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

Abstract

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 resistanceassociated 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.

Molecular Classification of Breast Cancer Utilizing Long Non-Coding RNA (lncRNA) Transcriptomes Identifies Novel Diagnostic lncRNA Panel for Triple-Negative Breast Cancer

“…Studies found that LINC00511 acted as a competing endogenous RNA (ceRNA) with NFIA (Nuclear Factor I A) to bind with miR-29c-3p, revealing the LINC00511/miR-29c-3p/NFIA axis as potential therapeutic targets for CRC treatment [ 33 , 34 ]. In a study on temozolomide (TMZ), the first-line chemotherapy drug for glioblastoma (GBM), LINC00511 expression upregulation correlated with the poor prognosis of GBM patients and LINC00511 silencing impaired the tolerance of TMZ, while its overexpression increased the TMZ resistance of sensitive GBM cells [ 35 ]. In addition to this, the silencing of LINC00511 expression suppressed cell viability, proliferation, migration, and invasion, and accelerated the apoptosis of glioma cells via a suggested miR-15a-5p/AEBP1 axis [ 36 ].…”

Systematic characterization and biological functions of non‐coding RNAs in glioblastoma

“…It has also been found that LINC00511 expression is increased in temozolomide‐resistant GBM cells compared with that of parental cells and is associated with a low OS rate in patients with GBM. The resistance mechanism is that LINC00511 sponges miR‐126‐5p and activates the Wnt/β‐catenin signalling pathway 98 . RNA methylation modification (m6A) is the most usual modification in eukaryotic mRNAs 99 .…”

Regulation of temozolomide resistance via lncRNAs: Clinical and biological properties of lncRNAs in gliomas (Review)

“…A literature search revealed various lncRNAs affecting TMZ resistance in glioma, as well as their functions and targets ( 62 - 82 ). This list of lncRNAs is presented in Table I .…”

“…The silencing of lncRNA miR-155 host gene (MIR155HG) expression was previously reported to promote glioma sensitivity to TMZ through the Wnt/β catenin pathway by inhibiting poly-pyrimidine tract-binding protein 1 expression ( 64 ). Furthermore, the knockdown of LINC00511 expression enhanced the sensitivity of U87-R glioma cells to TMZ by targeting miR-126-5p and activating Wnt/β-catenin signaling ( 82 ). It has also been previously reported that EGFR signaling plays a key role in GBM ( 85 ), by regulating lncRNA nuclear enriched abundant transcript 1 (NEAT1) expression and in turn promoting glioma cell growth by targeting the Wnt/β-catenin pathway.…”