A positive feedback loop of lncRNA-RMRP/ZNRF3 axis and Wnt/β-catenin signaling regulates the progression and temozolomide resistance in glioma.

Drug resistance strikingly limits the therapeutic effect of temozolomide (TMZ) (a common drug for glioma). Long non-coding RNA (lncRNA) RMRP has been found to be implicated in glioma progression. However, the effect of RMRP on TMZ resistance along with related molecular mechanisms is poorly defined in glioma. In the present study, RMRP, ZNRF3, and IGF2BP3 were screened out by bioinformatics analysis. The expression levels of lncRNAs and mRNAs were measured by RT-qPCR assay. Protein levels of genes were detected by western blot and immunofluorescence assays. ZNRF3 mRNA stability was analyzed using Actinomycin D assay. Cell proliferative ability and survival rate were determined by CCK-8 assay. Cell apoptotic pattern was estimated by flow cytometry. The effect of RMRP knockdown on the growth of TMZ-treated glioma xenograft tumors was explored in vivo. The relationships of IGF2BP3, RMRP, and ZNRF3 were explored by bioinformatics prediction analysis, RNA immunoprecipitation, luciferase, and RNA pull-down, and chromatin immunoprecipitation assays. The results showed that RMRP was highly expressed in glioma. RMRP knockdown curbed cell proliferation, facilitated cell apoptosis and reduced TMZ resistance in glioma cells, and hindered the growth of TMZ-treated glioma xenograft tumors. RMRP exerted its functions by down-regulating ZNRF3 in glioma cells. IGF2BP3 interacted with RMRP and ZNRF3 mRNA. IGF2BP3 knockdown weakened the interaction of Argonaute 2 (Ago2) and ZNRF3. RMRP reduced ZNRF3 expression and mRNA stability by IGF2BP3. RMRP knockdown inhibited β-catenin expression by up-regulating ZNRF3. The inhibition of Wnt/β-catenin signaling pathway by XAV-939 weakened RMRP-mediated TMZ resistance in glioma cells. β-catenin promoted RMRP expression by TCF4 in glioma cells. In conclusion, RMRP/ZNRF3 axis and Wnt/β-catenin signaling formed a positive feedback loop to regulate TMZ resistance in glioma. The sustained activation of Wnt/β-catenin signaling by RMRP might contribute to the better management of cancers.

Liu T ，Hu J ，Han B ，Tan S ，Jia W ，Xin Y ... -  《Cell Death & Disease》

MicroRNA‑301a/ZNRF3/wnt/β‑catenin signal regulatory crosstalk mediates glioma progression.

Sun J ，Ma Q ，Shu C ，Xiong J ，Li B ，Wu J ，Zhang S ，Li J ，Liu J ，Wang J ... -  《-》

MSC-AS1 knockdown inhibits cell growth and temozolomide resistance by regulating miR-373-3p/CPEB4 axis in glioma through PI3K/Akt pathway.

Li C ，Feng S ，Chen L 《-》

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

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.

Lu Y ，Tian M ，Liu J ，Wang K ... -  《-》

RPN2 is targeted by miR-181c and mediates glioma progression and temozolomide sensitivity via the wnt/β-catenin signaling pathway.

Sun J ，Ma Q ，Li B ，Wang C ，Mo L ，Zhang X ，Tang F ，Wang Q ，Yan X ，Yao X ，Wu Q ，Shu C ，Xiong J ，Fan W ，Wang J ... -  《Cell Death & Disease》