Abstract
BackgroundFibroblast growth factor (FGF) and tumor growth factor-β (TGFβ) have emerged as pivotal regulators during the progression of osteosarcoma (OS). LHX9 is one crucial transcription factor controlled by FGF, however, its function in OS has not been investigated yet.MethodsThe expression of LHX9, FRS2, BMP4, TGF-beta R1, SMAD2, beta-catenin and metastasis-related proteins was measured by real-time quantitative PCR (RT-qPCR) and Western blot. CCK-8 assay and colony formation assay were employed to determine the proliferation of OS cells, while scratch wound healing assay and transwell assay were used to evaluate their migration and invasion, respectively. In vivo tumor growth and metastasis were determined by subcutaneous or intravenous injection of OS cells into nude mice.ResultsLHX9 expression was evidently up-regulated in OS tumor tissues and cell lines. Knockdown of LHX9 impaired the proliferation, migration, invasion and metastasis of OS cells. Mechanistically, LHX9 silencing led to the down-regulation of BMP-4, β-catenin and metastasis-related proteins, which was also observed in beta-catenin knockdown OS cells. By contrast, FRS2 knockdown conduced to the up-regulation of LHX9, BMP4, β-catenin and TGF-βR1, while TGF-beta inhibition repressed the expression of LHX9 and metastasis-related proteins. Additionally, let-7c modulates LHX9 and metastasis-related proteins by suppressing TGF-beta R1 expression on transcriptional level.ConclusionsThis study revealed LHX9 was essential for the proliferation, migration, invasion, and metastasis of OS cells via FGF and TGF-β/β-catenin signaling pathways.
Highlights
Fibroblast growth factor (FGF) and tumor growth factor-β (TGFβ) have emerged as pivotal regulators during the progression of osteosarcoma (OS)
OS tissues and cell lines have increased LHX9 expression To comprehensively analyze the differences of gene expression profile between normal cells and OS cells, we firstly collected OS tumor tissues and peritumor tissues from patients and performed RNA-seq analysis
To see whether other LHX family members had similar expression changes, we further conducted real-time quantitative PCR (RT-qPCR) experiment to measure the relative expression of LHX1 to LHX9 (LHX1–9) with U2OS and hFOB1.19 cells, and the data showed that the expression of LHX 1, 7, 8 was lower, whereas the expression of LHX2, 4, 5, 6, 9 was higher in OS tumor tissues, LHX3 expression had no significant change in our experiment (Additional file 1: Figure S1A)
Summary
Fibroblast growth factor (FGF) and tumor growth factor-β (TGFβ) have emerged as pivotal regulators during the progression of osteosarcoma (OS). LHX9 is one crucial transcription factor controlled by FGF, its function in OS has not been investigated yet. OS (OS) is one of the most prevalent kinds of malignant bone tumors with high incidence in children and adolescents aged between 15 and 25. Previous studies have revealed that there are nine LHX members expressed in mammalian cells, who are named by LIM 1 to 9, and they play essential roles in the development of neuron system [2]. LHX9 has been implicated in the development of brain and heart [35, 46], and the reduced LHX9 expression was associated with the migration and invasion of malignant childhood gliomas [43], its function in OS was not clear. Our lab found that the expression of LHX9 was
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