Cancer Letters

Cancer Letters

Volume 321, Issue 2, 28 August 2012, Pages 195-202
Cancer Letters

Loss of Med1/TRAP220 promotes the invasion and metastasis of human non-small-cell lung cancer cells by modulating the expression of metastasis-related genes

https://doi.org/10.1016/j.canlet.2012.02.009Get rights and content

Abstract

Med1/TRAP220 is an essential component of the TRAP/Mediator complex. In this study, we present a novel function of Med1 in human non-small-cell lung cancer (NSCLC) progression. We found that the loss of Med1 expression was strongly associated with increased rates of invasion and metastasis in NSCLC patients. Consistent with lung cancer patient data, the knockdown of Med1 in NSCLC cell lines led to an increase in cell migration and invasion. Med1-depleted cells displayed an increase in metastasis in a xenograft tumor model and in an in vivo metastasis assay. Moreover, a microarray analysis revealed that the mRNA levels of the metastasis-related genes uPAR, ID2, ID4, PTP4A1, PKP3, TGM2, PLD1, TIMP2, RGS2, and HOXA4 were altered upon Med1 knockdown. Collectively, these results suggest that the loss of Med1 increases the invasive potential of human NSCLC cells by modulating the expression of metastasis-related genes.

Introduction

Lung cancer is the leading cause of cancer-related death for both men and women. Primary lung cancer can be classified as small-cell lung cancer (SCLC) or non-small-cell lung cancer (NSCLC). Approximately 85% of lung cancers are categorized as NSCLC, and the most common types of NSCLCs are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma [1]. Because NSCLCs are relatively resistant to chemotherapy and radiation therapy compared to SCLCs, a multi-faceted treatment regimen is often required for patients with NSCLC [2]. Despite recent advances in NSCLC treatment, the overall 5-year survival rate remains less than 14% [2], [3]. Metastasis is the most common cause of treatment failure and death in NSCLC patients. Therefore, identifying the critical regulators of NSCLC invasion and metastasis is important in order to understand the pathogenesis of NSCLC and improve its clinical treatment.

Med1 (also known as PBP/RB18A/TRAP220/DRIP205) is a component of the human TRAP/Mediator complex that plays an important role in the transcriptional control of various genes [4], [5]. In addition to its essential role as a transcriptional activator of several nuclear receptors, such as estrogen receptor (ER), thyroid receptor (TR), and androgen receptor (AR) [6], [7], recent studies have suggested that Med1 function is associated with tumorigenesis. Med1 interacts directly with the tumor suppressors p53 and Brca1 [8], [9]. The overexpression of Med1 has been reported in breast and prostate cancers [10], [11]; however, the downregulation of Med1 has also been observed in metastatic melanoma [12]. Although an increasing number of studies have suggested that Med1 is involved in tumorigenesis, the exact mechanistic role of Med1 in lung cancer progression remains unclear. We have previously shown that the loss of Med1 expression is strongly correlated with increased invasion, metastasis, and poor survival in human lung adenocarcinoma patients [13]. In this study, we investigate the role of Med1 in human NSCLC and show that reduced Med1 expression is strongly associated with an increased rate of invasion and metastasis in all of the NSCLC subtypes analyzed. We also demonstrate that the loss of Med1 promotes the invasive and metastatic potential of human NSCLC cells. Finally, we propose that Med1 may be a potent new prognostic marker and treatment target for NSCLC.

Section snippets

Clinical samples and Med1 immunohistochemistry

Tissue samples were obtained from 173 Korean patients who underwent surgical resection for primary NSCLC at Dong-A University Medical Center. The collection and use of these samples was approved by the Institutional Ethical Review Board (approval number 09-10-20). Three biopsy cores from different areas of each tumor were removed from each sample to produce a tissue microarray, and 4 μm-thick sections were taken for immunohistochemical staining. Immunohistochemical staining for Med1 was

Med1 expression is decreased in human NSCLC patients

To investigate the role of Med1 in lung cancer and to dissect the function of Med1 in promoting lung cancer metastasis, we first extended our analysis of Med1 expression to 171 non-small-cell lung cancer (NSCLC) patient tissue samples. These tissue samples represented all NSCLC subtypes: squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Med1 expression was analyzed by immunohistochemistry (IHC). Strikingly, we found that 120 of the 171 tumor samples (70%) showed low Med1

Discussion

In this study, we demonstrate that Med1 is an important regulator of metastasis in human NSCLC. In human NSCLC samples, the loss of Med1 was significantly associated with an increase in the invasive and metastatic potential of these tumors. Consistent with this observation, the knockdown of Med1 increased the migratory and invasive potential of human NSCLC cells in vitro. Moreover, the knockdown of Med1 increased the metastatic capacity of H1299 and A549 cells in a mouse xenograft model and in

Acknowledgments

This work was supported by Basis Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0008453) and by National Research Foundation of Korea (NRF) Grant funded by the Korea government (MEST) (2009-0093197).

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