Background Abnormal DNA methylation of tumor suppressor gene promoter has been found in breast cancer. Therefore, the current study set out to explore how DNA methyltransferase 1 (DNMT1) affects breast cancer through mediating miR-497/GPRC5A axis. Methods After loss and gain-of-function approaches were conducted in MCF-7/ADR and MCF-7 cells, cell viability, IC50 value, invasion, migration and apoptosis were measured, respectively. In addition, drug resistance, metastasis and apoptosis-related protein expression were examined using immunoblotting. ChIP and dual-luciferase reporter gene assays were carried out to validate relationship among DNMT1, miR-497, and GPRC5RA. Subcutaneous xenograft tumor model in nude mice was established to detect effects of DNMT1 on growth and metastasis of breast cancer in vivo. Results It was found that DNMT1 was notably increased, while miR-497 was poorly-expressed in breast cancer. Highly-expressed DNMT1 could promote chemotherapy resistance and metastasis of breast cancer. Meanwhile, DNMT1 modified methylation of CpG island in miR-497 promoter region, thereby repressing miR-497 level. In addition, miR-497 targeted GPRC5A expression to curb chemotherapy resistance and metastasis of breast cancer cells. Lastly, in vivo experiments showed that knockdown of DNMT1 could suppress breast cancer growth and metastasis. Conclusions Collectively, our findings indicated that DNMT1 may inhibit miR-497 and boost the expression of GPRC5A through methylation, thus augmenting breast cancer chemotherapy resistance and metastasis, which provides novel mechanistic insight into the unrecognized roles of DNMT1 in breast cancer.

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Background. Chemoresistance poses a great hindrance in the treatment of breast cancer (BC). Interestingly, exosome (Exo)-mediated transfer of long noncoding RNAs (lncRNAs) has been reported to regulate chemoresistance in diverse diseases. We herein investigate the potential role of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) transferred by BC cell-derived Exo in chemoresistance of BC cells. Methods. BC-related lncRNAs were identified. Exosomes were isolated and verified from BC cells. The expression patterns of MALAT1 were then examined in the adriamycin (ADR)-sensitive and resistant cells and the isolated Exo, followed by the analysis of the downstream microRNA (miRNA) of MALAT1. The role and mechanism of MALAT1 transmitted by BC cell-derived Exo in BC cell metastasis and chemoresistance were assessed. Results. MALAT1 was highly expressed in BC cells and their Exo. In addition, MALAT1 delivered by BC cell-derived Exo augmented the malignant properties and chemoresistance of BC cells. Mechanistically, MALAT1 bound to miR-1-3p and limited the miR-1-3p expression, which sequentially targeted the vasodilator-stimulated phosphoprotein (VASP) protein. Moreover, silencing of VASP inhibited the activation of the RAP1 member of RAS oncogene family (Rap1) signaling pathway, which led to the attenuation of BC cell malignant properties and chemoresistance. In vivo assay further validated the tumor-promoting effect of Exo-MALAT1 via regulation of the miR-1-3p/VASP/Rap1 axis. Conclusion. Collectively, MALAT1 loaded by BC cell-derived Exo can accelerate BC cell metastasis and chemoresistance via disruption of miR-1-3p-mediated inhibition of the VASP/Rap1 signaling axis.

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Background Lung squamous cell carcinoma (LUSC) is an important subtype of non-small cell lung cancer. Its special clinicopathological features and molecular background determine the limitations of its treatment. A recent study published on Science defined a newly regulatory cell death (RCD) form – cuproptosis. Which manifested as an excessive intracellular copper accumulation, mitochondrial respiration-dependent, protein acylation-mediated cell death. Different from apoptosis, pyroptosis, necroptosis, ferroptosis and other forms of regulatory cell death (RCD). The imbalance of copper homeostasis in vivo will trigger cytotoxicity and further affect the occurrence and progression of tumors. Our study is the first to predict the prognosis and immune landscape of cuproptosis-related genes (CRGs) in LUSC. Methods The RNA-seq profiles and clinical data of LUSC patients were downloaded from TCGA and GEO databases and then combined into a novel cohort. R language packages are used to analyze and process the data, and CRGs related to the prognosis of LUSC were screened according to the differentially expressed genes (DEGs). After analyzed the tumor mutation burden (TMB), copy number variation (CNV) and CRGs interaction network. Based on CRGs and DEGs, cluster analysis was used to classify LUSC patients twice. The selected key genes were used to construct a CRGs prognostic model to further analyze the correlation between LUSC immune cell infiltration and immunity. Through the risk score and clinical factors, a more accurate nomogram was further constructed. Finally, the drug sensitivity of CRGs in LUSC was analyzed. Results Patients with LUSC were divided into different cuproptosis subtypes and gene clusters, showing different levels of immune infiltration. The risk score showed that the high-risk group had higher tumor microenvironment score, lower tumor mutation load frequency and worse prognosis than the low-risk group. In addition, the high-risk group was more sensitive to vinorelbine, cisplatin, paclitaxel, doxorubicin, etoposide and other drugs. Conclusions Through bioinformatics analysis, we successfully constructed a prognostic risk assessment model based on CRGs, which can not only accurately predict the prognosis of LUSC patients, but also evaluate the patient 's immune infiltration status and sensitivity to chemotherapy drugs. This model shows satisfactory predictive results and provides a reference for subsequent tumor immunotherapy.