Friend leukemia virus integration 1 promotes tumorigenesis of small cell lung cancer cells by activating the miR-17-92 pathway.

Lingyu Li,Wei Song,Xu Yan,Xiaoying Zhang,Lei Zhou,Ailing Li,Wei Li,Jiuwei Cui,Ji-Fan Hu,Dehai Yu,Xue Wen

doi:10.18632/oncotarget.16715

Abstract

Small cell lung cancer (SCLC) is regarded as the most devastative type of human lung malignancies. The rapid and disseminated growth pattern remains the primary cause of poor clinical prognosis in patients with SCLC. However, the molecular factors that drive rapid progression of SCLC remain unclear. Friend leukemia virus integration 1 (FLI1), an Ets transcription factor family member, has been previously reported to act as a major driver of hematological malignancies. In this study, we explored the potential role of FLI1 in SCLC. Using immunohistochemical staining, we found that FLI1 was significantly upregulated in SCLC tissues, compared to that in non-small cell lung cancer (NSCLC) and normal lung tissues (p < 0.01). The expression score of FLI1 oncoprotein was associated with the extensive stage of SCLC and the overexpressed Ki67. Knockdown of FLI1 with small interfering RNA (siRNA) or short hairpin RNA (shRNA) promoted apoptosis and induced repression of cell proliferation, tumor colony formation and in vivo tumorigenicity in highly aggressive SCLC cell lines. Importantly, we discovered that FLI1 promoted tumorigenesis by activating the miR-17-92 cluster family. This study uncovers FLI1 as an important driving factor that promotes tumor growth in SCLC through the miR-17-92 pathway. FLI1 may serve as an attractive target for therapeutic intervention of SCLC.

Highlights

Small cell lung cancer (SCLC) is the most devastative type of human lung malignancies [1], accounting for approximately 15% of all lung cancer cases recorded [2]
The rapid and disseminated growth pattern remains the primary cause of poor clinical prognosis in patients with SCLC
We demonstrate that Friend leukemia virus integration 1 (FLI1) is an underlying oncogenic gene in tumorigenesis and development of SCLC

Summary

Introduction

Small cell lung cancer (SCLC) is the most devastative type of human lung malignancies [1], accounting for approximately 15% of all lung cancer cases recorded [2]. It has been shown that bi-allelic inactivation of TP53 and RB1 occurs in most the SCLC tumors, and loss of these two tumor suppressors are obligatory in the tumorigenesis and development of SCLC [6]. These genetic lesions alone are not sufficient to initiate tumor formation as demonstrated in the model of mouse erythroleukemia [7]. There must be some molecular regulators that play a vital role in the tumorigenesis of SCLC, in addition to the loss of TP53 and RB1

Methods

Results

Conclusion