<p>Integrative gene expression profiling reveals that dysregulated triple microRNAs confer paclitaxel resistance in non-small cell lung cancer via co-targeting MAPT</p>

Abstract

Background Paclitaxel has shown significant anti-tumor activity against non-small cell lung cancer (NSCLC); however, resistance to paclitaxel frequently occurs and represents a significant clinical problem and its underlying molecular mechanism remains elusive. Methods Long-term treatment of culture cell with paclitaxel was carried out to mimic the development of acquired drug resistance in NSCLC. Cell proliferation and clonogenic assay and apoptosis evaluation were carried out to determine the efficacy of paclitaxel on NSCLC cells. Western blot analyses were performed to determine the expression and activation of proteins. Apoptosis enzyme-linked immunosorbent assay was used to quantify cytoplasmic histone-associated DNA fragments. Microarray analyses were applied to explore both mRNA and miRNA expression profiles in NSCLC cells followed by integrative analysis. qRT-PCR was carried out to verify the differentially expressed mRNAs and miRNAs. Results The expression of 652 genes was shown to be changed at least 2-fold in paclitaxel-resistant NSCLC (H460_TaxR) cells with 511 upregulated and 141 downregulated as compared with that in parental H460 cells. The differentially expressed genes were functionally enriched in regulating the cell proliferation, cell death, and response to endogenous stimulus, and clustered in pathways such as cancer and signaling by the G protein-coupled receptor (GPCR). Moreover, 43 miRNAs were shown to be differentially expressed in H460_TaxR cells with 15 upregulated and 28 downregulated as compared with parental H460 cells. A total of 289 pairs of miRNA-potential target gene were revealed in H460_TaxR cells by bioinformatics analysis. Furthermore, integrative analysis of miRNAs and gene expression profiles revealed that dysregulated miR-362-3p, miR-766-3p, and miR-6507-3p might confer paclitaxel resistance in NSCLC via targeting MAPT simultaneously. Conclusion Our findings suggested that specific manipulation of MAPT-targeting miRNAs may be a novel strategy to overcome paclitaxel resistance in patients with NSCLC especially large-cell lung carcinoma.

Advances and Challenges in Understanding MicroRNA Function in Tauopathies: A Case Study of miR-132/212

“…A simple search of common miRNA target site prediction programs (e.g., targetscan.org) reveals several conserved binding sites within the tau 3 ′ UTR. Consistent with this, a handful of miRNAs have been shown to bind to tau mRNA, including miR-132 (19,20), miR-34 (11), miR-186 (21), miR-219 (22), miR-362 (23), and miR-766 (23). Most groups have relied on 3 ′ UTR luciferase reporter assays and mutagenesis to confirm gene expression regulation in vitro.…”

Integrative analyses identified ion channel genes GJB2 and SCNN1B as prognostic biomarkers and therapeutic targets for lung adenocarcinoma

“…The spearman correlation was used to calculate the correlation of GJB2 or SCNN1B and drug target genes, and those with p < 0.05 were selected as interest genes. Moreover, the drug-sensitive or drug-resistant genes in interest genes were identified from the literatures with key words of 19 drugs (shown in supplementary Table S2 [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47]). The interaction network of GJB2 or SCNN1B with target genes and drugs were constructed and visualized by Cytoscape v.3.5.…”

Network-based approach to identify prognosis-related genes in tamoxifen-treated patients with estrogen receptor-positive breast cancer

“…MAPT can also determine paclitaxel chemosensitivity by interacting with several miRNAs in gastric cancer and non-small cell lung cancer [37]. Moreover, clinical and in vitro studies have demonstrated that the expression level of MAPT is positively associated with ER expression, and is influenced by ER signaling [38,39].…”