Irradiated lung cancer cell-derived exosomes modulate macrophage polarization by inhibiting MID1 via miR-4655-5p.

Radiation Pneumonitis (RP) is one of the most common and severe complication in patients receiving thoracic radiotherapy. The release of cytokines contribute to activating the RP process. Macrophages also play an important role in the pathogenesis of RP. The differential activation of macrophages is regulated by microRNA (miRNA). Exosomes containing miRNAs are one of the important ways to mediate cellular communication. However, the exosomes mediate communication between tumor cells and macrophages during the pathogenesis of RP remains understudied. In this study, we isolated and characterized the exosomes secreted by lung cancer cells after irradiation. Co-culture of exosomes with macrophages revealed that exosomes could induce macrophage proliferation activation and M2 polarization. miRNA array was used to analyze the differential expression of miRNAs in exosomes, and it was found that miR-4655-5p was stably and highly expressed in exosomes. The function of miR-4655-5p in macrophages was confirmed by overexpression/inhibition of miR-4655-5p expression in macrophages. The targeting association between miR-4655-5p and MID1 was determined by bioinformatics prediction followed by a confirmatory dual luciferase reporter assay. We showed that miR-4655-5p regulate the macrophage proliferation and inflammatory response by forming a negative regulatory loop that alters MID1 activity and its downstream PP2Ac. Overall, our results indicated that exosomal miR-4655-5p secreted by lung cancer cells after irradiation promoted the proliferation and M2 polarization of macrophages. It can be speculated that exosomes play an immunomodulatory role in the pathogenesis of RP and provided a new target for the prevention and treatment of RP.

Radiotherapy concurrent versus sequential with endocrine therapy in breast cancer: A meta-analysis.

INTRODUCTION: This study compared treatment outcomes of radiotherapy concurrent with endocrine therapy and radiotherapy sequential with endocrine therapy in breast cancer. MATERIALS AND METHODS: Eligible studies of radiotherapy concurrent and sequential with endocrine therapy in breast cancer were retrieved through extensive searches of the PubMed, Medline, Embase, Cochrane library, FEBM, FMJS, Web of science, Wiley, CBM, CNKI, Wang fang, Cqvip databases from 2000 to 2014. Original English and Chinese publications of radiotherapy concurrent and sequential with endocrine therapy in breast cancer were included. The primary endpoint was radiation-induced toxicity including upper than grade 2 skin related toxicity, radiation pneumonia and pulmonary fibrosis; the second endpoint was survival date, including local recurrence, distant metastasis, 5-year OS, 10-year OS. RESULTS: Eleven eligible trials were identified, six in English and five in Chinese. Totally, there were 1291 women in concurrent groups, and 1179 in sequential groups. Statistical analysis showed that there was no statistical difference between concurrent and sequential groups in skin related toxicity (RR 1.20, 95% CI 0.92-1.56, P = 0.17), radiation pneumonia (RR 1.11, 95% CI 0.46-2.70, P = 0.81) and pulmonary fibrosis (RR 1.35, 95% CI 0.75-2.41, P = 0.32). Meanwhile, no statistical difference was found in survival data, (RR 0.97, 95% CI 0.79-1.28, P = 0.26), (RR 0.86, 95% CI 0.66-1.12, P = 0.27) in local recurrence and distant metastasis respectively, (RR 1.01, 95% CI 0.96-1.06, P = 0.65), (RR 0.98, 95% CI 0.93-1.02, P = 0.32) in 5-year and 10-year overall survival respectively. Stratification analysis was proceeded, grouped by tamoxifen and AI in different treatment timing, however, no statistical difference was found in radiation-induced toxicity and survival outcomes. CONCLUSION: Radiotherapy concurrent with endocrine therapy didn't increase or decrease neither the incidence of radiation-induced toxicity nor the survival rate compared with that of sequential group; Endocrine therapy drugs didn't influence outcomes in different treatment timing.

MicroRNAs level as an initial screening method for early-stage lung cancer: a bivariate diagnostic random-effects meta-analysis.

Accumulating studies suggested that microRNAs (miRNAs) can have high diagnostic value as a non-invasive and cost-effective procedure with high sensitivity and specificity in the detection of early-stage lung cancer. However, there is inconsistency observed in the results of relevant studies. Therefore, we performed this meta-analysis to evaluate diagnostic value of miRNAs based on all related studies. A total of 38 studies from 13 included articles were used for the analysis, consisting of 510 patients and 465 healthy controls. All analyses were performed on the R 3.2.0 software. The bivariate random-effects meta-analysis model was applied to obtain the following pooled parameters: sensitivity, 0.797 (95% CI: 0.756-0.832); false positive rate, 0.296 (95% CI: 0.250-0.346); and AUC, 0.818. In addition, subgroup analyses were conducted, showing not only that a combination of multiple miRNAs as biomarkers have greater diagnostic value for early-stage lung cancer (sensitivity, false positive rate and AUC of 83%, 25.2% and 0.858, respectively) had a higher diagnostic accuracy than single miRNA (sensitivity, false positive rate and AUC of 78.3%, 31.6% and 0.799, respectively), but also that specimen from circulating system (sensitivity, false positive rate and AUC of 82.5%, 30.5% and 0.836, respectively) provide better biomarkers than specimen from non-circulating system (sensitivity, false positive rate and AUC of 73.8%, 26.5% and 0.796, respectively). In summary, the current meta-analysis suggests that miRNAs as biomarkers, particularly a combination of multiple tumor-specific miRNAs from circulating system, have moderately high clinical diagnostic value in the detection of early-stage lung cancer. However, the clinical diagnostic utilization and additional improvements of miRNAs as biomarkers for early-stage lung cancer detection still remain to be further validated by more future studies.

Microarray Analysis of Long Non-coding RNA Expression Profile Associated with 5-Fluorouracil-Based Chemoradiation Resistance in Colorectal Cancer Cells.

BACKGROUND: Preoperative 5-fluorouracil (5-FU)-based chemoradiotherapy is a standard treatment for locally advanced colorectal cancer (CRC). However, CRC cells often develop chemoradiation resistance (CRR). Recent studies have shown that long non-coding RNA (lncRNA) plays critical roles in a myriad of biological processes and human diseases, as well as chemotherapy resistance. Since the roles of lncRNAs in 5-FU-based CRR in human CRC cells remain unknown, they were investigated in this study. MATERIALS AND METHODS: A 5-FU-based concurrent CRR cell model was established using human CRC cell line HCT116. Microarray expression profiling of lncRNAs and mRNAs was undertaken in parental HCT116 and 5-FU-based CRR cell lines. RESULTS: In total, 2,662 differentially expressed lncRNAs and 2,398 mRNAs were identified in 5-FU-based CRR HCT116 cells when compared with those in parental HCT116. Moreover, 6 lncRNAs and 6 mRNAs found to be differentially expressed were validated by quantitative real time PCR (qRT-PCR). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for the differentially expressed mRNAs indicated involvement of many, such as Jak- STAT, PI3K-Akt and NF-kappa B signaling pathways. To better understand the molecular basis of 5-FU-based CRR in CRC cells, correlated expression networks were constructed based on 8 intergenic lncRNAs and their nearby coding genes. CONCLUSIONS: Changes in lncRNA expression are involved in 5-FU-based CRR in CRC cells. These findings may provide novel insight for the prognosis and prediction of response to therapy in CRC patients.