Extracellular vesicles derived from lung cancer cells promote the progression of lung cancer by delivering miR-151a-5p.

Extracellular vesicles (EVs) participate in the occurrence and development of lung cancer. MiR-151a-5p has been reported to be highly expressed in the tumor tissues of lung cancer. The aim of this work was to investigate whether EVs can affect lung cancer progression by delivering miR-151a-5p. In this work, we found that miR-151a-5p was highly expressed in serum of lung cancer patients. Up-regulation of miR-151a-5p and down-regulation of Nedd4-binding partner-1 (N4BP1) were observed in lung cancer cell lines. The expression of miR-151a-5p was also increased in H520-derived EVs. H520-derived EVs promoted cell proliferation, inhibited apoptosis of H520 cells by delivering miR-151a-5p. EVs containing miR-151a-5p repressed E-cadherin expression and elevated N-cadherin and Vimentin expression to impede epithelial-mesenchymal transition (EMT) of H520 cells. Additionally, the interaction between miR-151a-5p and N4BP1 was verified by luciferase reporter assay, showing that miR-151a-5p interacted with N4BP1. MiR-151a-5p repressed N4BP1 expression by interacting with N4BP1. EVs containing miR-151a-5p promoted malignant phenotypes of H520 cells by targeting N4BP1. Finally, a tumor-bearing mouse model was constructed by inoculation of H520 cells with miR-151a-5p overexpression or knockdown. Overexpression of miR-151a-5p accelerated tumor growth of lung cancer in vivo, and repressed N4BP1 expression in the tumor tissues. Knockdown of miR-151a-5p caused opposite results. In conclusion, this work demonstrated that lung cancer cell-derived EVs secreted miR-151a-5p to promote cell proliferation, and inhibit apoptosis and EMT of lung cancer cells by targeting N4BP1, thereby accelerating lung cancer progression. Thus, this study suggests that EVs-derived miR-151a-5p may be a potential target for lung cancer treatment.

Silencing of UAP1L1 inhibits proliferation and induces apoptosis in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is recognized as one of the malignant tumors with poor prognosis. UAP1L1 (UDP-N-acetylglucosamine-1-like-1) affects numerous biological processes, which is a key regulator of the development of malignant tumors. The biological function and molecular mechanism of UAP1L1 in ESCC were explored in this study. The relationship between UAP1L1 and ESCC was analyzed by immunohistochemical staining, revealing the high expression of UAP1L1 in ESCC. Importantly, the increased expression of UAP1L1 indicated the deterioration of patients' condition, which has clinical significance. Furthermore, the loss-of-function assays demonstrated that knockdown of UAP1L1 inhibited the progression of ESCC on suppressing proliferation, hindering migration, and enhancing apoptosis in vitro. Moreover, the apoptosis of ESCC cells was induced by knockdown of UAP1L1 via regulating a variety of apoptosis-related proteins, such as upregulation of Bax, CD40, CD40L, Fas, FasL, IGFBP-6, p21, p27, p53, and SMAC. Additionally, further investigation indicated that UAP1L1 by affecting the PI3K/Akt, CCND1, and MAPK promotes the progression of ESCC. In vivo xenograft model further confirmed that knockdown of UAP1L1 inhibited the development of ESCC. In conclusion, UAP1L1 was involved in the development and progression of ESCC, which may provide a powerful target for future molecular therapies.

Low pretherapeutic serum albumin as a risk factor for poor outcome in esophageal squamous cell carcinomas.

The number of esophageal cancer patients is increasing worldwide and lots of patients suffer from malnutrition and hypoalbuminemic. Serum albumin is a widely acceptable method of assessing nutritional and inflammation status in cancer patients. But whether serum albumin has prognostic value with regard to short-term and long-term outcomes in patients who undergo esophagectomy for cancer is still unclear. We therefore investigated the prognostic role of serum albumin in patients with esophageal cancer. We retrospectively reviewed 208 patients who underwent esophagectomy from September 1, 2003 to December 31, 2008. Clinico-pathological characteristics and postoperative outcomes were compared between different pretherapeutic serum albumin classes: low (hypoalbuminemic), <35 g/l; middle, 35-40 g/l and high, >40 g/l. Older, female, and higher T-stages were more likely to be associated with hypoalbuminemic. Meanwhile, hypoalbuminemic patients had a higher rate of postoperative mortality and complications including sepsis, respiratory insufficiency, arrhythmia, and cardiac insufficiency. But for preoperative comorbidities, no significant difference was found between different pretherapeutic serum albumin classes. The overall 5-year survival rate was 28.6%, 43.9%, and 50.8% for patients with low, middle, and high pretherapeutic serum albumin levels, respectively. Hypoalbuminemic was associated with poor survival (P = 0.016). In a multivariate analysis, the pretherapeutic albumin level was proved to be an independent predictor of survival (hazard ratio = 0.731; 95% confidence interval: 0.544-0.982, P = 0.037). Pretherapeutic serum albumin level is a significant prognostic factor for short-term and long-term outcomes in patients who undergo esophagectomy for cancer, which therefore should be taken into consideration along with other well-defined prognostic factors for better preoperative assessment and prognostic evaluation.

Aggregation-Induced Emission Photosensitizer-Engineered Anticancer Nanomedicine for Synergistic Chemo/Chemodynamic/Photodynamic Therapy.

Photodynamic therapy (PDT) with aggregation-induced emission (AIE) photosensitizers (PSs) is a promising therapeutic strategy to achieve better anticancer results. However, eradicating solid tumors completely by PDT alone can be difficult owing to the inherent drawbacks of this treatment, and the combination of PDT with other therapeutic modalities provides opportunities to achieve cooperative enhancement interactions among various treatments. Herein, this work presents the construction of a biocompatible nanocomposite, namely CaO2@DOX@ZIF@ASQ, featuring light-responsive reactive oxygen species (ROS) generation and tumor-targeting oxygen and hydrogen peroxide discharge, as well as controlled doxorubicin (DOX) and copper ion release, thus allowing the combined PDT/CT/CDT effect by AIE PS-enhanced PDT, DOX-based chemotherapy (CT), and copper-involved Fenton-like reaction-driven chemodynamic therapy (CDT). In vitro and in vivo studies verify that the generation of both ROS and O2 by this nanomedicine, stimulated by light, exhibits superior anticancer efficacy, alleviating tumor hypoxia and achieving synergistic PDT/CT/CDT therapeutic effect. This multifunctional nanomedicine remarkably suppresses the tumor growth with minimized systemic toxicity, providing a new strategy for constructing multimodal PDT/CT/CDT therapeutic systems to overcome hypoxia limitations, and potentially increase the antitumor efficacy at lower doses of PSs and chemotherapeutic drugs, thus minimizing potential toxicity to non-malignant tissues.

Circ_0067934: a circular RNA with roles in human cancer.

A circular RNA (circRNA) is a non-coding RNA (ncRNA) derived from reverse splicing from pre-mRNA and is characterized by the absence of a cap structure at the 5' end and a poly-adenylated tail at the 3' end. Owing to the development of RNA sequencing and bioinformatics approaches in recent years, the important clinical value of circRNAs has been increasingly revealed. Circ_0067934 is an RNA molecule of 170 nucleotides located on chromosome 3q26.2. Circ_0067934 is formed via the reverse splicing of exons 15 and 16 in PRKCI (protein kinase C Iota). Recent studies revealed the upregulation or downregulation of circ_0067934 in various tumors. The expression of circ_0067934 was found to be correlated with tumor size, TNM stage, and poor prognosis. Based on experiments with cancer cells, circ_0067934 promotes cancer cell proliferation, migratory activity, and invasion when overexpressed or downregulated. The potential mechanism involves the binding of circ_0067934 to microRNAs (miRNAs; miR-545, miR-1304, miR-1301-3p, miR-1182, miR-7, and miR-1324) to regulate the post-transcriptional expression of genes. Other mechanisms include inhibition of the Wnt/ß-catenin and PI3K/AKT signaling pathways. Here, we summarized the biological functions and possible mechanisms of circ_0067934 in different tumors to enable further exploration of its translational applications in clinical diagnosis, therapy, and prognostic assessments.

The TLR4/ERK/PD­L1 axis may contribute to NSCLC initiation.

Infection and inflammation serve an important role in tumor development. Toll­like receptor 4 (TLR4) is a pivotal component of the innate and adaptive immune response during infection and inflammation. Programmed­death ligand 1 (PD­L1) is hypothesized as an important factor for non­small cell lung cancer (NSCLC) immune escape. In the present study, the relationship between TLR4 and PD­L1, in addition to the associated molecular mechanism, were investigated. TLR4 and PD­L1 expression in lung cancer tissues were detected using immunohistochemistry, whilst overall patient survival was measured using the Kaplan­Meier method. The A549 cell line stimulated using lipopolysaccharide (LPS) was applied as the in vitro inflammatory NSCLC model. Associated factors were investigated using reverse transcription­quantitative PCR and western blotting. Lung cancer tissues exhibited increased PD­L1 and TLR4 levels compared with those of adjacent para­cancerous tissues, where there was a positive correlation between TLR4 and PD­L1 expression. In addition, increased expression of these two proteins was found to be linked with poorer prognoses. Following the stimulation of A549 cells with LPS, TLR4 and PD­L1 expression levels were revealed to be upregulated in a dose­dependent manner, where the ERK and PI3K/AKT signaling pathways were found to be activated. Interestingly, in the presence of inhibitors of these two pathways aforementioned, upregulation of PD­L1 expression was only inhibited by the MEK inhibitor PD98059, which can inhibit ERK activity. These data suggested that the ERK signaling pathway is necessary for the TLR4/PD­L1 axis. In conclusion, data from the present study suggest that TLR4 and PD­L1 expression can serve as important prognostic factors for NSCLC, where TLR4 activation may induce PD­L1 expression through the ERK signaling pathway.