LINC01189-miR-586-ZEB1 feedback loop regulates breast cancer progression through Wnt/β-catenin signaling pathway.
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ABSTRACT:
SUBMITTER: Zhang D
PROVIDER: S-EPMC8408558 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
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Project description:BACKGROUNDAberrant activation of Wnt/?-catenin signaling pathway is considered to be an important issue in progression and metastasis of various human cancers, especially in colorectal cancer (CRC). MiR-452 could activate of Wnt/?-catenin signaling. But the mechanism remains unclear.METHODSThe expression of miR-452 in CRC and normal tissues was detected by real-time quantitative PCR. The effect of miR-452 on CRC growth and invasion was conducted by functional experiments in vitro and in vivo. Bioinformatics and cell luciferase function studies verified the direct regulation of miR-452 on the 3'-UTR of the GSK3?, which leads to the activation of Wnt/?-catenin signaling.RESULTSMiR-452 was upregulated in CRC compared with normal tissues and was correlated with clinical significance. The luciferase reporter system studies affirmed the direct regulation of miR-452 on the 3'-UTR of the GSK3?, which activate the Wnt/?-catenin signaling. The ectopic upregulation of miR-452 significantly inhibited the expression of GSK3? and enhanced CRC proliferation and invasion in vitro and in vivo. Meanwhile, knockdown of miR-452 significantly recovered the expression of GSK3? and attenuated Wnt/?-catenin-mediated cell metastasis and proliferation. More important, T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors, which are crucial downstream molecules of the Wnt/?-catenin signaling pathway was verified as a valid transcription factor of miR-452's promoter.CONCLUSIONSOur findings first demonstrate that miR-452-GSK3?-LEF1/TCF4 positive feedback loop induce CRC proliferation and migration.
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