Autocrine activity of BDNF induced by the STAT3 signaling pathway causes prolonged TrkB activation and promotes human non-small-cell lung cancer proliferation.

Bo Chen,Yan Liang,Yunhe An,Zheng He,Jianqing Wu,Weihong Zhao

doi:10.1038/srep30404

Abstract

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin superfamily, which has been implicated in the pathophysiology of the nervous system. Recently, several studies have suggested that BDNF and/or its receptor, tropomyosin related kinase B (TrkB), are involved in tumor growth and metastasis in several cancers, including prostate cancer, neuroblastoma, pancreatic ductal carcinoma, hepatocellular carcinoma, and lung cancer. Despite the increasing emphasis on BDNF/TrkB signaling in human tumors, how it participates in primary tumors has not yet been determined. Additionally, little is known about the molecular mechanisms that elicit signaling downstream of TrkB in the progression of non-small-cell lung cancer (NSCLC). In this study, we report the significant expression of BDNF in NSCLC samples and show that BDNF stimulation increases the synthesis of BDNF itself through activation of STAT3 in lung cancer cells. The release of BDNF can in turn activate TrkB signaling. The activation of both TrkB and STAT3 contribute to downstream signaling and promote human non-small-cell lung cancer proliferation.

Highlights

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin superfamily, which has been implicated in the pathophysiology of the nervous system
Studies have established Signal transducer and activator of transcription 3 (STAT3) as a downstream mediator of Trk signaling and functions in PC12 cells and in the major pelvic ganglia (MPG) of rats[14,15,16]. It is not known whether STAT3 is a mediator of BDNF/ tropo-myosin-related kinase B (TrkB) signaling in lung cancers
We report that BDNF stimulation increases the activation of STAT3, which in turn promotes the synthesis of BDNF in A549 and H1299 cells

Summary

Introduction

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin superfamily, which has been implicated in the pathophysiology of the nervous system. Several studies have shown that BDNF and/or its receptor, tropo-myosin-related kinase B (TrkB), are involved in cancer growth and metastasis in several cancers, including neuroblastoma[4], pancreatic ductal carcinoma[5], prostate cancer[6], hepatocellular carcinoma[7], and lung cancer[8]. Members of the signal transducer and activator of transcription (STAT) family of transcription factors are potential targets for the treatment and prevention of cancers, including non-small-cell lung cancer[9,10,11,12]. Studies have established STAT3 as a downstream mediator of Trk signaling and functions in PC12 cells and in the major pelvic ganglia (MPG) of rats[14,15,16] It is not known whether STAT3 is a mediator of BDNF/ TrkB signaling in lung cancers. We show that the release of BDNF can in turn activate prolonged TrkB signaling

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Results

Conclusion