Musashi1 as a potential therapeutic target and diagnostic marker for lung cancer

Xiao-Yang Wang,R Ilona Linnoila,Laodong Li,Dangyu Li,Robert I Glazer,Luiz O F Penalva,Biwen Mo,Huina Yu,Hideyuki Okano

doi:10.18632/oncotarget.1034

Abstract

Lung cancer remains one of the leading causes of cancer-related deaths worldwide with a 5-year survival rate of less than 20%. One approach to improving survival is the identification of biomarkers to detect early stage disease. In this study, we investigated the potential of the stem cell and progenitor cell marker, Musashi1 (Msi1), as a diagnostic marker and potential therapeutic target for lung cancer. Functional studies in A549 bronchioalveolar carcinoma and NCI-H520 squamous cell carcinoma cells revealed that Msi1 was enriched in spheroid cultures of tumor cells and in the CD133+ cell population. Downregulation of Msi1 by lentivirus-mediated expression of an Msi1 shRNA reduced spheroid colony proliferation. Growth inhibition was associated with reduced nuclear localization of β-catenin and inhibition of the processing of intracellular Notch. In primary lung cancer, Msi1 protein expression was elevated in 86% of 202 tissue microarray specimens, and Msi1 mRNA was increased in 80% of 118 bronchoscopic biopsies, including metastatic disease, but was rarely detected in adjacent normal lung tissue and in non-malignant diseased tissue. Msi1 was expressed in a diffuse pattern in most tumor subtypes, except in squamous cell carcinomas, where it appeared in a focal pattern in 50% of specimens. Thus, Msi1 is a sensitive and specific diagnostic marker for all lung cancer subtypes.

Highlights

Lung cancer is the most common cause of cancerrelated mortality worldwide [1], and despite modern diagnostic and therapeutic advances, the 5-year survival rate following resection has improved only in patients diagnosed with early stage disease
Msi1 expression was enriched in A549 and H520 lung cancer cells under cell culture conditions that promoted the formation of less differentiated spheroid colonies shown to be enriched for stem-like cells [33]
Cells sorted for CD133, a cell population enriched in tumor initiating cells [27,28,29], were further enriched for Msi1, in agreement with Msi1 as a stem cell or early progenitor cell marker, and consistent with its enrichment in CD133+ breast cancer “mammospheres” [24], and poorly differentiated oral squamous cell carcinomas [34]

Summary

Introduction

Lung cancer is the most common cause of cancerrelated mortality worldwide [1], and despite modern diagnostic and therapeutic advances, the 5-year survival rate following resection has improved only in patients diagnosed with early stage disease. Only one out of eight patients diagnosed with lung cancer can be effectively treated due to the prevalence of rapidly metastatic disease [2], and a key aspect of improving survival is the diagnosis of early disease. Lung cancer is often diagnosed by bronchoscopic biopsy, and bronchial brushing and bronchial lavage have been used as adjuncts to bronchoscopy for histological, cytological [3] and molecular [4] analysis. With the advent of genomics and personalized medicine, the diagnosis and www.impactjournals.com/oncotarget.

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