YB-1 regulates tumor growth by promoting MACC1/c-Met pathway in human lung adenocarcinoma.

Tao Guo,Lei Zhao,Lei Jiang,Chundong Gu,Lingzhi Xu,Xiaoyuan Xue,Yan Zhang,Rafael Rosell,Mengying Yang,Peng Wang,Patrick C Ma,Nan Li,Jinxiu Li,Shilei Zhao,Zhuoshi Li

doi:10.18632/oncotarget.18262

Abstract

Aberrant overexpression of the transcription/translation factor Y-box-binding protein (YB-1) is associated with poor prognosis of lung adenocarcinoma, however the underlying mechanism by which YB-1 acts has not been fully elucidated. Here, we reported that inhibition of YB-1 diminished proliferation, migration and invasion of lung adenocarcinoma cells. Interestingly, we identified metastasis associated in colon cancer-1 (MACC1) as a target of YB-1. Depletion of YB-1 markedly decreased MACC1 promoter activity and suppressed the MACC1/c-Met signaling pathway in lung adenocarcinoma cells. Additionally, chromatin immunoprecipitation (ChIP) assay demonstrated that YB-1 bound to the MACC1 promoter. Moreover, YB-1 was positively correlated with MACC1, and both proteins were over-expressed in lung adenocarcinoma tissues. The Cox-regression analysis indicated that high YB-1 expression was an independent risk factor for prognosis in enrolled patients. Furthermore, depletion of YB-1 attenuated tumorigenesis in a xenograft mouse model and reduced MACC1 expression in tumor tissues. Collectively, our data suggested that targeting YB-1 suppressed lung adenocarcinoma progression through the MACC1/c-Met pathway and that the high expression of YB-1/MACC1 is a potential prognostic marker in lung adenocarcinoma.

Highlights

Lung cancer is the main cause of cancer death worldwide [1]
Y-box-binding protein-1 (YB-1) was positively correlated with metastasis associated in colon cancer-1 (MACC1), and both proteins were over-expressed in lung adenocarcinoma tissues
In the lung adenocarcinoma tissue specimens, the expression level of YB-1 and MACC1 were much higher than in the normal lung tissues adjacent to tumor lesions (Figure 5C), and YB-1 expression was positively correlated with MACC1 expression (Figure 5E, R2=0.8136, p

Summary

Introduction

Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers, with adenocarcinoma as the most common subtype followed by squamous carcinoma [2]. Most patients with NSCLC are diagnosed at late stages, when curative treatment is not feasible due to tumor dissemination, invasion and distant metastases [3]. These facts highlight the need for better understanding of the underlying molecular pathways and mechanisms of lung cancer metastasis, in order to develop novel therapeutic approaches. Recent studies showed that the dysregulated activation of the HGF/cMet pathway correlates with the progression of a wide range of human cancers and is thought to contribute to EMT, tumor proliferation, invasion and metastasis [11,12,13,14,15]. The functional pathways and molecular mechanism by which YB-1 acts in lung adenocarcinoma has not been fully elucidated

Methods

Results

Conclusion