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The Roles of FOXM1 in Pancreatic Stem Cells and Carcinogenesis Ming Quan1,3, Peipei Wang2, Jiujie Cui1,3, Yong Gao2 and Keping Xie3*

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The Roles of FOXM1 in Pancreatic Stem Cells and Carcinogenesis Ming Quan1,3, Peipei Wang2, Jiujie Cui1,3, Yong Gao2 and Keping Xie3* Quan et al. Molecular Cancer 2013, 12:159 http://www.molecular-cancer.com/content/12/1/159 REVIEW Open Access The roles of FOXM1 in pancreatic stem cells and carcinogenesis Ming Quan1,3, Peipei Wang2, Jiujie Cui1,3, Yong Gao2 and Keping Xie3* Abstract Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses among all cancers. Over the past several decades, investigators have made great advances in the research of PDAC pathogenesis. Importantly, identification of pancreatic cancer stem cells (PCSCs) in pancreatic cancer cases has increased our understanding of PDAC biology and therapy. PCSCs are responsible for pancreatic tumorigenesis and tumor progression via a number of mechanisms, including extensive proliferation, self-renewal, high tumorigenic ability, high propensity for invasiveness and metastasis, and resistance to conventional treatment. Furthermore, emerging evidence suggests that PCSCs are involved in the malignant transformation of pancreatic intraepithelial neoplasia. The molecular mechanisms that control PCSCs are related to alterations of various signaling pathways, for instance, Hedgehog, Notch, Wnt, B-cell-specific Moloney murine leukemia virus insertion site 1, phosphoinositide 3-kinase/AKT, and Nodal/Activin. Also, authors have reported that the proliferation-specific transcriptional factor Forkhead box protein M1 is involved in PCSC self-renewal and proliferation. In this review, we describe the current knowledge about the signaling pathways related to PCSCs and the early stages of PDAC development, highlighting the pivotal roles of Forkhead box protein M1 in PCSCs and their impacts on the development and progression of pancreatic intraepithelial neoplasia. Keywords: Transcription factors, Oncogenic switch, Progression, Stem cells, Therapeutic targets, Molecular biomarkers Introduction roles of pancreatic CSCs (PCSCs) in pancreatic cancer de- The incidence of pancreatic cancer is increasing annu- velopment and progression is imperative. ally, especially in industrialized countries [1]. Despite CSC research has resulted in many advances in the ever-increasing research efforts over the past few de- fundamental understanding and clinical management of cades, prognoses for pancreatic cancer remain among several solid tumors, including brain, breast, head and the poorest for all cancers. It is also one of the leading neck, lung, prostate, colon, ovarian, and pancreatic can- causes of cancer-related mortality in developed coun- cer [5-11]. CSCs are now widely accepted to be a sub- tries, with a median survival duration of 6 months and population of tumor cells with the capacity for extensive 5-year overall survival rate of less than 5% [2,3]. Conven- proliferation, self-renewal, multipotency, high tumori- tional therapies, such as surgery, radiation therapy, chemo- genicity, and treatment resistance. Moreover, CSCs have therapy, and combinations of them, have had a limited a high propensity for invasiveness and metastasis [12]. impact on the course of this aggressive neoplasm, which is CSCs in pancreatic cancer cases are characterized by ex- characterized by rapid metastasis and resistance to these pression of the cell surface markers CD44, CD24, and therapies [4]. Researchers recently demonstrated that the epithelial-specific antigen (ESA; epithelial cell adhesion presence of cancer stem cells (CSCs) in pancreatic tumors molecule [EpCAM]) [13]. Authors reported that CD133+ contributes to the early metastasis and chemotherapeutic cells in primary pancreatic tumors and pancreatic cancer drug resistance of pancreatic cancer [5]. Therefore, eluci- cell lines represent those with enhanced, potent prolifer- dating the molecular mechanisms underlying the critical ative capacity [14]. Increasingly, studies have demon- strated that the presence of PCSCs combined with drug * Correspondence: [email protected] resistance and high levels of metastasis contribute to 3Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX therapy failure, resulting in the high mortality rates for 77030, USA pancreatic cancer [5]. Furthermore, researchers have Full list of author information is available at the end of the article © 2013 Quan et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Quan et al. Molecular Cancer 2013, 12:159 Page 2 of 14 http://www.molecular-cancer.com/content/12/1/159 proposed that Forkhead box protein M1 (FOXM1) is in- Further categorization of these alterations using whole volved in the self-renewal of PCSCs, and tumorigenesis exome sequencing revealed that they corresponded to 12 and metastasis of pancreatic cancer cells [15]. core signaling pathways, which contained several import- FOXM1 is a member of the Forkhead box transcrip- ant genes already confirmed to be drivers in the early tion factor superfamily, which consists of more than stages of PDAC development, such as cellular processes 50 members sharing a conserved winged-helix DNA- (KRAS), DNA damage control (tumor suppressor 53 binding domain. FOXM1 is a proliferation-specific tran- [TP53]), cell-cycle regulation (cyclin-dependent kinase scription factor whose expression is correlated with the inhibitor 2a [CDKN2A]), and transforming growth factor proliferative ability of cells [16]. FOXM1 is well known (TGF)-β signaling (SMAD4) [29]. The progression of to be a key cell-cycle regulator for both transition from PanIN from trivial dysplastic epithelium (PanIN-1) to cy- G1 to S phase and progression from G2 phase to mitosis tologic and nuclear atypia (PanIN-2 and −3, respectively) [17]. Increasing evidence suggests that FOXM1 expres- and, ultimately, invasive carcinoma corresponds to the sion is substantially elevated in most human malignan- gradual accumulation of genetic alterations. These al- cies, such as glioblastoma, lung cancer, hepatocellular terations include activating mutation of the oncogene carcinoma (HCC), breast cancer, and pancreatic cancer, KRAS and inactivation of the tumor suppressor genes and plays a crucial role in tumorigenesis, angiogenesis, CDKN2A, TP53, and SMAD4 [28,30,31]. invasion, and metastasis [17-23]. Also, several recent studies suggested that FOXM1 is involved in self-renewal KRAS and proliferation of CSCs [15,24,25]. However, the mo- The earliest and most important genetic alterations ob- lecular mechanisms by which FOXM1 signaling regulates served in pancreatic carcinogenesis are activating muta- PCSCs in pancreatic cancer development and progres- tions of KRAS [32-34]. At least 90% of PanIN-1 lesions sion remain poorly understood. harbor mutations of KRAS, and the average concentra- A deeper comprehension of PSCSs would likely pro- tion of mutant KRAS alleles in PanIN lesions increases vide a new perspective on and increased understanding markedly along with the PanIN grade; ultimately, almost of the mechanisms that govern the development of pan- all PanIN lesions have KRAS mutations [30,35]. Re- creatic cancer. In this review, we briefly describe the searchers have identified three major point mutations in crucial role of FOXM1 in PCSCs in pancreatic cancer codons 12, 13, and 61 that lead to the association of ab- development and progression with a focus on recent normal KRAS protein products with malignant trans- insight into the cross-talk between FOXM1 and signal- formation, with mutations in codon 12 being the most ing pathways in PCSCs here and below. important to pancreatic carcinogenesis [32,33]. KRAS encodes for a guanosine triphosphate (GTP)-binding The roles of FOXM1 and signaling pathways in protein that functions as a crucial modulator of a series the early stages of pancreatic ductal of cellular processes, such as proliferation, survival, and adenocarcinoma development motility. Ras activity in cells is tightly regulated, and Ras Over the past few decades, increasing evidence has dem- is normally bound to guanosine diphosphate (GDP) in an onstrated that almost all pancreatic cancers progress inactive state. Exogenous signals such as growth factor from diverse premalignant lesions to invasive carcin- stimulation trigger the removal of GDP from Ras, allow- omas. Precursors of pancreatic cancer include pancreatic ing for GTP to bind and activate downstream effectors. intraepithelial neoplasia (PanIN), intraductal papillary Activated ras feeds multiple signaling pathways, including mucinous neoplasms (IPMNs), mucinous cystic neo- the Ras/Raf/mitogen-activated protein kinase (MAPK) plasms (MCNs), and intraductal tubular papillary neo- pathway and the phosphoinositide 3-kinase (PI3K)/AKT plasms (ITPNs) [26-28]. Pancreatic carcinoma in general signaling pathway, which have diverse roles in cytoskeletal may arise from any of these precursor lesions, yet pan- alterations, cell-cycle progression, and apoptosis inhib- creatic ductal adenocarcinoma (PDAC) in particular is ition. Activating mutations of KRAS contribute to loss of much more closely associated with PanIN than with the intrinsic GTPase activity of Ras protein; consequently, other precursor lesions. PanIN lesions
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