Abstract
Recent studies have reported that cancer associated fibroblasts (CAFs) and glioma stem-like cells (GSCs) played active roles in glioma progression in tumor microenvironment (TME). Long non-coding RNAs (lncRNAs) have been found to be closely associated with glioma development in recent years, however, their molecular regulatory mechanisms on CAFs in GSCs remodeled TME kept largely unelucidated. Our study found that GSCs could induce malignant transformation of fibroblasts (t-FBs) based on dual-color fluorescence tracing orthotopic model. Associated with poor prognosis, Lnc HOXA transcript antisense RNA, myeloid-specific 1 (HOTAIRM1) was highly expressed in high-grade gliomas and t-FBs. Depleting HOTAIRM1 inhibited the proliferation, invasion, migration, and even tumorigenicity of t-FB. Conversely, overexpression of HOTAIRM1 promoted malignancy phenotype of t-FB. Mechanistically, HOTAIRM1 directly bound with miR-133b-3p, and negatively regulated the latter. MiR-133b-3p partly decreased the promotion effect of HOTAIRM1 on t-FBs. Furthermore, transforming growth factor-β (TGFβ) was verified to be a direct target of miR-133b-3p. HOTAIRM1 can modulate TGFβ via competing with miR-133b-3p. Collectively, HOTAIRM1/miR-133b-3p/TGFβ axis was involved in modulating t-FBs malignancy in TME remodeled by GSCs, which had the potential to serve as a target against gliomas.
Highlights
Gliomas are the most prevalent primary intrinsic tumors in the central nervous system, and glioblastoma multiforme (GBM) accounts for nearly half of gliomas [1,2,3]
HOTAIRM1 expression in gliomas was evaluated in The Cancer Genome Atlas (TCGA) database, indicating HOTAIRM1 upregulation in gliomas compared with adjacent normal brain tissue (Figure 1A)
The role of lncHOTAIRM1 was highly associated with the pro-tumor abilities of transformed fibroblasts, including promoting proliferation, invasion, migration, and tumorigenesis on transformation of fibroblasts (t-FBs)
Summary
Gliomas are the most prevalent primary intrinsic tumors in the central nervous system, and glioblastoma multiforme (GBM) accounts for nearly half of gliomas [1,2,3]. The treatment is constantly optimized [4], GBM is regarded as one of the most malignant and aggressive cancer, which is characterized of poor prognosis and low overall survival. HOTAIRM1 Promotes Malignancy of Fibroblasts have focused on the interactions between GSCs and stromal cells in TME, which is regarded as crucial element for glioma progression recently [5]. Among the stromal cells in TME, fibroblasts are key components involved in progression and metastasis of various malignancies [6, 7]. As a significant crosstalk mediator between cancer and stroma in TME, fully exploring the roles of CAFs may help to develop new possible therapeutic approaches against gliomas [9]. The roles of fibroblasts in gliomas TME, and their interactions or crosstalk with GSCs have not been fully elucidated up to now
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