LINC00511 facilitates Temozolomide resistance of glioblastoma cells via sponging miR‐126‐5p and activating Wnt/β‐catenin signaling

Jul 30, 2021Journal of biochemical and molecular toxicology

LINC00511 helps glioblastoma cells resist Temozolomide by blocking miR-126-5p and activating the Wnt/β-catenin pathway

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Abstract

LINC00511 was identified as a TMZ resistance-associated lncRNA in U87-R cells.

LINC00511 was found to be upregulated in TMZ-resistant U87-R cells and glioblastoma samples.
High levels of LINC00511 correlated with poor prognosis in glioblastoma patients.
Silencing LINC00511 reduced TMZ resistance in U87-R cells, while overexpressing it increased resistance in sensitive GBM cells.
Wnt/β-catenin signaling was activated in U87-R cells, and inhibiting this pathway increased sensitivity to TMZ.
LINC00511 is located primarily in the cytoplasm and regulates Wnt/β-catenin activation by binding to miR-126-5p.

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Temozolomide (TMZ) is the first-line chemotherapy drug for glioblastoma (GBM) but acquired TMZ resistance is frequently observed. Thus, a TMZ resistant GBM cell line U87-R was established to search for potential long noncoding RNAs (lncRNAs) used in TMZ resistance. In our study, LINC00511 was identified as a TMZ resistance-associated lncRNA in U87-R cells by transcriptome RNA sequencing. The potential functions of LINC00511 were evaluated by quantitative real-time polymerase chain reaction, cell viability assay, colony formation assay, western blot, soft agar assay, flow cytometry, tumor xenograft model, immunofluorescence, sphere formation assay, fluorescent in situ hybridization, luciferase reporter assay, and RNA pull-down assay. We found that LINC00511 was upregulated in U87-R cells and GBM samples, and correlated with poor prognosis of GBM patients. Silencing LINC00511 impaired TMZ tolerance of U87-R cells, while LINC00511 overexpression increased TMZ resistance of sensitive GBM cells. Wnt/β-catenin signaling was activated in U87-R cells, and inhibiting Wnt/β-catenin signaling enhanced TMZ sensitivity. Furthermore, LINC00511 was mainly distributed in the cytoplasm of GBM cells and regulated Wnt/β-catenin activation by acting as a molecular sponge for miR-126-5p. Multiple genes of Wnt/β-catenin signaling such as DVL3, WISP1, and WISP2 were targeted by miR-126-5p. MiR-126-5p restoration impaired TMZ resistance of GBM cells. In conclusion, our results provided a novel insight into acquired TMZ resistance of GBM cells and suggested LINC00511 as a potential biomarker or therapeutic target for GBM patients.

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LINC00511 facilitates Temozolomide resistance of glioblastoma cells via sponging miR‐126‐5p and activating Wnt/β‐catenin signaling

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