Abstract. At present, one of the major problems of cancer therapy is drug resistance. Breast cancer resistance protein (BCRP), a marker of the multidrug-resistant phenotype, affects drug absorption, distribution, metabolism, and excretion in normal tissues. Meanwhile, extracellular vesicles (EVs) have attracted increasing attention as a medium of cell-to-cell communication. However, the association between BCRP and circulating EVs remains unclear. The present study demonstrated that patients who did not respond or had progressive/ stable disease following chemotherapy had markedly higher BCRP levels compared to those that did not receive chemotherapy. Moreover, BCRP was upregulated at the mRNA and protein levels in tumor-derived circulating EVs from patients with a poor response to chemotherapy. Interestingly, the results also demonstrated that BCRP was co-expressed with MUC1, which is frequently expressed in breast cancer and is exported via EVs, and both BCRP and MUC1 were up-regulated after chemotherapy. In conclusion, the present study indicates that tumor-derived circulating EVs that carry BCRP may serve as a predictive biomarker of the response to chemotherapy for breast cancer. In addition, the results provide a window for individualized treatment to overcome resistance to chemotherapeutic drugs.

Neural invasion (NI) is a vital pathological characteristic of gastric cancer (GC), which correlates with tumor recurrence and a worse prognosis. Long noncoding RNAs (lncRNAs) play critical roles in various biological processes. However, the involvement of lncRNAs in NI of GC (GC-NI) remains unclear. DIAPH2-AS1 was upregulated in NI-positive GC tissues, which was confirmed by qRT-PCR. The higher expression of DIAPH2-AS1 predicted NI and worse survival for GC patients. Both in vitro and in vivo experiments, including wound-healing assay, Transwell assay, DRG-GC cells co-culture model, the mouse sciatic nerve model, and the lung metastasis model, indicated that DIAPH2-AS1 promoted the migration, invasion, and NI potential of GC cells. Mechanistically, pulldown assay and RNA immunoprecipitation assay revealed that DIAPH2-AS1 interacted with NSUN2. Subsequent experiments indicated that DIAPH2-AS1 stabilized NSUN2 from ubiquitin-proteasomal degradation via masking the K577 and K579 of NSUN2. The protection of DIAPH2-AS1 on NSUN2 improved the stability of NTN1 mRNA via m5C modification, which finally induced GC-NI. Our work uncovered DIAPH2-AS1 as a novel oncogenic lncRNA in GC-NI and validated the DIAPH2-AS1-NSUN2-NTN1 axis as a potential therapeutic target for NI-positive GC.