Overexpression of PEAK1 contributes to epithelial\u2013mesenchymal transition and tumor metastasis in lung cancer through modulating ERK1/2 and JAK2 signaling

Chenbo Ding,Guoqiu Wu,Hongbo Xu,Wei Gao,Xiyong Wang,Hairu Wu,Wendong Tang,Wei Xu,Xiaobo Fan

doi:10.1038/s41419-018-0817-1

Abstract

Pseudopodium-enriched atypical kinase 1 (PEAK1), a novel non-receptor tyrosine kinase, has been demonstrated to act as an oncogenic regulator in breast and pancreatic cancers. However, the role of PEAK1 in the progression and metastasis of lung cancer is still unknown. Here, we observed that ectopic PEAK1 expression promoted lung cancer cell migration and invasion, while PEAK1 knockout resulted in suppressed cell migration and invasion. Interestingly, cell proliferation did not significantly increase or decrease in either the PEAK1 overexpression or knockout groups compared with the corresponding control cells. In addition, PEAK1 overexpression could induce epithelial-to-mesenchymal transition (EMT) and the expression of matrix metalloproteinase-2 (MMP2) and MMP9 both in vitro and in vivo, whereas PEAK1 knockout had the opposite effects. Then, we had confirmed that PEAK1 was significantly upregulated in lung cancer tissues, and correlated with a higher tumor node metastasis stage. Moreover, PEAK1 upregulation markedly enhanced the activation of extracellular signal-regulated kinase-1/2 (ERK1/2) and Janus kinase-2 (JAK2) signaling in lung cancer cells. Further work demonstrated that the combination of PD98059 with AZD1480 could reverse the effects of PEAK1-induced EMT, cell migration and invasion. Our findings highlight a newer mechanism for PEAK1 in regulating EMT and metastasis in lung cancer, which might serve as a therapeutic target for lung cancer patients.

Highlights

Lung cancer is the most frequently diagnosed malignance and the main cause of cancer-related death in the USA, China and other countries[1,2]
Neither upregulated nor silenced Pseudopodium-enriched atypical kinase 1 (PEAK1) expression significantly affected cell proliferation (Fig. S1). These results suggest that PEAK1 promotes cell migration and invasion in non-small cell lung cancer (NSCLC)
We provide convincing evidence of the oncogenic role of PEAK1 in metastasis and epithelial-tomesenchymal transition (EMT) progression in NSCLC

Summary

Introduction

Lung cancer is the most frequently diagnosed malignance and the main cause of cancer-related death in the USA, China and other countries[1,2]. 85% of lung cancer patients are diagnosed with non-small cell lung cancer (NSCLC)[3], and more than 80% of NSCLC cases are diagnosed at an advanced stage with activating epidermal growth factor receptor (EGFR) mutations[4]. Cisplatin plus gemcitabine is a standard chemotherapy regimen for the first-line treatment of advanced NSCLC5. There is a serious problem of an increasing number of patients developing therapeutic resistance due to long-term chemotherapy and the occurrence of metastasis. It has been widely identified that epithelial–mesenchymal transition-inducing transcription factors (EMT-TFs), matrix metalloproteinases (MMPs) and signaling cascades are directly or indirectly involved in cancer cell metastasis[6,7]. EMT allows NSCLC cells to acquire invasive properties and to develop metastatic growth characteristics, and therapeutic resistance[6].

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