Background. miR-139-5p is lowly expressed in various human cancers and exerts its antitumor effect through different molecular mechanisms, yet the molecular mechanism of miR-139-5p in lung adenocarcinoma (LUAD) remains to be further elucidated. The study is aimed at investigating the role and the regulatory mechanism of miR-139-5p in LUAD progression. Methods. Differential analysis was performed on miRNA expression data in the TCGA-LUAD dataset. qRT-PCR was employed to detect the transcription levels of miR-139-5p and MAD2L1 in LUAD cells, while western blot was carried out for the detection of MAD2L1 protein expression. CCK-8 and Transwell assays were implemented to assess LUAD cell proliferation, migration, and invasion. A dual-luciferase reporter gene assay was conducted to verify the direct targeting relationship between miR-139-5p and MAD2L1. Results. miR-139-5p was significantly downregulated in LUAD cells in comparison with that in human normal bronchial epithelial cells. Overexpressing miR-139-5p inhibited LUAD cell proliferation, migration, and invasion, while opposite results could be observed when miR-139-5p was inhibited. MAD2L1 was identified as a direct target of miR-139-5p in LUAD. Besides, the inhibitory effect of miR-139-5p overexpression on LUAD cell proliferation, migration, and invasion was attenuated by overexpressing MAD2L1. Conclusion. Our study suggests that miR-139-5p is lowly expressed in LUAD cells and inhibits LUAD cell proliferation, migration, and invasion by targeted suppressing MAD2L1 expression. It is of potential significance for the prognosis and treatment of LUAD.

Tyrosine kinase inhibitors (TKIs) are an effective treatment strategy for non-small cell lung cancer (NSCLC) patients harboring mutations that result in constitutive activation of the epidermal growth factor receptor (EGFR). However, most patients eventually develop resistance to TKIs. This occurs due to additional EGFR mutations or the activation of bypass signaling pathways. In our previous work, we demonstrated that Marsdenia tenacissima extract (MTE) restored gefitinib sensitivity in resistant NSCLC cells with EGFR T790M or K-ras mutations. However, the potential efficacy of MTE in NSCLC cells with resistance mediated by Axl and c-Met, and the related molecular mechanisms need to be elucidated. In this study we evaluated the ability of MTE to restore erlotinib/gefitinib sensitivity in TKI resistant HCC827/ER cells and xenograft mice models. Our results demonstrate that MTE overcomes erlotinib and gefitinib resistance driven by Axl and c-Met in vitro and in vivo. Combination therapy significantly suppressed EGFR downstream molecules and the c-Met and Axl activated bypass signaling pathways. Moreover, we observed that MTE is more efficient at restoring resistance to erlotinib than gefitinib. As the Axl and c-Met mediated bypass pathways share the same downstream signaling cascade as EGFR, simultaneous targeting of these pathways is a promising strategy to overcome acquired resistance of TKIs. Our results demonstrate that MTE treatment attenuates Axl phosphorylation and the associated epithelial-mesenchymal transition, suggesting MTE treatment may be a potential therapeutic strategy for overcoming erlotinib and gefitinib cross-resistance in NSCLC, especially for erlotinib resistance.

Ovarian hyperstimulation syndrome (OHSS) is one of the most dangerous iatrogenic complications in controlled ovarian hyperstimulation (COH). The exact molecular mechanism that induces OHSS remains unclear. In recent years, accumulating evidence found that exosomal miRNAs participate in many diseases of reproductive system. However, the specific role of miRNAs, particularly the follicular fluid‐derived exosomal miRNAs in OHSS remains controversial. To identify differentially expressed follicular fluid exosomal miRNAs from OHSS and non‐OHSS patients, the analysis based on miRNA‐sequence was conducted. The levels of 291 miRNAs were significantly differed in exosomes from OHSS patients compared with normal control, and exosomal miR‐27 was one of the most significantly down‐regulated miRNAs in the OHSS group. By using MiR‐27 mimic, we found it could increase ROS stress and apoptosis by down‐regulating the expression of p‐ERK/Nrf2 pathway by negatively regulating SPRY2. These data demonstrate that exosomal miRNAs are differentially expressed in follicular fluid between patients with and without OHSS, and follicular fluid exosomal miR‐27 may involve in the pathological process of OHSS development.

Accumulating evidence suggests that exosomes can affect lung adenocarcinoma (LUAD) progression. However, there is still a lack of understanding of the global influence of exosome-related genes (ERGs) on prognostic relevance, tumor microenvironment features, and immunotherapy responsiveness in patients with LUAD. In the TCGA dataset, differential analysis of 490 LUAD samples and 59 normal samples yielded 30 ERGs with differential expression. We have created a predictive signature based on 10 overall survival (OS)-related ERGs and confirmed it in two external cohorts (GSE72094 and GSE68465) via the least absolute shrinkage and selection operator (LASSO) and Cox regression analysis in the TCGA dataset. The new signature revealed superior robustness and prognostic capacity for overall patient survival. Univariate and multivariate Cox regression analyses indicated that this signature was an independent risk factor for survival in patients with LUAD. In addition, for predicting the 1-year, 3-year, and 5-year OS of LUAD patients, we developed a nomogram and confirmed its predictive ability via the C-index and calibration curve. In addition, patients categorized by risk score exhibited distinct immunological states, stemness index, immune subtypes, and immunotherapy response. In conclusion, we created a risk signature for LUAD that was tightly associated with the immune landscape and therapeutic response. Also, such a risk signature effectively promotes the ability of the clinicians in making more precise and individualized treatment recommendations for patients with LUAD.