and dual luciferase reporter analysis were performed to confirm the regulatory effect of miR-525-5p on FGF11 expression. CCK-8 assay and transwell migration assay were employed to examine cellular proliferation, migration and invasion. Gene set enrichment analysis (GSEA) was performed to identify the signaling pathway associated with FGF11 expression. Finally, the functional role of FGF11 in NSCLC tumor growth was evaluated by in vivo study. Results FGF11 was upregulated in NSCLC tumor tissues and tumor cell lines. High FGF11 expression was associated with a poor prognosis in NSCLC patients. In vitro loss- and gain-of function experiments demonstrated that FGF11 knockdown inhibited, whereas FGF11 overexpression promoted the proliferation, migration and invasion of NSCLC cells. Dual luciferase reporter assay confirmed that FGF11 was downregulated by miR-525-5p, and the effect of FGF11 on cell proliferation, migration and invasion could be interfered by miR-525-5p. GSEA analysis further revealed that FGF11 expression was enriched with genes in hypoxia signaling pathway and the oncogenic function of FGF11 could be suppressed by knocking down HIF-1α in NSCLC cells. Moreover, FGF11 knockdown suppressed NSCLC tumor growth whereas FGF11 overexpression promoted tumor growth in vivo. Conclusions Our study showed that FGF11 functions as an oncogene in tumor NSCLC progression. miR-525-5p seems to negatively regulate FGF11 and the oncogenic role of FGF11 is dependent on the upregulation of HIF-1α. Our study suggests that targeting FGF11 and HIF-1α may serve as novel strategies for the treatment of NSCLC.

Integrated spatial analysis of gene mutation and gene expression for understanding tumor diversity in formalin-fixed paraffin-embedded lung adenocarcinoma

“…In the pre-and post-treatment tumors, the marker of cells considered the origin of adenocarcinomas, such as AT2 composing the alveolar space and Clara cells composing the bronchioles ( 40 ), were highly expressed. Cancer-associated fibroblast (CAF) markers in cancer growth and invasion ( 41 ) were highly expressed in tumor stroma. Conversely, myofibroblast markers ( 42 ), fibroblast activated and differentiated during wound healing, involved in tissue repair in collaboration with other stroma, and mast cell markers were highly expressed in the remission stroma.…”

Apelin Promotes Endothelial Progenitor Cell Angiogenesis in Rheumatoid Arthritis Disease via the miR-525-5p/Angiopoietin-1 Pathway

“…Numerous miRNAs also control angiogenesis during RA progression ( 49 ). MiR-525-5p has been implicated in multiple cancers, including for instance glioma ( 50 ), cervical cancer ( 51 ) and NSCLC ( 52 ), but no evidence to date has indicated the involvement of miR-525-5p with RA progression. In this study, stimulation of RASFs with APLN inhibited miR-525-5p expression and transfecting them with miR-525-5p mimic antagonized APLN-promoted upregulation of Ang1 expression and EPC angiogenesis.…”

Hypoxia signaling in human health and diseases: implications and prospects for therapeutics

“…270 Wu et al found that fibroblast growth factor 11 (FGF11) is upregulated in NSCLC tumor tissues and cell lines, and high expression of FGF11 is related to a poor prognostic outcome in NSCLC patients. 271 miR-525-5p negatively regulates FGF11 while FGF11 promotes the expression of HIF-1α for NSCLC progression. 271 On the other hand, T-lymphokine-activated killer celloriginated protein kinase (TOPK) positively regulates HIF-1α expression and promotes Snail expression, leading to EMT and invasion of NSCLC.…”

“…271 miR-525-5p negatively regulates FGF11 while FGF11 promotes the expression of HIF-1α for NSCLC progression. 271 On the other hand, T-lymphokine-activated killer celloriginated protein kinase (TOPK) positively regulates HIF-1α expression and promotes Snail expression, leading to EMT and invasion of NSCLC. 272 In response to hypoxia, elevated lncRNA-AC020978 accelerates proliferation and the glycolytic metabolism of NSCLC by regulating PKM2-enhanced HIF-1α transactivation activity.…”