MiR-337-3p and Its Targets STAT3 and RAP1A Modulate Taxane Sensitivity in Non-Small Cell Lung Cancers

Liqin Du,Ignacio I Wistuba,Jeoffrey J Schageman,Adi F Gazdar,Robert Borkowski,Maria C Subauste,Chin-Rang Yang,Christopher Desevo,John D Minna,Milind Suraokar,Rachel Greer,Alexander Pertsemlidis,Michael Baker,Zhenze Zhao

doi:10.1371/journal.pone.0039167

Abstract

NSCLC (non-small cell lung cancer) often exhibits resistance to paclitaxel treatment. Identifying the elements regulating paclitaxel response will advance efforts to overcome such resistance in NSCLC therapy. Using in vitro approaches, we demonstrated that over-expression of the microRNA miR-337-3p sensitizes NCI-H1155 cells to paclitaxel, and that miR-337-3p mimic has a general effect on paclitaxel response in NSCLC cell lines, which may provide a novel adjuvant strategy to paclitaxel in the treatment of lung cancer. By combining in vitro and in silico approaches, we identified STAT3 and RAP1A as direct targets that mediate the effect of miR-337-3p on paclitaxel sensitivity. Further investigation showed that miR-337-3p mimic also sensitizes cells to docetaxel, another member of the taxane family, and that STAT3 levels are significantly correlated with taxane resistance in lung cancer cell lines, suggesting that endogenous STAT3 expression is a determinant of intrinsic taxane resistance in lung cancer. The identification of a miR-337-3p as a modulator of cellular response to taxanes, and STAT3 and RAP1A as regulatory targets which mediate that response, defines a novel regulatory pathway modulating paclitaxel sensitivity in lung cancer cells, which may provide novel adjuvant strategies along with paclitaxel in the treatment of lung cancer and may also provide biomarkers for predicting paclitaxel response in NSCLC.

Highlights

Paclitaxel is a microtubule-targeting agent initially isolated from the conifer Taxus brevifolia – the yew tree has a long history of medicinal uses [1] – and is widely used in the treatment of human cancers, including lung cancer
To further evaluate the regulation of paclitaxel response by miR-337-3p, we examined the effect of miR-337-3p inactivation on paclitaxel sensitivity in H1155 cells
We further examined the effect of miR337-3p overexpression on STAT3 and RAP1A levels in H1993, a NSCLC cell line that is defined as paclitaxel-resistant, with an undefined IC50

Summary

Introduction

Paclitaxel is a microtubule-targeting agent initially isolated from the conifer Taxus brevifolia – the yew tree has a long history of medicinal uses [1] – and is widely used in the treatment of human cancers, including lung cancer. For NSCLC, resistance to paclitaxel is common, with response rates ranging from 21% to 24% [2,3] Mechanisms for such resistance include over-expression of P-glycoprotein, alterations in tubulin composition, and mutations in b-tubulin [4,5,6,7]. A recent study indicated that a large group of protein-coding genes belonging to a wide range of functional classes is potentially involved in modulating paclitaxel resistance in cancer treatment [8]. We are interested in the potential involvement of microRNAs (miRNAs) in modulating paclitaxel response in lung cancer treatment. MiRNAs are short, 19 to 23 nucleotide RNAs found in multiple organisms that regulate gene expression largely by decreasing levels of target messenger RNAs [9,10] and have been shown to play important roles in regulating a broad range of pathological processes, including cancer pathogenesis. Several studies have explored the therapeutic effects of miRNA mimics and inhibitors and demonstrated the potential of these classes of oligonucleotides as therapeutic agents [11,12,13,14,15,16]

Methods

Results

Conclusion