Identification of microRNAs involved in pathways which characterize the expression subtypes of NSCLC.

Dysregulation of microRNAs is a common mechanism in the development of lung cancer, but the relationship between microRNAs and expression subtypes in non-small-cell lung cancer (NSCLC) is poorly explored. Here, we analyzed microRNA expression from 241 NSCLC samples and correlated this with the expression subtypes of adenocarcinomas (AD) and squamous cell carcinomas (SCC) to identify microRNAs specific for each subtype. Gene set variation analysis and the hallmark gene set were utilized to calculate gene set scores specific for each sample, and these were further correlated with the expression of the subtype-specific microRNAs. In ADs, we identified nine aberrantly regulated microRNAs in the terminal respiratory unit (TRU), three in the proximal inflammatory (PI), and nine in the proximal proliferative subtype (PP). In SCCs, 1, 5, 5, and 9 microRNAs were significantly dysregulated in the basal, primitive, classical, and secretory subtypes, respectively. The subtype-specific microRNAs were highly correlated to specific gene sets, and a distinct pattern of biological processes with high immune activity for the AD PI and SCC secretory subtypes, and upregulation of cell cycle-related processes in AD PP, SCC primitive, and SCC classical subtypes were found. Several in silico predicted targets within the gene sets were identified for the subtype-specific microRNAs, underpinning the findings. The results were significantly validated in the LUAD (n = 492) and LUSC (n = 380) TCGA dataset (False discovery rates-corrected P-value < 0.05). Our study provides novel insight into how expression subtypes determined with discrete biological processes may be regulated by subtype-specific microRNAs. These results may have importance for the development of combinatory therapeutic strategies for lung cancer patients.

miRNA expression changes during the course of neoadjuvant bevacizumab and chemotherapy treatment in breast cancer.

One of the hallmarks of cancer is sustained angiogenesis. Favorable results have been reported in some breast cancer (BC) patients receiving antiangiogenic therapy with bevacizumab (Bev) in combination with chemotherapy, and further knowledge on how Bev can be optimally combined with conventional treatment to increase efficacy is strongly needed. In this randomized, neoadjuvant phase II clinical trial, 132 patients with HER2-negative, nonmetastatic BC were treated with Bev in combination with sequential chemotherapy. Biopsies were sampled before treatment, after 12 weeks with anthracycline and after taxane therapy at week 25. MicroRNA (miRNA) expression profiling was performed on biopsies from each time point. Altogether, 241 biopsies were analyzed with the aim of identifying miRNA-based biomarkers of response to therapy. Results from the miRNA analyses were reported for the ER-positive cohort, which were previously demonstrated to benefit from antiangiogenic therapy in this study. For both treatment arms of this cohort, significantly different expression was observed for 217 miRNAs between objective responding and nonresponding patients before treatment initiation. These miRNAs have been linked to regulation of epithelial-mesenchymal transition, metastasis, and tumor growth, among other processes. Bev in combination with chemotherapy resulted in similar miRNA changes to chemotherapy alone. However, the deregulation of miRNA expression occurred earlier in the Bev arm. In both arms, tumor suppressor miRNAs were found upregulated after treatment, while oncogenic miRNAs were downregulated in the Bev arm. Patients responding to Bev showed a strong correlation between deregulated miRNAs and decreased proliferation score during the course of treatment, with downregulation of miR-4465 as the strongest indicator of reduced proliferation. Integrative analyses at miRNA-, gene-, and protein expression further indicated a longitudinal decrease in proliferation. Altogether, the results indicate that proliferation might represent a predictive factor for increased Bev sensitivity, which may aid in the identification of patients who could potentially benefit from Bev.

Deregulation of cancer-related miRNAs is a common event in both benign and malignant human breast tumors.

MicroRNAs (miRNAs) are endogenous non-coding RNAs, which play an essential role in the regulation of gene expression during carcinogenesis. The role of miRNAs in breast cancer has been thoroughly investigated, and although many miRNAs are identified as cancer related, little is known about their involvement in benign tumors. In this study, we investigated miRNA expression profiles in the two most common types of human benign tumors (fibroadenoma/fibroadenomatosis) and in malignant breast tumors and explored their role as oncomirs and tumor suppressor miRNAs. Here, we identified 33 miRNAs with similar deregulated expression in both benign and malignant tumors compared with the expression levels of those in normal tissue, including breast cancer-related miRNAs such as let-7, miR-21 and miR-155. Additionally, messenger RNA (mRNA) expression profiles were obtained for some of the same samples. Using integrated mRNA/miRNA expression analysis, we observed that overexpression of certain miRNAs co-occurred with a significant downregulation of their candidate target mRNAs in both benign and malignant tumors. In support of these findings, in vitro functional screening of the downregulated miRNAs in non-malignant and breast cancer cell lines identified several possible tumor suppressor miRNAs, including miR-193b, miR-193a-3p, miR-126, miR-134, miR-132, miR-486-5p, miR-886-3p, miR-195 and miR-497, showing reduced growth when re-expressed in cancer cells. The finding of deregulated expression of oncomirs and tumor suppressor miRNAs in benign breast tumors is intriguing, indicating that they may play a role in proliferation. A role of cancer-related miRNAs in the early phases of carcinogenesis and malignant transformation can, therefore, not be ruled out.