Enhancement of tumor initiation and expression of KCNMA1, MORF4L2 and ASPM genes in the adenocarcinoma of lung xenograft after vorinostat treatment.

Wei-Ying Kuo,Hsin-Ell Wang,Jhih-Shian Lee,Juri Gelovani,Kang-Ping Lin,Chun-Yi Wu,Teh-Ying Chou,Luen Hwu,Chun-Ming Tsai,Cheng-Han Tsai,Ren-Shyan Liu

doi:10.18632/oncotarget.3536

Abstract

Cancer stem cells (CSCs) are usually tolerant to chemotherapy and radiotherapy and associated with tumor relapse. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI), is currently being used in clinical trials of lung cancer. However, SAHA facilitates the formation of induced pluripotent stem cells from somatic cells. We hypothesized that SAHA would mediate the CSCs properties and subsequently confer a more malignant phenotype in lung cancer. Transfected H1299 lung cancer cells, which stably expresses a triple fused reporter gene (DsRedm-Fluc-tTKsr39) under the control of CMV promoter was used to establish a xenograft mouse model. After the treatment of SAHA, H1299 cell line and tumor xenografts were sorted by fluorescence-activated cell sorting (FACS) based on aldehyde dehydrogenase (ALDH) activity. We found that SAHA could suppress the growth of xenografted H1299 tumors with decreased proportion of ALDHbr lung cancer cells indicating that SAHA may target CSCs. However, SAHA significantly enhanced the tumor initiating capacity and the expression of malignant genes such as KCNMA1, MORF4L2 and ASPM in the remaining living ALDHbr cells. These findings suggested that SAHA treatment created a more drug-resistant state in residual ALDHbr cells. The in vivo imaging technique may facilitate searching and characterization of CSCs.

Highlights

In the cancer stem cell (CSC) paradigm, cancer originates from the uncommon cells with characteristics of pluripotency and self-renewal [1]
These results suggest that treatment of lung cancer cell with Suberoylanilide hydroxamic acid (SAHA) leads to the induction of epithelial–mesenchymal transitions (EMT) phenotype
We further investigated the effect of SAHA on CSC populations by using qRTPCR and found that all the analyzed genes was strongly up-regulated by at least 10-fold in SAHA-treated ALDHbr cells when compared with untreated cells (Fig.1C)

Summary

Introduction

In the cancer stem cell (CSC) paradigm, cancer originates from the uncommon cells with characteristics of pluripotency and self-renewal [1]. CSCs were first identified in leukemia and more recently in solid tumors. This subpopulation of cancer cells has ability to escape chemotherapy and driving tumor recurrence [2]. It is urging to develop effective therapeutic approaches to eliminate CSCs. a long-standing problem is the www.impactjournals.com/oncotarget paucity of specific markers to identify and isolate CSCs from common tumor cells and to investigate their roles in tumorigenesis. Mounting evidences suggest that the tumor microenvironment is responsible for conditioning the stem cell status itself. Previous studies reported that non-SP cells and CD133─ cells can generate tumors in NOD/SCID mice [4, 5]

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