Short Communication
MTDH and FOXM1, Two Master Regulators in Gynecologic Cancer
Shujie Yang1, Kimberly K Leslie1,2 and Xiangbing Meng1,2*
1Departments of Obstetrics and Gynecology, The University of Iowa, USA
2Holden Comprehension Cancer Center, The University of Iowa, USA

Drug resistance and metastasis are the major challenges for treatment of gynecologic cancers. Tumor heterogeneity caused by diverse driver mutations in gynecologic cancers restricts the effective application targeted therapies. Both FOXM1 and MTDH are overexpressed and correlated with drug resistance and metastasis in various types of cancers including gynecologic cancers. Accumulated clinical and 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, myc and loss of function mutations in tumor suppressor genes such as p53 and PTEN. We discuss FOXM1 and MTDH as potential prognostic markers and therapeutic targets in gynecologic cancers.
FOXM1; MTDH/AEG-1/LYRIC; NPM; ARF; DNA repair; Gynecologic cancers; Targeted therapy

PARP: Poly-ADP-Ribose Polymerase; VEGF: Vascular Endothelial Growth Factor; VEGFR: Vascular Endothelial Growth Factor Receptors; PDGF: Platelet-Derived Growth Factor; FGF: Fibroblast Growth Factor; HNSCC: Head and Neck Squamous Cell Carcinoma; ESCC: Esophageal Squamous Cell Carcinoma; FOXO: Forkhead box class O; XRCC1: X-ray Repair Cross-Complementing protein 1; BRCA2: Breast Cancer-Associated gene 2; HR: Homologous Recombination; NHEJ: Non-Homologous End Joining; GFP: Green Fluorescent Protein; CNV: Copy Number Variations; DSB: Double Strand Break; BRIP1: BRCA1-associated BACH1 helicase; LPS: Lipo Poly Saccharides; OS: Overall Survival; PFS: Progress Free Survival; HCC: HepatoCellular Carcinoma; EOC: Epithelial Ovarian Cancer; Alb/MTDH: A transgenic mouse with hepatocyte-specific expression of AEG-1 by directing the expression of human AEG-1 under an upstream enhancer region fused to the 335-base-pair core region of mouse albumin promoter.
Although survival rate in gynecologic cancers have improved somewhat in the last decades, there are still many challenges including early diagnosis, prevention, drug resistance, metastasis and drug toxicity [1]. Tumor heterogeneity limits effective application of a standard single treatment modality in gynecologic cancers [2]. These complexities represent major challenges and impediments to developing effective cancer therapies. Newly emerging targeted molecular inhibitors, especially when used in combination with chemotherapy, are promising and may allow us to tailor treatment to individual patient and tumor genetic profiles [2,3]. Currently, mammalian target of rapamycin (mTOR) inhibitors, poly-ADP-ribose polymerase (PARP) inhibitors, tyrosine-kinase inhibitors for vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and components of the EGFR pathway are being tested in clinical trials for gynecologic cancers [4]. Identification of new molecule(s) that are key effectors of carcinogenesis and progression in many tumor types and which can be targeted therapeutically would be a significant advancement in the development of new treatments. We propose that two such molecules, FOXM1 [5-9] and MTDH [10-13], meet these criteria and can serve as novel diagnostic markers and therapeutic targets. Accumulated clinical and functional studies have demonstrated involvement of both FOXM1 and MTDH in cell proliferation, chemoresistance, angiogenesis, invasion, and metastasis in various types of human cancers. Therefore, FOXM1 and MTDH have been identified as prognostic markers.
Overexpression of MTDH and FOXM1 in cancers
Elevated FOXM1 expression has been reported in various types of malignancies including gynecologic cancers. Overexpression of FOXM1 has been observed in 87% of high-grade serous ovarian tumors [14]. FOXM1 has been identified as one of the most commonly upregulated genes in human solid tumors in several gene expression profiling studies. The forkhead box class O (FOXO) family is comprised of multifunctional transcription factors (FOXO1, FOXO3a, FOXO4 and FOXO6) involved in fine-tuning a broad repertoire of downstream target genes which impact in cell cycle arrest, invasion, migration, and resistance to therapy [15]. Inactivation and suppression of FOXO, in particular FOXO1 and FOXO3a, have been implicated in tumorigenesis and cancer progression. However, Forkhead subfamily member FOXM1 functions as a classic oncogene [16-17]. FOXO and FOXM1 bind to the same response elements in target genes. Target gene transcription activated by FOXM1 is usually repressed by FOXO. FOXM1 itself is a direct target repressed by FOXO (Figure 1). This repression is released by the inhibition of FOXO proteins via the PI3K-AKT-FOXO axis. Sensitivity to many anti-cancer drugs, including chemotherapy agents paclitaxel, doxorubicin, cisplatin and targeted therapies lapatinib, gefitinib, imatinib, and tamoxifen, are determined through PI3K-AKT and downstream FOXO –FOXM1 axis [22-26].
Figure 1 A model illustrating diverse mechanisms of activation of FOXM1 (A) and MTDH (B) and possible crosstalk between these two oncogenes in gynecologic cancer. It is proposed that MTDH activates FOXM1 by interacting with NPM [18] or activating the PI3K/AKT signal transduction pathway [19-20]. FOXM1 likely induces MTDH transcription by increasing expression of myc [21]. According to the cancer genome atlas project (TCGA) data analysis of 489 high-grade serous (HGS) ovarian cancers, 67% of cases demonstrated a defect in the Rb pathway, and 45% had activation of PI3K/Ras. Eighty-four percent of cases were marked by elevated expression of FoxM1 [14]. A p53 mutation was detected at 96% of cases. FOXM1 can activate the transcription of genes which control the cell cycle, DNA repair and metastasis. Overexpression of MTDH impacts miRNA function and the process of translation via direct protein and mRNA binding interactions.

Figure 1 A model illustrating diverse mechanisms of activation of FOXM1 (A) and MTDH (B) and possible crosstalk between these two oncogenes in gynecologic cancer. It is proposed that MTDH activates FOXM1 by interacting with NPM [18] or activating the PI3K/AKT signal transduction pathway [19-20]. FOXM1 likely induces MTDH transcription by increasing expression of myc [21]. According to the cancer genome atlas project (TCGA) data analysis of 489 high-grade serous (HGS) ovarian cancers, 67% of cases demonstrated a defect in the Rb pathway, and 45% had activation of PI3K/Ras. Eighty-four percent of cases were marked by elevated expression of FoxM1 [14]. A p53 mutation was detected at 96% of cases. FOXM1 can activate the transcription of genes which control the cell cycle, DNA repair and metastasis. Overexpression of MTDH impacts miRNA function and the process of translation via direct protein and mRNA binding interactions.

An inverse relationship between MTDH expression level and OS (overall survival), PFS (progression free survival) and metastasis free survival has been observed in a large number of studies in diverse cancers [27-29]. MTDH overexpressions was detected in more than 40% of breast cancers compared to normal tissues and was strongly correlated with poor outcome and metastasis in more than 1000 breast cancer patients. Genomic amplification is one of the mechanisms for the increased MTDH expression in breast cancer [30]. For the most lethal gynecological cancer in Western countries, epithelial ovarian cancer (EOC), high MTDH expression was detected in 64.8% with peritoneal metastasis and 83.7% with lymph node metastasis among 157 patients with EOC, including 49 patients with lymph node metastasis and 128 patients with peritoneal dissemination [31,32]. For the most common type of ovarian cancer, ovarian serous carcinoma, expression of MTDH was significantly higher in patients with stage II–IV tumors which were resistant to cisplatin than in sensitive patients [33-35]. Median PFS and OS were 30.4 months and 35.28 months, respectively, in the high MTDH expression group versus 63.6 months and >50 months in the low MTDH expression group (p<0.001). Thus, increased expression of MTDH predicts for poor response to cisplatin and shorter survival. Correlation of MTDH expression with surgical debulking has been confirmed in a systemic review of 279 patients with stage 3 or 4 serous EOC in the Cancer Genome Atlas ovarian cancer data set. In endometrial cancer, the most common cancer of the female genital tract, overall 5-year survival rate is more than 80% if disease is diagnosed early. However, a substantial percentage of patients will relapse and develop metastatic disease. A biomarker to identify high risk patients up front needs to be developed. We propose that MTDH may serve this purpose. MTDH expression is increased.
Molecular mechanisms of increased expression FOXM1 and MTDH in cancer
There are six mechanisms through which FOXM1 expression is elevated in different types of cancers. These are: (i) amplification of the FOXM1 gene locus. The FOXM1 locus is located at chromosome 12p13, a region frequently amplified in non-Hodgkin's lymphoma (NHL), cervical carcinomas and breast adenocarcinomas [36,37] (ii) Increased protein stability. FOXM1 stability in cancer cells is increased via the Wnt signaling pathway [38] direct interaction with nucleophosmin [39] and phosphorylation by Cdk4,6/cyclinD complexes (Figure 1) [40] (iii) Increased transcription. Transcription of FOXM1 is activated through the action of transcription factors E2F, c-Myc, and hypoxia-inducible factor-1 (HIF-1) [41-43]. (iv) Mutations in the tumor suppressor genes p53 and Rb. FOXM1is regulated by two major tumor suppressors Rb and p53. Transcription of FOXM1 is repressed by p53 via a direct interaction on the p53 response element of the FoxM1 promoter. Inactivation of p53 releases FOXM1 transcriptional repression in cancers [44-46]. Rb inhibits FOXM1-mediated downstream transcription by directly interacting with FOXM1. Phosphorylation of Rb by Cyclin D1/Cdk4 disrupts the repression of FOXM1 by Rb [47] (v) Activation by oncogenic signaling pathways. FOXM1 is activated by oncogenic signaling pathways including PI3K/Akt, EGFR, Raf/MEK/MAPK, and Hedgehog [48]. (vi) Reduced expression of FOXM1 targeting microRNAs results in the reduction of FOXM1 in cancer cells. Five miRNAs, miR-370, miR-31, miR-34, miR-134 and miR-200b, have been shown to reduce FOXM1 expression at the mRNA or protein level [49-53].
MTDH is also regulated in cancer by a variety of mechanisms. (i) MTDH overexpression results from amplification of the MTDH locus at chromosome 8q22 in breast tumors [30] (ii) Activation of H-ras markedly induces expression of MTDH through the PI3K/AKT signaling pathway by increasing the association of c-Myc to the E-box elements of the MTDH promoter (Figure 1) [54,21] (iii) Induction of MTDH expression by hypoxia and glucose deprivation. Stabilization of HIF-1α in response to activation of the PI3K/AKT pathway results in induction of MTDH in glioma cells [55]. The increased expression of MTDH which is associated with glucose deprivation is dependent on the production of reactive oxygen species (ROS); in turn, increased MTDH inhibits ROS production [56] (iv) LPS (lipopolysaccharides) can induce MTDH via activation of the NF-kB pathway in human promonocytic cells and in breast cancer cells. MTDH is required for LPS-induced NF-kB activation via a positive feedback loop between MTDH and NF-kB. MTDH mediated IL-8 and MMP-9 expression is critical in LPS-induced invasion and metastasis [57,58] (v) Reduced expression of tumor suppressor miRNAs such as miR375 and miR26a, which target MTDH, result in increased MTDH levels in cancer cells [59-61]. MTDH is a direct target of three miRNAs, miR-26a, miR-375 and miR-136. MiR-26a represses MTDH expression by directly targeting the 3'UTR of MTDH mRNA in breast cancer cells [61] miR-375 is a well-known tumor suppressor and has been shown to downregulate the expression of MTDH by binding to its 3'-UTR [59-60]. Reverse expression patterns of decreased miR-375 and increased MTDH have been observed in several tumor types including including Head and Neck Squamous Cell Carcinoma (HNSCC), Esophageal Squamous Cell Carcinoma (ESCC), liver cancer and breast cancer [56,57]. MTDH was also identified as a target of miR-136 in glioma cells [62].
Role of FOXM1 and MTDH in drug resistance
The role of FOXM1 in DNA repair, which occurs by homologous recombination (HR) but not non-homologous end joining (NHEJ), has been demonstrated using an integrated direct repeat green fluorescent protein (GFP) reporter system of DSB (double strand break) repair in HeLa cells. Two critical proteins for HR repair, BRIP1 (BRCA1-associated BACH1 helicase) [63] and Rad51, [64] have been identified as direct transcriptional targets of FOXM1 by promoter analysis and chromatin-immunoprecipitation. Correlation of FOXM1 with the expression of two other DNA repair genes, XRCC1 (X-ray repair cross-complementing protein 1) and BRCA2 (breast cancer-associated gene 2), has been observed in osteosarcoma cells [65]. The occurrence of genomic instability in cancer cells with FOXM1 overexpression has also been shown by LOH (loss of heterozygosity) and copy number variations (CNV) measurement. The role of FOXM1 in the DNA damage response and in DSB HR repair implicates it as an attractive target for therapies employing DNA damaging agents such as platinum, topoisomerase inhibitors, IR, or alkylators. Indeed, targeting FOXM1 increases the sensitivity of tumor cells to DNA damaging agents [66-68].
A transgenic mouse with hepatocyte-specific expression of MTDH (Alb/MTDH) accelerated development of HCC when exposed to the hepatocarcinogen, N-nitrosodiethylamine (DEN) compared to wild type mouse [69].Alb/AEG-1 hepatocytes display significant resistance to senescence. Reduced ROS levels and fewer senescent cells as well as activation of ATM, ATR, CHK1, and CHK2 occurs in Alb/AEG-1 hepatocytes following isolation compared to control hepatocytes. This indicates that MTDH is involved in the DDR response. A further development has been the identification of MTDH as a new RNA binding protein with the potential to control the levels of important DNA repair factors at the post-transcriptional level. Association of MTDH with various mRNAs was recently identified by RNA-binding protein immunoprecipitation followed by microarray analysis (RIP-chip) [18]. The mRNAs bound to MTDH encode various functional proteins including multiple members of the Fanconi pathway (FANCA, FANCD2, FANCI) [18,70]. An attractive hypothesis is that high expression of MTDH allows cancer cells to rapidly repair DNA in the setting of cell stress, including chemotherapy, and this potentiates therapeutic resistance.
Therapeutic opportunities of targeting FOXM1 and MTDH
There are a number of ways in which FOXM1 and MTDH can be targeted. Thiazole compounds, Siomycin A and thiostrepton, have been identified as potential FOXM1 small chemical inhibitors [71,72]. Both Siomycin A and thiostrepton can repress the transcriptional activity of FOXM1 and decrease FOXM1 at the mRNA and protein level in cancer cells. The action of both Siomycin A and thiostrepton could be related to their ability to function as proteasome inhibitors [73]. Neither agent causes any anti-proliferation or apoptotic effects on untransformed cells, thus making them potentially attractive therapeutic drugs for cancers with FOXM1 overexpression. FOXM1 is regulated by NPM1 and ARF [74,75] NPM promotes cancer cell survival and FOXM1 is a novel inhibitory target of p19 (ARF). A p19 (ARF) 26-44 peptide containing nine D-Arg residues was sufficient to reduce FOXM1 transcriptional activity and tumor proliferation in HCC. Interaction of FOXM1 with the multifunctional protein NPM has been observed by mass spectrometry analysis, co-immunoprecipitation and glutathione S-transferase pull-down. Knockdown of NPM caused significant down-regulation of FOXM1 in cancer cells to the levels found in normal cells. The interaction between FOXM1 and NPM could potentially be disrupted by peptides or small molecules, leading to a FOXM1 targeted therapy. A potential future therapeutic strategy might be to delivery RNA molecules which target MTDH or FOXM1; however, employing RNA-based regimens for treatment will require significantly more research and development before they can be widely used in patients. The potential anticancer agents ursolic acid [76,77] and cryptotanshinone [78] have been found to repress expression of MTDH in ovarian and prostate cancer. HIF-1α was shown to be involved in the repression of MTDH by cryptotanshinone [78]. In addition, cadmium chloride reduced MTDH expression and NF-kB activity in breast cancer cells [79].
Conclusion and future perspectives
In summary, both MTDH and FOXM1 are emerging as critical master regulators of cancer development that may affect all of the hallmarks of cancer. Both FOXM1 and MTDH might become markers routinely used in a clinical diagnostic laboratory as well as therapeutic targets to overcome drug resistance in diverse cancers. The presence of increased MTDH on the surface of cancer cells might be developed as antibody-based diagnostic or therapeutic [80-82]. Further work to understand the function of MTDH is warranted. The following questions must be investigated; 1. What is the biological significance of MTDH in normal physiological conditions? 2. Do any of the different isoforms/modifications of MTDH identified from sequence predictions contribute to the impact of MTDH in cancer? MTDH has a broad range of protein and RNA binding partners in different cellular components. 3. Does MTDH function as a scaffold protein or does it directly influence the function or expression of its different binding partners? Understanding these basic cellular and biochemical properties of MTDH will help in the development of effective inhibitors. For FOXM1, more studies are needed to develop more specific inhibitors of FOXM1 to achieve clinical benefits. Oncogenic miRNAs regulated by FOXM1 could be developed as new therapeutic targets. In addition, tumor suppressor miRNAs that repress FOXM1 could be developed as FOXM1 inhibitors.
This work was partially supported by NIH Grant 2R01CA99908-11 to K.K.L., the Department of Obstetrics and Gynecology Research Development Fund at the University of Iowa. We also thank Dr. Eric Devor for assistance in manuscript preparation.

  1. Suh DH, Kim JW, Kim K, Kim HJ, Lee KH. Major clinical research advances in gynecologic cancer in 2012. J Gynecol Oncol. 2013; 24: 66-82.
  2. Smolle E, Taucher V, Pichler M, Petru E, Lax S, Haybaeck J. Targeting signaling pathways in epithelial ovarian cancer. Int J Mol Sci. 2013; 14: 9536-9555.
  3. Tomao F, Papa A, Rossi L, Caruso D, Panici PB, Venezia M, et al. Current status of bevacizumab in advanced ovarian cancer. Onco Targets Ther. 2013; 6: 889-899.
  4. Hall M, Gourley C, McNeish I, Ledermann J, Gore M, Jayson G, et al. Targeted anti-vascular therapies for ovarian cancer: current evidence. Br J Cancer. 2013; 108: 250-258.
  5. Wierstra I. FOXM1 (Forkhead box M1) in Tumorigenesis: Overexpression in Human Cancer, Implication in Tumorigenesis, Oncogenic Functions, Tumor-Suppressive Properties, and Target of Anticancer Therapy. Adv Cancer Res. 2013; 119: 191-419.
  6. Wierstra I. The transcription factor FOXM1 (Forkhead box M1): proliferation-specific expression, transcription factor function, target genes, mouse models, and normal biological roles. Adv Cancer Res. 2013; 118: 97-398.
  7. Teh MT. FOXM1 coming of age: time for translation into clinical benefits? Front Oncol. 2012; 2: 146.
  8. Teh MT. Cells brainwashed by FOXM1: do they have potential as biomarkers of cancer? Biomark Med. 2012; 6: 499-501.
  9. Alvarez-Fernández M, Medema RH. Novel functions of FoxM1: from molecular mechanisms to cancer therapy. Front Oncol. 2013; 3: 30.
  10. Lee SG, Kang DC, Desalle R, Sarkar D, Fisher PB. AEG-1/MTDH/LYRIC, the Beginning: Initial Cloning, Structure, Expression Profile, and Regulation of Expression. Adv Cancer Res. 2013; 120: 1-38.
  11. Emdad L, Das SK, Dasgupta S, Hu B, Sarkar D, Fisher PB. AEG-1/MTDH/LYRIC: Signaling Pathways, Downstream Genes, Interacting Proteins, and Regulation of Tumor Angiogenesis. Adv Cancer Res. 2013; 120: 75-111.
  12. Wan L, Kang Y. Pleiotropic Roles of AEG-1/MTDH/LYRIC in Breast Cancer. Adv Cancer Res. 2013; 120: 113-134.
  13. Sarkar D, Fisher PB. AEG-1/MTDH/LYRIC: Clinical Significance. Adv Cancer Res. 2013; 120: 39-74.
  14. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011; 474: 609-615.
  15. Lam EW, Brosens JJ, Gomes AR, Koo CY. Forkhead box proteins: tuning forks for transcriptional harmony. Nat Rev Cancer. 2013; 13: 482-495.
  16. Zhao F, Lam EW. Role of the forkhead transcription factor FOXO-FOXM1 axis in cancer and drug resistance. Front Med. 2012; 6: 376-380.
  17. Gomes AR, Zhao F, Lam EW. Role and regulation of the forkhead transcription factors FOXO3a and FOXM1 in carcinogenesis and drug resistance. Chin J Cancer. 2013; 32: 365-370.
  18. Meng X, Zhu D, Yang S, Wang X, Xiong Z, Zhang Y, et al. Cytoplasmic Metadherin (MTDH) provides survival advantage under conditions of stress by acting as RNA-binding protein. J Biol Chem. 2012; 287: 4485-4491.
  19. Meng X, Brachova P, Yang S, Xiong Z, Zhang Y, Thiel KW, et al. Knockdown of MTDH sensitizes endometrial cancer cells to cell death induction by death receptor ligand TRAIL and HDAC inhibitor LBH589 co-treatment. PLoS One. 2011; 6: e20920.
  20. Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H, Tanaka Y, et al. Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity. Oncogene. 2007; 26: 7647-7655.
  21. Lee SG, Su ZZ, Emdad L, Sarkar D, Fisher PB. Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc. Proc Natl Acad Sci U S A. 2006; 103: 17390-17395.
  22. Gartel AL. The oncogenic transcription factor FOXM1 and anticancer therapy. Cell Cycle. 2012; 11: 3341-3342.
  23. Halasi M, Gartel AL. Targeting FOXM1 in cancer. Biochem Pharmacol. 2013; 85: 644-652.
  24. Halasi M, Gartel AL. FOX(M1) news--it is cancer. Mol Cancer Ther. 2013; 12: 245-254.
  25. Halasi M, Gartel AL. Suppression of FOXM1 sensitizes human cancer cells to cell death induced by DNA-damage. PLoS One. 2012; 7: e31761.
  26. Wang M, Gartel AL. The suppression of FOXM1 and its targets in breast cancer xenograft tumors by siRNA. Oncotarget. 2011; 2: 1218-1226.
  27. Li J, Yang L, Song L, Xiong H, Wang L, Yan X, et al. Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1. Oncogene. 2009; 28: 3188-3196.
  28. Li J, Zhang N, Song LB, Liao WT, Jiang LL, Gong LY, et al. Astrocyte elevated gene-1 is a novel prognostic marker for breast cancer progression and overall patient survival. Clin Cancer Res. 2008; 14: 3319-3326.
  29. Li C, Li R, Song H, Wang D, Feng T, Yu X, et al. Significance of AEG-1 expression in correlation with VEGF, microvessel density and clinicopathological characteristics in triple-negative breast cancer. J Surg Oncol. 2011; 103: 184-192.
  30. Hu G, Chong RA, Yang Q, Wei Y, Blanco MA, Li F, et al. MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer. Cancer Cell. 2009; 15: 9-20.
  31. Meng F, Luo C, Ma L, Hu Y, Lou G. Clinical significance of astrocyte elevated gene-1 expression in human epithelial ovarian carcinoma. Int J Gynecol Pathol. 2011; 30: 145-150.
  32. Li C, Liu J, Lu R, Yu G, Wang X, Zhao Y, et al. AEG -1 overexpression: a novel indicator for peritoneal dissemination and lymph node metastasis in epithelial ovarian cancers. Int J Gynecol Cancer. 2011; 21: 602-608.
  33. Li C, Li Y, Wang X, Wang Z, Cai J, Wang L, et al. Elevated expression of astrocyte elevated gene-1 (AEG-1) is correlated with cisplatin-based chemoresistance and shortened outcome in patients with stages III-IV serous ovarian carcinoma. Histopathology. 2012; 60: 953-963.
  34. Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013; 497: 67-73.
  35. Song H, Li C, Lu R, Zhang Y, Geng J. Expression of astrocyte elevated gene-1: a novel marker of the pathogenesis, progression, and poor prognosis for endometrial cancer. Int J Gynecol Cancer. 2010; 20: 1188-1196.
  36. Green MR, Aya-Bonilla C, Gandhi MK, Lea RA, Wellwood J, Wood P, et al. Integrative genomic profiling reveals conserved genetic mechanisms for tumorigenesis in common entities of non-Hodgkin's lymphoma. Genes Chromosomes Cancer. 2011; 50: 313-326.
  37. Korver W, Roose J, Heinen K, Weghuis DO, de Bruijn D, van Kessel AG, et al. The human TRIDENT/HFH-11/FKHL16 gene: structure, localization, and promoter characterization. Genomics. 1997; 46: 435-442.
  38. Zhang N, Wei P, Gong A, Chiu WT, Lee HT, Colman H, et al. FoxM1 promotes β-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis. Cancer Cell. 2011; 20: 427-442.
  39. Bhat UG, Jagadeeswaran R, Halasi M, Gartel AL. Nucleophosmin interacts with FOXM1 and modulates the level and localization of FOXM1 in human cancer cells. J Biol Chem. 2011; 286: 41425-41433.
  40. Anders L, Ke N, Hydbring P, Choi YJ, Widlund HR, Chick JM, et al. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell. 2011; 20: 620-634.
  41. Millour J, de Olano N, Horimoto Y, Monteiro LJ, Langer JK, Aligue R, et al. ATM and p53 regulate FOXM1 expression via E2F in breast cancer epirubicin treatment and resistance. Mol Cancer Ther. 2011; 10: 1046-1058.
  42. Blanco-Bose WE, Murphy MJ, Ehninger A, Offner S, Dubey C, Huang W, et al. C-Myc and its target FoxM1 are critical downstream effectors of constitutive androstane receptor (CAR) mediated direct liver hyperplasia. Hepatology. 2008; 48: 1302-1311.
  43. Xia LM, Huang WJ, Wang B, Liu M, Zhang Q, Yan W, et al. Transcriptional up-regulation of FoxM1 in response to hypoxia is mediated by HIF-1. J Cell Biochem. 2009; 106: 247-256.
  44. Barsotti AM, Prives C. Pro-proliferative FoxM1 is a target of p53-mediated repression. Oncogene. 2009; 28: 4295-4305.
  45. Qu K, Xu X, Liu C, Wu Q, Wei J, Meng F, et al. Negative regulation of transcription factor FoxM1 by p53 enhances oxaliplatin-induced senescence in hepatocellular carcinoma. Cancer Lett. 2013; 331: 105-114.
  46. Pandit B, Halasi M, Gartel AL. p53 negatively regulates expression of FoxM1. Cell Cycle. 2009; 8: 3425-3427.
  47. Wierstra I, Alves J. Transcription factor FOXM1c is repressed by RB and activated by cyclin D1/Cdk4. Biol Chem. 2006; 387: 949-962.
  48. Teh MT, Wong ST, Neill GW, Ghali LR, Philpott MP, Quinn AG. FOXM1 is a downstream target of Gli1 in basal cell carcinomas. Cancer Res. 2002; 62: 4773-4780.
  49. Feng Y, Wang L, Zeng J, Shen L, Liang X, Yu H, et al. FoxM1 is Overexpressed in Helicobacter pylori-Induced Gastric Carcinogenesis and Is Negatively Regulated by miR-370. Mol Cancer Res. 2013; 11: 834-844.
  50. Lin PC, Chiu YL, Banerjee S, Park K, Mosquera JM, Giannopoulou E, et al. Epigenetic repression of miR-31 disrupts androgen receptor homeostasis and contributes to prostate cancer progression. Cancer Res. 2013; 73: 1232-1244.
  51. Li J, Wang Y, Luo J, Fu Z, Ying J, Yu Y, et al. miR-134 inhibits epithelial to mesenchymal transition by targeting FOXM1 in non-small cell lung cancer cells. FEBS Lett. 2012; 586: 3761-3765.
  52. Zhang X, Zeng J, Zhou M, Li B, Zhang Y, Huang T, et al. The tumor suppressive role of miRNA-370 by targeting FoxM1 in acute myeloid leukemia. Mol Cancer. 2012; 11: 56.
  53. Liu S, Guo W, Shi J, Li N, Yu X, Xue J, et al. MicroRNA-135a contributes to the development of portal vein tumor thrombus by promoting metastasis in hepatocellular carcinoma. J Hepatol. 2012; 56: 389-396.
  54. Lee SG, Su ZZ, Emdad L, Sarkar D, Franke TF, Fisher PB. Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling. Oncogene. 2008; 27: 1114-1121.
  55. Lee HJ, Jung DB, Sohn EJ, Kim HH, Park MN, Lew JH, et al. Inhibition of Hypoxia Inducible Factor Alpha and Astrocyte-Elevated Gene-1 Mediates Cryptotanshinone Exerted Antitumor Activity in Hypoxic PC-3 Cells. Evid Based Complement Alternat Med. 2012; 2012: 390957.
  56. Noch E, Bookland M, Khalili K. Astrocyte-elevated gene-1 (AEG-1) induction by hypoxia and glucose deprivation in glioblastoma. Cancer Biol Ther. 2011; 11: 32-39.
  57. Emdad L, Sarkar D, Su ZZ, Randolph A, Boukerche H, Valerie K, et al. Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis. Cancer Res. 2006; 66: 1509-1516.
  58. Sarkar D, Park ES, Emdad L, Lee SG, Su ZZ, Fisher PB. Molecular basis of nuclear factor-kappaB activation by astrocyte elevated gene-1. Cancer Res. 2008; 68: 1478-1484.
  59. He XX, Chang Y, Meng FY, Wang MY, Xie QH, Tang F, et al. MicroRNA-375 targets AEG-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo. Oncogene. 2012; 31: 3357-3369.
  60. Nohata N, Hanazawa T, Kikkawa N, Mutallip M, Sakurai D, Fujimura L, et al. Tumor suppressive microRNA-375 regulates oncogene AEG-1/MTDH in head and neck squamous cell carcinoma (HNSCC). J Hum Genet. 2011; 56: 595-601.
  61. Zhang B, Liu XX, He JR, Zhou CX, Guo M, He M, et al. Pathologically decreased miR-26a antagonizes apoptosis and facilitates carcinogenesis by targeting MTDH and EZH2 in breast cancer. Carcinogenesis. 2011; 32: 2-9.
  62. Yang Y, Wu J, Guan H, Cai J, Fang L, Li J, et al. MiR-136 promotes apoptosis of glioma cells by targeting AEG-1 and Bcl-2. FEBS Lett. 2012; 586: 3608-3612.
  63. Monteiro LJ, Khongkow P, Kongsema M, Morris JR, Man C, Weekes D, et al. The Forkhead Box M1 protein regulates BRIP1 expression and DNA damage repair in epirubicin treatment. Oncogene. 2012; .
  64. Zhang N, Wu X, Yang L, Xiao F, Zhang H, Zhou A, et al. FoxM1 inhibition sensitizes resistant glioblastoma cells to temozolomide by downregulating the expression of DNA-repair gene Rad51. Clin Cancer Res. 2012; 18: 5961-5971.
  65. Tan Y, Raychaudhuri P, Costa RH. Chk2 mediates stabilization of the FoxM1 transcription factor to stimulate expression of DNA repair genes. Mol Cell Biol. 2007; 27: 1007-1016.
  66. Wilson MS, Brosens JJ, Schwenen HD, Lam EW. FOXO and FOXM1 in cancer: the FOXO-FOXM1 axis shapes the outcome of cancer chemotherapy. Curr Drug Targets. 2011; 12: 1256-1266.
  67. Park YY, Jung SY, Jennings NB, Rodriguez-Aguayo C, Peng G, Lee SR, et al. FOXM1 mediates Dox resistance in breast cancer by enhancing DNA repair. Carcinogenesis. 2012; 33: 1843-1853.
  68. Kwok JM, Peck B, Monteiro LJ, Schwenen HD, Millour J, Coombes RC, et al. FOXM1 confers acquired cisplatin resistance in breast cancer cells. Mol Cancer Res. 2010; 8: 24-34.
  69. Srivastava J, Siddiq A, Emdad L, Santhekadur PK, Chen D, Gredler R, et al. Astrocyte elevated gene-1 promotes hepatocarcinogenesis: novel insights from a mouse model. Hepatology. 2012; 56: 1782-1791.
  70. Meng X, Thiel KW, Leslie KK. Drug Resistance Mediated by AEG-1/MTDH/LYRIC. Adv Cancer Res. 2013; 120: 135-157.
  71. Radhakrishnan SK, Bhat UG, Hughes DE, Wang IC, Costa RH, Gartel AL. Identification of a chemical inhibitor of the oncogenic transcription factor forkhead box M1. Cancer Res. 2006; 66: 9731-9735.
  72. Bhat UG, Halasi M, Gartel AL. Thiazole antibiotics target FoxM1 and induce apoptosis in human cancer cells. PLoS One. 2009; 4: e5592.
  73. Bhat UG, Halasi M, Gartel AL. FoxM1 is a general target for proteasome inhibitors. PLoS One. 2009; 4: e6593.
  74. Costa RH, Kalinichenko VV, Major ML, Raychaudhuri P. New and unexpected: forkhead meets ARF. Curr Opin Genet Dev. 2005; 15: 42-48.
  75. Kalinichenko VV, Major ML, Wang X, Petrovic V, Kuechle J, Yoder HM, et al. Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Genes Dev. 2004; 18: 830-50.
  76. Liu K, Guo L, Miao L, Bao W, Yang J, Li X, et al. Ursolic acid inhibits epithelial-mesenchymal transition by suppressing the expression of astrocyte-elevated gene-1 in human nonsmall cell lung cancer A549 cells. Anticancer Drugs. 2013; 24: 494-503.
  77. Song YH, Jeong SJ, Kwon HY, Kim B, Kim SH, Yoo DY. Ursolic acid from Oldenlandia diffusa induces apoptosis via activation of caspases and phosphorylation of glycogen synthase kinase 3 beta in SK-OV-3 ovarian cancer cells. Biol Pharm Bull. 2012; 35: 1022-1028.
  78. Lee HJ, Jung DB, Sohn EJ, Kim HH, Park MN, Lew JH, et al. Inhibition of Hypoxia Inducible Factor Alpha and Astrocyte-Elevated Gene-1 Mediates Cryptotanshinone Exerted Antitumor Activity in Hypoxic PC-3 Cells. Evid Based Complement Alternat Med. 2012; 2012: 390957.
  79. Luparello C, Longo A, Vetrano M. Exposure to cadmium chloride influences astrocyte-elevated gene-1 (AEG-1) expression in MDA-MB231 human breast cancer cells. Biochimie. 2012; 94: 207-213.
  80. Chen X, Dong K, Long M, Lin F, Wang X, Wei J, et al. Serum anti-AEG-1 auto-antibody is a potential novel biomarker for malignant tumors. Oncol Lett. 2012; 4: 319-323.
  81. Brown DM, Ruoslahti E. Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell. 2004; 5: 365-374.
  82. Medine EI, Odaci D, Gacal BN, Gacal B, Sakarya S, Unak P, et al. A new approach for in vitro imaging of breast cancer cells by anti-metadherin targeted PVA-pyrene. Macromol Biosci. 2010; 10: 657-663.

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.
Right Table
Current Issue Vol.1.1
Content:   Home  |  Aims & Scope  |  Early Online  |  Current Issue  | 
Journal Info:   Editorial Board  |  Article Processing Charges  |  FAQs
Contact Us
2952 Market Street, Suite 140
San Diego, California 92102, USA
Tel: 1-619-373-8030
Fax: 1-619-793-4845
Toll free number: 1-800-762-9856
Copyright © 2013 JSciMed Central. All rights reserved.