MAPK13 is preferentially expressed in gynecological cancer stem cells and has a role in the tumor-initiation

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Abstract

Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as small subpopulation of cancer cells that are endowed with higher tumor-initiating ability. CSCs/CICs are resistant to standard cancer therapies including chemotherapy and radiotherapy, and they are thus thought to be responsible for cancer recurrence and metastasis. Therefore, elucidation of molecular mechanisms of CSCs/CICs is essential to cure cancer. In this study, we analyzed the gene expression profiles of gynecological CSCs/CICs isolated as aldehyde dehydrogenase high (ALDHhigh) cells, and found that MAPK13, PTTG1IP, CAPN1 and UBQLN2 were preferentially expressed in CSCs/CICs. MAPK13 is expressed in uterine, ovary, stomach, colon, liver and kidney cancer tissues at higher levels compared with adjacent normal tissues. MAPK13 gene knockdown using siRNA reduced the ALDHhigh population and abrogated the tumor-initiating ability. These results indicate that MAPK13 is expressed in gynecological CSCs/CICs and has roles in the maintenance of CSCs/CICs and tumor-initiating ability, and MAPK13 might be a novel molecular target for treatment-resistant CSCs/CICs.

Introduction

Gynecological cancers are common malignancies for female with more than 70,000 new cases and more than 20,000 death in the United States [1]. Surgical treatment is the first choice for early localized cases. However, gynecological cancers especially ovarian cancers are asymptomatic in early stages and often are found in advanced stages. Chemotherapy including platinum and taxane are used for treatment of advanced gynecological cancers; however, the efficacy of chemotherapy is limited. Recent approaches such as anti-vascular endothelial growth factor (VEGF) monoclonal antibody (Bevacizumab) improved the progression free survival and symptoms of platinum-resistant ovarian cancer cases [2], [3], but did not improved the overall survival, and novel approaches are expected for gynecological cancers.

Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as small subpopulation of cancer cells that are endowed with higher tumor-initiating ability, self-renewal ability and differentiation ability [4]. CSCs/CICs are resistant to standard treatments including chemotherapy and radiotherapy [5], and eradication of CSCs/CICs are essential to cure cancer. CSCs/CICs like normal stem cells can regenerate the disease, and such of distinct subpopulation was identified by several methods. The first human CSCs/CICs were identified from acute myeloid leukemia as CD34+CD38- population [6]. In the following works, human CSCs/CICs were identified in several solid malignancies [7]. Gynecological CSCs/CICs were successfully isolated by several methods [8], [9], [10], [11], [12]. Gynecological CSCs/CICs were defined by their tumor-initiating ability; however, the molecular mechanisms how CSCs/CICs obtain such phenotypes are still elusive.

In this study, we analyzed the gene expression profiles of gynecological CSCs/CICs isolated as aldehyde dehydrogenase (ALDH) high population and found that mitogen-activated protein kinase (MAPK) 13 is preferentially expressed in gynecological CSCs/CICs, and analyzed the molecular functions of MAPK13 by siRNA.

Section snippets

Ethics statement

Mice were maintained and experimented on in accordance with the guidelines of and after approval by the Committee of Sapporo Medical University School of Medicine, Animal Experimentation Center under permit number 08–006. Any animal found unhealthy or sick was promptly euthanized. All studies were approved by the Institutional Review Board (IRB) of Sapporo Medical University Hospital. Written informed consent was obtained from all patients according to the guidelines of the Declaration of

Identification of genes expressed in gynecological cancer stem-like cells

In the previous studies, we successfully isolated gynecological CSCs/CICs as aldehyde dehydrogenase high (ALDHhigh) cells by Aldefluor assay and analyzed the gene expression profile by a cDNA microarray and found heat shock protein 27 (HSP27) was preferentially expressed in gynecological CSCs/CICs [11], [16] (submitted). In this study, we further analyzed the genes that are preferentially expressed in gynecological CSCs/CICs according to the results of cDNA microarray. RT-PCR analysis revealed

Discussion

In this study, we investigated the gene expression profile of gynecological CSCs/CICs and found that MAPK13, PTTG1IP, CAPN1 and UBQLN2 were preferentially expressed in CSCs/CICs. MAPK13 belongs to the MAP kinase family and is related to wide variety of cellular processes. MAPK13 is described to be overexpressed in cholangiocarcinoma and has a role in cell motility and invasion by gene knockdown studies [17]. Interestingly, Mapk13 gene knockout decreased the colitis-induced colon cancer, and the

Acknowledgments

This study was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to N. S.), program for developing the supporting system for upgrading education and research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to N. S.), Health and Labour Sciences Research Grants, a grant-in-aid of Ono Cancer Research Fund (to T. T.), Sagawa Foundation for Promotion of Cancer Research (to Y.H.),

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