Central Medical Journal of Obstetrics and Gynecology

Editorial *Corresponding author Xiangbing Meng, Department of Obstetrics and Gynecology, The University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, Iowa 52242, USA, MTDH and FOXM1, Two Master Tel: 3193358212; Fax: 3193358448; Email: xiangbing- [email protected] Regulators in Gynecologic Submitted: 31 August 2013 Accepted: 31 August 2013 Published: 02 September 2013 Cancer Copyright Shujie Yang1, Kimberly K Leslie1,2 and Xiangbing Meng1,2* © 2013 Yang et al. 1Departments of Obstetrics and Gynecology, The University of Iowa, USA OPEN ACCESS 2Holden Comprehension Cancer Center, The University of Iowa, USA Keywords • FOXM1 Abstract • MTDH/AEG-1/LYRIC Drug resistance and metastasis are the major challenges for treatment of • NPM gynecologic cancers. Tumor heterogeneity caused by diverse driver mutations in • ARF gynecologic cancers restricts the effective application targeted therapies. Both FOXM1 • DNA repair and MTDH are overexpressed and correlated with drug resistance and metastasis • Gynecologic cancers in various types of cancers including gynecologic cancers. Accumulated clinical and • Targeted therapy functional studies have demonstrated that elevated expression of both FOXM1 and MTDH is the consequence of diverse activating mutations in oncogenes such as PI3K, Ras, and loss of function mutations in tumor suppressor such as and PTEN. We discuss FOXM1 and MTDH as potential prognostic markers and therapeutic targets in gynecologic cancers.

Abbreviations especially when used in combination with chemotherapy, are promising and may allow us to tailor treatment to individual PARP: Poly-ADP-Ribose Polymerase; VEGF: Vascular 2, ]. Currently, mammalian Endothelial Growth Factor; VEGFR: Vascular Endothelial Growth Factor Receptors; PDGF: Platelet-Derived Growth Factor; FGF: patient and tumor genetic profiles [ 3 Fibroblast Growth Factor; HNSCC: Head and Neck Squamous target of rapamycin (mTOR) inhibitors, poly-ADP-ribose Cell Carcinoma; ESCC: Esophageal Squamous Cell Carcinoma; polymerase (PARP) inhibitors, tyrosine-kinase inhibitors for FOXO: Forkhead box class O; XRCC1: X-ray Repair Cross- vascular endothelial growth factor (VEGF), vascular endothelial Complementing 1; BRCA2: Breast Cancer-Associated growth factor receptors (VEGFR), platelet-derived growth factor 2; HR: Homologous Recombination; NHEJ: Non-Homologous cancers(PDGF), fibroblast [4 growth factor (FGF), and components of the End Joining; GFP: Green Fluorescent Protein; CNV: Copy Number EGFR pathway are being tested in clinical trials for gynecologic Variations; DSB: Double Strand Break; BRIP1: BRCA1-associated ]. Identification of new molecule(s) that are key BACH1 helicase; LPS: Lipo Poly Saccharides; OS: Overall Survival; effectors of carcinogenesis and progression in many tumor types PFS: Progress Free Survival; HCC: HepatoCellular Carcinoma; thatand whichtwo such can molecules,be targeted FOXM1 therapeutically [ -9] and would MTDH be [10 a significant- ], meet EOC: Epithelial Ovarian Cancer; Alb/MTDH: A transgenic mouse advancementthese criteria in and the candevelopment serve as of novel new diagnostictreatments. markers We propose and 5 13 with hepatocyte-specific expression of AEG-1 by directing therapeutic targets. Accumulated clinical and functional studies promoter.the expression of human AEG-1 under an upstream enhancer have demonstrated involvement of both FOXM1 and MTDH in region fused to the 335-base-pair core region of mouse albumin cell proliferation, chemoresistance, angiogenesis, invasion, and Introduction metastasis in various types of human cancers. Therefore, FOXM1 Although survival rate in gynecologic cancers have andO verexpression MTDH have been of identified MTDH a asnd prognostic FOXM1 in markers. cancers improved somewhat in the last decades, there are still many Elevated FOXM1 expression has been reported in various types challenges including early diagnosis, prevention, drug resistance, metastasis and drug toxicity [1]. Tumor heterogeneity limits ovarianof malignancies tumors [ including14 gynecologic cancers. Overexpression gynecologic cancers [2]. These complexities represent major mostof FOXM1 commonly has been upregulated observed genes in 87% in human of high-grade solid tumors serous in effective application of a standard single treatment modality in ]. FOXM1 has been identified as one of the therapies. Newly emerging targeted molecular inhibitors, challenges and impediments to developing effective cancer several gene expression profiling studies. The forkhead box class O (FOXO) family is comprised of multifunctional transcription Cite this article: Yang S, Leslie KK, Meng X (2013) MTDH and FOXM1, Two Master Regulators in Gynecologic Cancer. Med J Obstet Gynecol 1(2): 1011. Yang et al. (2013) Email: [email protected] Central

impactfactors in (FOXO1, cell cycle FOXO3a, arrest, FOXO4invasion, and migration, FOXO6) and involved resistance in fine- to MTDH expression group versus 63.6 months and >50 months therapytuning a [ broad repertoire of downstream target genes which in the low MTDH expression group (p<0.001). Thus, increased expression of MTDH predicts for poor response to cisplatin 15]. Inactivation and suppression of FOXO, in particular and shorter survival. Correlation of MTDH expression with FOXO1 and FOXO3a, have been implicated, ]. FOXO in tumorigenesis and FOXM1 Atlassurgical ovarian debulking cancer has data been set. confirmed In endometrial in a systemic cancer, review the most of bindand cancer to the sameprogression. response However, elements Forkhead in target subfamilygenes. Target member gene 279 patients with stage 3 or 4 serous EOC in the Cancer Genome transcriptionFOXM1 functions activated as a classic by FOXM1 oncogene is usually [16 17 repressed by FOXO. Figure 1 common cancer of the female genital tract, overall 5-year survival rate is more than 80% if disease is diagnosed early. However, FOXM1 itself is a direct target repressed by FOXO ( ). a substantial percentage of patients will relapse and develop drugs,This repression including is chemotherapy released by the agents inhibition paclitaxel, of FOXO doxorubicin, thismetastatic purpose. disease. MTDH A expression biomarker is to increased. identify high risk patients up via the PI3K-AKT-FOXO axis. Sensitivity to many anti-cancer front needs to be developed. We propose that MTDH may serve Molecular mechanisms of increased expression FOXM1 and MTDH in cancer FOXOcisplatin –FOXM1 and targeted axis [22 therapies- ]. lapatinib, gefitinib, imatinib, and tamoxifen, are determined through PI3K-AKT and downstream There are six mechanisms through which FOXM1 An inverse relationship26 between MTDH expression level

expression is elevated in different types of cancers. These are: and OS (overall survival), PFS (progression free survival) and -29]. MTDH overexpressions (i) amplification of the FOXM1 gene locus. The FOXM1 locus is metastasis free survival has been observed in a large number located at 12p13, a region frequently amplified of studies in diverse cancers [27 breast adenocarcinomas [ , normal tissues and was strongly correlated with poor outcome in non-Hodgkin’s lymphoma (NHL), cervical carcinomas and andwas detected metastasis in more in more than than40% 1000of breast breast cancers cancer compared patients. to pathway [ ] direct interaction36 37] with(ii) Increased nucleophosmin protein [stability.] and FOXM1 stability in cancer cells is increased via the WntFigure signaling 1 MTDH expression in breast cancer [ ]. For the most lethal 38 39 Genomic amplification is one of the mechanisms for the increased [40 phosphorylation by Cdk4,6/cyclinD complexes ( ) 30 ] (iii) Increased transcription. Transcription of FOXM1 is gynecological cancer in Western countries, epithelial ovarian 41- activated through the action of transcription factors E2F, c-Myc, cancer (EOC), high MTDH expression was detected in 64.8% with peritoneal metastasis and 83.7% with lymph node metastasis and hypoxia-inducible factor-1 (HIF-1) [ 43]. (iv) Mutations in the tumor suppressor genes p53 and Rb. FOXM1is regulated [among, 157 patients with EOC, including 49 patients with lymph node metastasis and 128 patients with peritoneal dissemination by two major tumor suppressors Rb and p53. Transcription of FOXM1 is repressed by p53 via a direct interaction on the p53 in31 patients32]. For with the most stage common II–IV tumors type of which ovarian were cancer, resistant ovarian to releases FOXM1 transcriptional repression in cancers [44- response element of the FoxM1 promoter. Inactivation of p53 cisplatinserous carcinoma, than in sensitive expression patients of MTDH [ - was]. Mediansignificantly PFS andhigher OS ]. Rb inhibits FOXM1-mediated downstream transcription

33 35 46 were 30.4 months and 35.28 months, respectively, in the high byActivation directly by interacting oncogenic withsignaling FOXM1. pathways. Phosphorylation FOXM1 is activated of Rb by PTEN PI3K Cyclin D1/Cdk4 disrupts the repression of FOXM1 by Rb [47] (v) (A) (B) Ha-ras AKT MTDH FOXM1 PI3K by oncogenic signaling pathways including PI3K/Akt, EGFR, Raf/

AKT ARF FOXO3a MEK/MAPK, and Hedgehog [48]. (vi) Reduced expression of Rb NPM myc NFκB andFOXM1 miR-200b, targeting have microRNAs been shown results to reduce in the FOXM1 reduction expression of FOXM1 at p53 FOXM1 thein cancer mRNA cells. or protein Five miRNAs, level [49 miR-370,- ]. miR-31, miR-34, miR-134 MTDH 53 Cell cycle : PLK1 ,CCNB1,survivin, Cdc25C ,myc Metastasis: stathmin, VEGF, MMP-2 Ago-2 MTDH is also regulated in cancer by a variety of mechanisms. DNA repair: Rad51, BRCA2/FANCD1, BRIP m7G ORF AAAAAA MTDH (i) MTDH overexpression results from amplification of the MTDH locus at chromosome 8q22 in breast tumors [30] (ii) Activation of Figure 1 H-ras markedly induces expression of MTDH throughFigure 1the 21PI3K/, ] A model illustrating diverse mechanisms of activation of FOXM1 (A) and cancer. It is proposed that MTDH activates FOXM1 by interacting with NPM [ ] AKT signaling pathway by increasing the association of c-Myc MTDH (B) and possible crosstalk between these two oncogenes in gynecologic 19-20]. FOXM1 likely to the E-box elements of the MTDH promoter ( ) [ 54 18 21]. According to or activating the PI3K/AKT signal transduction pathway [ (iii) Induction of MTDH expression by hypoxia and glucose induces MTDH transcription by increasing expression of myc [ [deprivation. Stabilization of HIF-1α in response to activation of the the cancer genome atlas project (TCGA) data analysis of 489 high-grade serous PI3K/AKT pathway results in induction of MTDH in glioma cells (HGS) ovarian cancers, 67% of cases demonstrated a defect in the Rb pathway, 14 55]. The increased expression of MTDH which is associated with and 45% had activation of PI3K/Ras. Eighty-four percent of cases were marked productionglucose deprivation [ is dependent on the production of reactive by elevated expression of FoxM1 [ ]. A p53 mutation was detected at 96% of oxygen species (ROS); in turn, increased MTDH inhibits ROS cases. FOXM1 can activate the transcription of genes which control the cell cycle, 56] (iv) LPS (lipopolysaccharides) can induce MTDH DNA repair and metastasis. Overexpression of MTDH impacts miRNA function and in breast cancer cells. MTDH is r and the process of translation via direct protein and mRNA binding interactions. via activation of the NF-kB pathway in human promonocytic cells equired for LPS-induced NF- Med J Obstet Gynecol 1(2): 1011 (2013) 2/6 Yang et al. (2013) Email: [email protected] Central kB activation via a T herapeutic opportunities of targeting FOXM1 and MTDH induced invasion andpositive metastasis feedback [ loop, between MTDH and NF- kB. MTDH mediated IL-8 and MMP-9 expression is critical in LPS- target MTDH, result in increased MTDH57 58 ]levels (v) Reduced in cancer expression cells [ - be targeted. Thiazole compounds, Siomycin A and thiostrepton, of tumor suppressor miRNAs such as miR375 and miR26a, which There are a number of ways in which FOXM1 and MTDH can 59 inhibitors [ , ]. Both Siomycin A and thiostrepton can repress have been identified as potential FOXM1 small chemical 61]. MTDH is a direct target of three miRNAs, miR-26a, miR-375] and miR-136. MiR-26a represses MTDH expression by directly 71 72 targeting the 3’UTR of MTDH mRNA in breast cancer cells [61 Siomycinthe transcriptional A and thiostrepton activity of could FOXM1 be related and decrease to their FOXM1 ability to at the mRNA and protein level in cancer cells.]. Neither The action agent of causes both miR-375, is a]. well-known tumor suppressor and has been shown to downregulate the expression of MTDH by binding to its 3’- and increased MTDH have been observed in several tumor types function as proteasome inhibitors [73 UTR [59 60 Reverse expression patterns of decreased miR-375 cells, thus making them potentially attractive therapeutic drugs including including Head and Neck Squamous Cell Carcinoma any anti-proliferation or apoptotic effects on untransformed

NPM1 and ARF [ , ] NPM promotes cancer cell survival and cancer and breast cancer [ , ]. for cancers with FOXM1 overexpression. FOXM1 is regulated by (HNSCC), Esophageal Squamous Cell Carcinoma (ESCC), liver ]. 74 75 56 57 MTDH was also identified as a FOXM1 is a novel inhibitory target of p19 (ARF). A p19 (ARF) R targetole of of FmiR-136OXM1 andin glioma MTD cellsH in [62 drug resistance 26-44 peptide containing nine D-Arg residues was sufficient to NPMreduce has FOXM1 been transcriptional observed by mass activity spectrometry and tumor analysis,proliferation co- in HCC. Interaction of FOXM1 with the multifunctional protein has Thebeen role demonstrated of FOXM1 in DNAusing repair, an integrated which occurs direct by repeat homologous green recombination (HR) but not non-homologous end joining (NHEJ), immunoprecipitation and glutathione S-transferase pull-down. Knockdown of NPM caused significant down-regulation of fluorescent protein (GFP) reporter system of DSB (double strand interaction between FOXM1 and NPM could potentially be [ ] FOXM1 in cancer cells to the levels found in normal cells. The break) repair in HeLa cells. Two critical proteins for HR repair, disrupted by peptides or small molecules, leading to a FOXM1 BRIP1by promoter (BRCA1-associated analysis andBACH1 chromatin-immunoprecipitation. helicase) [63] and Rad51, 64 have been identified as direct transcriptional targets of FOXM1 be to delivery RNA molecules which target MTDH or FOXM1; targeted therapy. A potential future therapeutic strategy might Correlation of FOXM1 with the expression of two other DNA canhowever, be widely employing used in RNA-basedpatients. The regimens potential for anticancer treatment agents will observedrepair genes, in osteosarcoma XRCC1 (X-ray cells repair [ cross-complementing protein ursolicrequire acidsignificantly [ , ] andmore cryptotanshinone research and development [ before they instability1) and BRCA2 in cancer (breast cells cancer-associated with FOXM1 overexpression gene 2), has has been also 65]. The occurrence of genomic 76 77 78] have been found to repress expression of MTDH in ovarian and prostate cancer. been shown by LOH (loss of heterozygosity) and copy number cryptotanshinone [ ]. In addition, cadmium chloride reduced damage response and in DSB HR repair implicates it as an HIF-1α was shown to be involved in the repression of MTDH by variations (CNV) measurement. The role of FOXM1 in the DNA MTDH expression and NF-kB activity in breast cancer cells [ ]. 78 such as platinum, topoisomerase inhibitors, IR, or alkylators. Conclusion and future perspectives 79 attractive target for therapies employing DNA damaging agents In summary, both MTDH and FOXM1 are emerging as critical to DNA damaging agents [ - ]. Indeed, targeting FOXM1 increases the sensitivity of tumor cells 66 68 markersmaster regulators routinely usedof cancer in a clinical development diagnostic that laboratory may affect as all well of A transgenic mouse with hepatocyte-specific expression asthe therapeutichallmarks of targets cancer. to Both overcome FOXM1 drug and resistanceMTDH might in become diverse comparedof MTDH (Alb/MTDH) to wild type accelerated mouse [ development].Alb/AEG-1 of hepatocytes HCC when exposed to the hepatocarcinogen, N-nitrosodiethylamine (DEN) cancer cells might be developed as antibody-based diagnostic 69 orcancers. therapeutic The presence [ - ]. of Furtherincreased work MTDH to on understand the surface the of display significant resistance to senescence. Reduced ROS levels comparedand fewer senescent to control cells hepatocytes. as well as activation This indicates of ATM, that ATR, MTDH CHK1, is 80 82 and CHK2 occurs in Alb/AEG-1 hepatocytes following isolation function of MTDH is warranted. The following questions must be investigated; 1. What is the biological significance of MTDH involved in the DDR response. A further development has been in normal physiological conditions? 2. Do any of the different the identification of MTDH as a new RNA binding protein with isoforms/modifications of MTDH identified from sequence the potential to control the levels of important DNA repair factors predictions contribute to the impact of MTDH in cancer? at the post-transcriptional level. Association of MTDH with MTDH has a broad range of protein and RNA binding partners [various]. mRNAs was recently identified by RNA-binding protein in different cellular components. 3. Does MTDH function as a immunoprecipitation followed by microarray analysis (RIP-chip) scaffold protein or does it directly influence the function or 18 The mRNAs bound to MTDH, ]. An encode attractive various hypothesis functional is expression of its different binding partners? Understanding these proteins including multiple members of the Fanconi pathway basic cellular and biochemical properties of MTDH will help in the (FANCA, FANCD2, FANCI) [18 70 development of effective inhibitors. For FOXM1, more studies are needed to develop more specific inhibitors of FOXM1 to achieve andthat this high potentiates expression therapeutic of MTDH resistance. allows cancer cells to rapidly be developed as new therapeutic targets. In addition, tumor repair DNA in the setting of cell stress, including chemotherapy, clinical benefits. Oncogenic miRNAs regulated by FOXM1 could

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Cite this article Yang S, Leslie KK, Meng X (2013) MTDH and FOXM1, Two Master Regulators in Gynecologic Cancer. Med J Obstet Gynecol 1(2): 1011.

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