LncRNA CBR3-AS1 Regulates of Breast Cancer Drug Sensitivity as a Competing Endogenous RNA Through the JNK1/MEK4‑Mediated MAPK Signal Pathway

Abstract

Background: Adriamycin (ADR) resistance is one of the main obstacles to improve the clinical prognosis of breast cancer (BRCA) patients. Long non-coding RNAs (lncRNAs) can regulate cell behavior, but the role of these RNAs in anti ADR of BRCA remains unclear. Here we aim to investigate the imbalance of a particular long noncoding RNA, lncRNA CBR3 antisense RNA 1 (CBR3-AS1), and its role in ADR resistance.Methods: Microarray analysis of ADR-resistant BRCA cells was performed to identify CBR3-AS1. CCK8 assay and colony formation assay were used to detect the sensitivity of BRCA cells to ADR. Dual-luciferase reporter, RNA pull down, IHC and Western blot were used to verify the relationship between CBR3-AS1, miRNA and target genes. In vivo, the effect of CBR3-AS1 on BRCA resistance was observed by xenograft tumor model. The role of CBR3-AS1 in influencing ADR sensitivity was verified by clinical BRCA specimens, TCGA, CCLE, and GDSC databases.Results: Here, we found that lncRNA CBR3-AS1 was significantly increased in BRCA tissues and was closely correlated with poor prognosis. CBR3-AS1 overexpression promoted ADR resistance in BRCA cells in vitro and in vivo. Mechanistically, we identified that CBR3-AS1 functioned as a competitive endogenous RNA by acting as a molecular sponge of miR-25-3p. MEK4 and JNK1 of MAPK pathway were the direct downstream proteins of CBR3-AS1 / miR-25-3p axis in BRCA cells.Conclusions: In summary, our findings demonstrate that CBR3-AS1 plays a critical role in the chemotherapy resistance of BRCA by mediating the miR-25-3p, MEK4/JNK1 regulatory axis. The potential of CBR3-AS1 as an oncogene and therapeutic biomarker of BRCA was identified.

Network Pharmacology-Based Dissection of the Comprehensive Molecular Mechanisms of the Herbal Prescription FDY003 Against Estrogen Receptor-Positive Breast Cancer

“…[136][137][138][139] c-Jun N-Terminal Protein Kinase 1 (JNK1; encoded by MAPK8) regulates the survival, apoptosis, metastasis, and inflammation of ERPBC cells, and it also mediates the pharmacological effects of anticancer drugs. [140][141][142][143][144][145] Malfunction and loss-of-function polymorphisms of TP53 induce the development and progression of ERPBC, and the expression and mutation status of this gene are correlated with the survival and prognostic outcomes of BC patients. 77,[146][147][148][149][150][151][152][153][154] Vascular endothelial growth factor (VEGF)-A (encoded by VEGFA) may contribute to the metastasis, angiogenesis, growth, and drug resistance of ERPBC cells, 89,[155][156][157] and its expression level and polymorphisms may act as genetic markers for the risk, progression and recurrence, clinical outcomes for endocrine and antiangiogenic therapies, and survival of patients.…”

Multi-omics analysis identifies distinct subtypes with clinical relevance in lung adenocarcinoma harboring KEAP1/NFE2L2

“…The natural log value of the fitted half-maximal inhibitory concentration [LN(IC50)] of each drug was adopted to select caner-associated drugs which were specifically sensitive to mutant subtypes (C1 and C2). Many attempts have been made to perform in vitro pharmacogenomic response analyses based on the publicly available GDSC datasets [51][52][53]. The parameter IC50 was also adopted in previous studies [54][55][56].…”

Long Non-Coding RNAs Expression in Breast Cancer: CBR3-AS1 LncRNA as a Sensitive Biomarker

“…Ronnau et al, (2014) reported CBR3-AS1 as a potential biomarker for prostate cancer (Rönnau et al, 2014). Also, a recent study showed its activity in breast cancer drug sensitivity through MAPK Signal Pathway (Zhang et al, 2020). Although Zhang et al performed Adriamycin resistance breast cancer cells, we used fresh tissue to identify the potential lncRNA biomarker.…”

“…On the other hand, due to the role of RAB6C gene (coding a centrosomal protein) in cell division (Kubiak et al, 2020), lcnRNA RAB6C-AS1 can be considered as a possible factor in the development of various cancers. Previously, the effect of carbonyl reductase gene (CBR3-AS1) has been shown in doxorubicin disposition of breast cancer (Xie et al, 2020), but there has been limited number of studies on the role of lcnRNA CBR3-AS1 (21q.22.2) in breast cancer (Zhang et al, 2020). However, the upregulation of CBR3-AS1 lcnRNA has been identified in prostate cancer and esophageal squamous carcinoma .…”