The Multifaceted Role of MTDH/AEG-1 in Cancer Progression Guohong Hu,1 Yong Wei,1 and Yibin Kang1,2

Published OnlineFirst September 1,09-0049 2009; DOI: 10.1158/1078-0432.CCR-09-0049 Published Online First on September 1, 2009 as 10.1158/1078-0432.CCR-09-0049 Molecular Pathways

Abstract Cancer is the result of the progressive acquisition of multiple malignant traits through the accumulation of genetic or epigenetic alterations. Recent studies have established a functional role of MTDH (Metadherin)/AEG-1 (Astrocyte Elevated Gene 1) in several crucial aspects of tumor progression, including transformation, evasion of apoptosis, invasion, metastasis, and chemoresistance. Overexpression of MTDH/AEG-1 is frequently observed in melanoma, glioma, neuroblastoma, and carcinomas of breast, prostate, liver, and esoph- agus and is correlated with poor clinical outcomes. MTDH/AEG-1 functions as a downstream mediator of the transforming activity of oncogenic Ha-Ras and c-Myc. Furthermore, MTDH/AEG-1 overexpression activates the PI3K/Akt, nuclear factorκB(NFκB), and Wnt/β-catenin signaling pathways to stimulate proliferation, invasion, cell survival, and chemoresistance. The lung-homing domain of MTDH/AEG-1 also mediates the adhesion of tumor cells to the vasculature of distant organs and promotes metastasis. These findings suggest that therapeutic targeting of MTDH/AEG-1 may simultaneously suppress tumor growth, block metastasis, and enhance the efficacy of chemotherapeutic treatments. (Clin Cancer Res 2009;15(18):OF1–5)

Background protein ZO-1 in polarized rat prostate epithelial cells (9), and as a novel transmembrane protein that is present in cytoplasm, Cancer progression is driven by the accumulation of numer- endoplasmic reticulum, perinuclear regions, and nucleolus (10). ous genetic and epigenetic alterations that promote tumor ini- MTDH/AEG-1 orthologs were found in most vertebrate spe- – tiation, expansion, and metastasis (1 3). In the past few cies but not in non-vertebrates. Although evolutionally highly decades, massive efforts in cancer research have led to the iden- conserved, MTDH/AEG-1 does not have any recognizable pro- tification of a seemingly exhaustive list of oncogenes, tumor tein domains except three putative lysine-rich nuclear localiza- suppressors, and signal pathways that are potential targets for tion signals (NLS). Human MTDH/AEG-1 encodes a 582-amino Metadherin MTDH, anticancer therapeutics. ( also known as acid protein with a calculated molecular mass of 64 kDa. AEG-1 Lyric ,and ), a novel gene that was cloned only 5 years MTDH/AEG-1 is expressed in variable levels in most tissues. ago, has emerged in recent years as a potentially crucial medi- Antibodies against MTDH/AEG-1 often detect multiple proteins ator of tumor malignancy and a key converging point of a com- with molecular weights ranging from 75 to 80 kDa to 20 kDa, plex networkof oncogenic signaling pathways (4, 5). possibly because of alternative splicing and/or posttranslational modification (7–10).MTDH/AEG1isrichinbothlysine Cloning and molecular characteristics. MTDH/AEG-1 was (12.3%) and serine (11.6%) residues that are targets for post- originally reported as a novel late response gene induced in translational modifications such as acetylation and ubiquitina- human fetal astrocytes after HIV-1 infection or treatment with tion of lysines (11) and phosphorylation of serine and viral glycoprotein gp120 or TNF-α (6). Full-length MTDH/AEG- threonine. How posttranscriptional and posttranslational mod- 1 cDNA was subsequently cloned by four independent groups ifications of MTDH/AEG-1 influence its function and localiza- (7–10). Brown and colleagues used a phage display screen to tion is currently unknown. identify a lung-homing peptide in MTDH that allowed the Immunofluorescence and immunohistochemical analysis of specific adhesion of mouse 4T1 mammary tumor cells to lung MTDH/AEG-1 often showed perinuclear and cytoplasmic stain- vascular endothelium (8). The mouse-rat ortholog of MTDH/ ing as well as some nuclear rim, nucleolar, and general nuclear AEG-1 was also found to encode the lysine-rich CEACAM-1 co- diffuse staining in various cell types (4, 7, 9, 10). Cytoplasmic isolated protein (Lyric) that colocalizes with the tight junction membrane localization of MTDH/AEG-1 has also been detected by immunostaining of nonpermeablized mouse 4T1 mammary tumor cells and by FACS (8). TNF-α treatment, 1 Authors'Affiliations: Department of Molecular Biology, Princeton which up-regulates MTDH/AEG-1 expression, as well as ectopic University, Princeton, New Jersey and 2Breast Cancer Program, Cancer Institute of New Jersey, New Brunswick, New Jersey overexpression of MTDH/AEG-1, has been shown to enhance Received 4/30/09; revised 5/14/09; accepted 5/15/09; published OnlineFirst nuclear localization of MTDH/AEG-1 in HeLa cells (12). 9/1/09. Nuclear localization of MTDH/AEG-1 is probably mediated Requests for reprints: Yibin Kang, Department of Molecular Biology, by three putative lysine-rich NLS sequences, although the Princeton University, Princeton, New Jersey 08544. Phone: 609-258-8834; Fax: 609-258-2340; E-mail: [email protected]. exact mechanism and functional significance of MTDH/AEG-1 F 2009 American Association for Cancer Research. nuclear and nucleolar translocation is still under investigation doi:10.1158/1078-0432.CCR-09-0049 (11, 12). Several independent protein motif analysis methods

www.aacrjournals.org OF1 Clin Cancer Res 2009;15(18) September 15, 2009 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst September 1, 2009;09-0049 DOI: 10.1158/1078-0432.CCR-09-0049 Molecular Pathways predict a single transmembrane domain (amino acids 52–74) in man fetal astrocytes (13) and MTDH/AEG-1 knockdown sup- MTDH/AEG-1. However, there is still a debate about whether pressed Ras-induced colony formation (13). Ras plays an MTDH/AEG-1 is a type Ib membrane protein (C-terminal in essential role in regulating cell growth, survival, stress response, the cytoplasmic side with no signal peptide), or a type II protein cytoskeleton reorganization, and migration by activating a (C-terminal outside) based on computational modeling (7, 9) number of downstream signaling pathways, including the and experiment evidence (8, 9). Although a considerable amount Raf/MAPK pathway (cell proliferation), the PI3K-Akt pathway of workis still required to fully characterize the molecular and (cell survival), the Rac-Rho pathway (cytoskeletal reorganiza- biochemical properties of MTDH/AEG-1, functional and clinical tion), and the Rac-JNK/p38 pathways (stress response; ref. evidence accumulated in recent years strongly support an impor- 14–18). When inhibitors for various Ras downstream signaling tant role for MTDH/AEG-1 in cancer development. pathways were tested, only PI3K/Akt inhibitors LY294002 and Integration of oncogenic pathways. MTDH/AEG-1 contri- PTEN were able to blockthe MTDH/AEG-1 promoter activation butes to several hallmarks of metastatic cancers, including aber- by Ras, suggesting the involvement of PI3K/Akt pathway in rant proliferation, survival under stressful conditions such as MTDH/AEG-1 regulation (13). Promoter mapping subsequent- serum deprivation and chemotherapy, and increased migration, ly identified two E-boxes (binding sites for c-Myc) in the -356 invasiveness, and metastasis. Overexpression of MTDH/AEG-1 to -302 region of the MTDH/AEG-1 promoter that is essential synergizes with oncogenic Ha-Ras to enhance soft-agar colony for activation by Ras (13). Linking the Akt activation to c-Myc formation of immortalized melanocyte and astrocyte (7). Con- regulation of MTDH/AEG-1 is the phosphorylation and inacti- versely, MTDH/AEG-1 was activated at the transcription level vation of GSK3β, a serine-threonine kinase that phosphorylates upon transient or stable transfection of oncogenic Ras in hu- and destabilizes c-Myc (13, 19, 20). Collectively, these data link

Fig. 1. MTDH/AEG-1 promotes tumor progression through the integration of multiple signaling pathways. Oncogenic Ha-Ras increases MTDH/AEG-1 expression through the activation of the PI3K/Akt pathway, which phosphorylates and inactivates GSK3β, and subsequently enhances the stabilization and binding of c-Myc to the MTDH/AEG-1 promoter. MTDH/AEG-1 can activate AKT, NFκB, and Wnt/β-catenin pathways to promote proliferation, survival, and invasion. Activation of NFκB signaling is in part mediated by the direct interaction of MTDH/AEG-1 with p65 and CBP, a general transcriptional co-activator. MTDH/AEG-1 activates the Wnt/β-catenin pathway through increasing the activity of MAPK kinases ERK and p38, which phosphorylates GSK3β and stabilized β-catenin. Furthermore, MTDH/AEG-1 increases the expression of LEF-1, a transcriptional cofactor for β-catenin. The prometastasis function of MTDH/AEG-1 is mediated by the interaction of the LHD of MTDH/AEG-1 with an unknown receptor in endothelial cells. The broad spectrum chemoresistance function of MTDH/AEG-1 is mediated by a number of downstream genes that promote the resistance to multiple chemotherapeutic agents. Proteins with direct interactions with MTDH/AEG1 are shown in green. Dotted line indicates pathways yet to be fully validated or characterized.

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MTDH/AEG-1 in Tumor Progression

Ras activation of MTDH/AEG-1 through PI3K-Akt-GSK3β-Myc nuclear translocation of β-catenin. Furthermore, MTDH/AEG-1 signaling (Fig. 1) in transformed astrocytes. overexpression also increases the level of LEF-1, a transcription Depending on the cell types tested, overexpression of MTDH/ factor that interacts with β-catenin to activate gene expression AEG-1 can activate several downstream pathways, including the in the nucleus. Specific inhibitors of the MAPK pathway are able Akt pathway, the nuclear factor κB(NFκB) pathway, and the to abolish the oncogenic effect of MTDH/AEG-1 in matrigel Wnt/β-catenin pathway, to enhance different aspects of tumor invasion and anchorage-independent growth (28). malignancy. MTDH/AEG-1 overexpression inhibits serum Metastasis. A lung-homing domain (LHD, amino acids 378- starvation-induced apoptosis in normal astrocytes and fibro- 440 in mouse or 381-443 in human) in MTDH/AEG1 was iden- blasts, but not in Ras-transformed cells (21). When a panel tified by Brown and colleagues in a phage display experiment to of pathway-specific inhibitors was used to probe the down- be a mediator of 4T1 mouse mammary tumor cell adhesion to stream mediator for the prosurvival function of MTDH/AEG- lung vasculature (8). Neutralizing antibodies against LHD- or 1, only the PI3K inhibitor LY294002, PTEN, and dominant siRNA-silencing of MTDH/AEG-1 efficiently reduced lung metas- negative Akt were able to attenuate MTDH/AEG-1-dependent tasis of 4T1 cancer cells. Conversely, overexpression of MTDH/ survival under serum-deprived conditions (21). MTDH/AEG-1 AEG-1 in the human embryonic kidney cells HEK293 led to en- overexpression increases phosphorylation of Akt and GSK3β, hanced localization of these cells to lung vasculatures (8). The with subsequent c-Myc stabilization and MDM2 phosphoryla- endothelial adhesion and metastasis-promoting function of tion, decrease of p53 and CDK inhibitor p21CIP1,aswellas MTDH/AEG-1 has been validated using the MDA-MB-231 xeno- phosphorylation of Bad, a proapoptotic member of the Bcl-2 graft model of breast cancer metastasis (29). In this model family in astrocytes (21). These results indicate that MTDH/ system, MTDH/AEG-1 was found to not only promote lung AEG-1-dependent cell growth and survival is mediated by Akt metastasis, but also modestly increase bone metastasis. MTDH/ signaling downstream of PI3K (21). Thus, MTDH/AEG-1 is both AEG-1 may promote metastasis through the interaction of the a downstream target of Akt and an upstream activator of the LHD with an unknown receptor expressed in the surface of PI3K-Akt pathway, although the mechanism of PI3K pathway endothelial cells, or indirectly through the activation of signaling activation by MTDH/AEG-1 remains unknown (Fig. 1). pathways, such as NFκB, that activate the expression of adhesion Through the activation of Akt, MTDH/AEG-1 may affect a molecules. number of additional Akt downstream factors that are crucial Chemoresistance. In addition to promoting cell survival in for cellular proliferation and survival. MTDH/AEG-1 knockdown the serum starvation condition through activating the PI3K- induces apoptosis of prostate cancer cells through the reduction Akt signaling pathway (21, 22), a more general role for of Akt activity and upregulation of FOXO3a activity (22). FOX- MTDH/AEG-1 to confer broad-spectrum chemoresistance has O3a is a pro-apoptosis forkhead transcription factor that is ex- also been discovered recently (29, 30). Pharmacogenomic anal- ported from the nucleus following phosphorylation by Akt ysis of the NCI-60 panel of cancer cell lines revealed a signifi- (19, 23). The activator protein 1 (AP-1) and NFκB, two other cant correlation of MTDH/AEG-1 overexpression with the transcription regulators downstream of the PI3K/Akt pathway, resistance of cancer cells to a broader spectrum of chemical are also regulated by MTDH/AEG-1 expression (12, 22). compounds. In vitro and in vivo chemoresistance analyses MTDH/AEG-1 enhances nuclear accumulation, DNA binding, showed that MTDH/AEG-1 knockdown sensitizes several differ- and transcriptional activities of NFκBinHelacells(12).The ent breast cancer cell lines to paclitaxel, doxorubicin, cisplatin, NFκB heterodimer p50 and p65 function as transcriptional 4-hydroxycylcophosphamide, hydrogen peroxide, and UV- factors to regulate a variety of cellular phenotypes including ap- radiation. The chemoresistance function of MTDH/AEG-1 has optosis, inflammation, immune response, and oncogenic prolif- also been extended to neuroblastoma (30) and prostate cancer.3 eration (24–26). NFκB can be activated by MTDH/AEG-1 MTDH/AEG-1 does not affect the uptake or retention of chemo- through PI3K/Akt, which activates the IKK kinase to phosphory- therapy drugs. Instead, MTDH/AEG-1 may increase chemoresis- late and destabilize the NFκB inhibitor IκB. Alternatively, tance by promoting cell survival after chemotherapeutic stress. MTDH/AEG-1 has been found to physically interact with the This could be mediated by the prosurvival pathways such as NFκB subunit p65 directly and promote its translocation to PI3K and NFκB, or through other downstream genes of the nucleus (12). Furthermore, MTDH/AEG-1 may bridge the MTDH/AEG-1 that directly regulate chemoresistance. Microarray interaction between p65 and CBP, a ubiquitous transcriptional analysis of breast cancer cells revealed that MTDH/AEG-1 knock- co-activator of NFκB in glioma cells (Fig. 1; ref. 12, 27). In down led to decreased expression of chemoresistance genes Hela cells, ectopic overexpression of MTDH/AEG-1 resulted ALDH3A1, MET, HSP90, and HMOX1, and increased expression in up-regulation of several NFκB-responsive cell adhesion of pro-apoptotic genes BNIP3 and TRAIL (29). Among these molecules, such as ICAM-2 and ICAM-3, selectin E, selectin L, genes, ALDH3A1 and MET were validated to partially contribute and selectin P ligands, as well as many other important mediators to the chemoresistance role of MTDH/AEG-1 in MDA-MB-231 of tumor malignancy, such as IL-6, IL-8, toll-like receptors TLR-4 breast cancer cells (29). Microarray analysis of MTDH/AEG-1 and TLR-5, MMP9, and transcription factors c-Jun and c-Fos overexpression in HepG2 cells reveal another panel of genes that (12, 22). may also contribute to chemoresistance. These genes included More recently, MTDH/AEG-1 has also been connected with the drug-metabolizing enzymes for different chemotherapeutic Wnt/β-catenin pathway in hepatocellular carcinoma cells agents, such as dihydropyrimidine dehydrogenase (DPYD), cyto- through the activation of the Raf/MEK/MAPK branch of the Ras chrome P4502B6 (CYP2B6), dihydrodiol dehydrogenase signaling pathway (28). The MTDH/AEG-1-expressing clones of (AKR1C2), and the ATP-binding cassette transporter ABCC11 human hepatocellular carcinoma HepG3 cells displayed stronger activities of several MAP kinases, including ERK and p38. These kinases phosphorylate GSK3β and increase the stability and 3 G. Hu et al., unpublished results.

www.aacrjournals.org OF3 Clin Cancer Res 2009;15(18) September 15, 2009 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst September 1, 2009;09-0049 DOI: 10.1158/1078-0432.CCR-09-0049 Molecular Pathways for drug efflux (28). Together, these genes may mediate the Hepatocellular carcinoma. In hepatocellular carcinoma cells, broad-spectrum chemoresistance function of MTDH/AEG-1 in expression of MTDH/AEG1 gradually increases from stage I to different cancer types. IV and with a decreasing degree of differentiation (28). MTDH/ AEG-1 overexpression enhances anchorage-independent growth, matrigel invasion, in vivo tumorigenicity, and angiogenesis Clinical-Translational Advances through the enhancement of PI3K/Akt, MAPK, and Wnt/β-catenin pathways (28). Consistent with the role of MTDH/AEG-1 in many different MTDH/AEG-1 overexpression has also been documented in aspects of tumor malignancy, recent clinical studies have convin- glioma, melanoma, and neuroblastoma (7, 30). Overall, MTDH/ cingly linked MTDH/AEG-1 with tumor progression and poor AEG-1 overexpression is strongly correlated with advanced tu- clinical outcomes in many cancer types, including breast cancer, mor characteristics and poor clinical outcomes and is a promis- prostate cancers, glioma, esophageal cancer, and hepatocellular ing target for novel therapeutics. carcinoma. These findings suggest that MTDH/AEG-1 may be de- Clinical translation and therapeutic targeting strategy. First veloped as a powerful independent poor-prognosis marker and a of all, MTDH/AEG-1 overexpression or genomic amplification molecular target for anticancer therapeutics. can be used as biomarker to identify subgroups of patients who Breast cancer. MTDH/AEG-1 is expressed in low levels or is require more aggressive treatment and are likely to benefit from absent in most of normal human breast tissues, but was found to MTDH/AEG-1 targeted therapies. Patients with MTDH/AEG-1 be frequently overexpressed in breast cancer cell lines or breast overexpression or amplification in their tumors are more likely tumors (7, 8, 29, 31). Two independent analyses using breast tu- to suffer from metastatic recurrence and may need to be moni- mor samples collected in the United States and in China revealed tored closely for clinical signs of relapse so that therapeutic in- strikingly similar patterns of MTDH/AEG-1 expression and clin- ventions can be applied early enough for optimal outcomes. ical association (29, 31). MTDH/AEG-1 is abundantly expressed Furthermore, for these high-riskpatients, a higher dose of che- in about 44 to 47% of the primary tumors and is significantly motherapy may be required and combination of chemotherapy correlated with clinical stage, tumor size, lymph node spread, dis- with MTDH/AEG-1 inhibition may help increase the efficacy of tant metastasis, and poor survival (29, 31). MTDH/AEG-1 expres- chemotherapy. There are several possible avenues to develop sion was not correlated with other common clinicopathological novel cancer treatments on the basis of molecular targeting of parameters including age, estrogen receptor, progesterone recep- MTDH/AEG-1. Neutralizing antibodies against MTDH/AEG-1 tor, HER2, and p53 status. No significant difference of MTDH/ can be used to blockits function in endothelial adhesion and re- AEG-1 expression is observed in basal or luminal subtypes of duce the riskof metastasis (8). Polyclonal antibodies against the breast tumors (29). Multivariate analysis suggested that MTDH/ LHD of MTDH/AEG-1 has been shown to reduce lung metastasis AEG-1 expression is an independent prognostic indicator for the by 40% when co-injected with 4T1 mouse mammary tumor cells in experimental lung metastasis assays (8). Similar experiments survival of patients with breast cancer (29, 31). MTDH/AEG-1 using different treatment windows in preclinical metastasis mod- is located at chromosome 8q22, a region frequently amplified els of human breast cancer need to be tested to further validate in many cancers and is associated with poor prognosis (29, the feasibility of this approach before humanized monoclonal 32–35). Indeed, MTDH/AEG-1 is consistently found to be over- antibodies against MTDH/AEG-1 can be developed for clinical expressed in breast tumors with genomic gain of 8q22 (29), trials. Alternatively, siRNA-based reagents can be developed to although a substantial fraction of tumors with normal copies reduce MTDH/AEG-1 expression if the high efficiency of siRNA of MTDH/AEG-1 also overexpress the protein, suggesting alterna- delivery to tumors in vivo can be achieved. Indeed, inhibition tive mechanisms of MTDH/AEG-1 up-regulation (e.g., through of MTDH/AEG-1 expression by RNA interference has been c-Myc activation). Genomic gain of 8q22 has also been asso- shown to effectively reduce metastasis by three- to tenfold in ciated with increased expression of MTDH/AEG-1 in glioma and an MDA-MB-231 xenograft model of breast cancer lung metasta- liver cancers (7, 28). sis (29). Furthermore, MTDH/AEG-1 knockdown sensitizes che- Esophageal squamous cell carcinoma. Similar to the breast moresistant MDA-MB-231 breast tumors to paclitaxel or cancer studies, immunohistochemical analysis of 168 esophageal squamous cell carcinoma (ESCC) specimens revealed that doxorubicin (29). In hepatocellular carcinoma, adenoviral deliv- 47.6% of tumors exhibited high levels of MTDH/AEG-1 expres- ery of MTDH/AEG-1-targeting shRNA inhibits xenograft primary sion (36). Overexpression of MTDH/AEG-1 was significantly tumor growth in mice (28). Thus, MTDH/AEG-1 inhibition may correlated with the clinical stage and various tumor grading be applied in neoadjuvant or adjuvant settings to not only in- parameters, as well as shorter survival. Multivariate analysis crease the response rate of chemotherapy and reduce tumor again indicated that MTDH/AEG-1 expression as an indepen- growth, but also to reduce the systemic spread of metastatic can- dent poor-prognostic indicator for ESCC patients (36). cer. Finally, identification of functionally important interactions Prostate cancer. MTDH/AEG-1 is overexpressed in prostate between MTDH/AEG-1 and its partners may lead to the discovery cancer samples and cell lines compared with benign prostatic of small molecule compounds targeting MTDH/AEG-1. Because hyperplasia tissue samples and normal prostate epithelial cells a considerable level of MTDH/AEG-1 is located in the cytoplasm (11, 22).3 MTDH/AEG-1 inhibition reduces cell viability and and nucleus, inhibitors that blockits intracellular functions may promotes apoptosis of prostate cancer cells, but not normal be needed to effectively reduce its multiple functions in promot- prostate epithelial cells (22). MTDH/AEG-1 is also shown to af- ing tumor malignancy. However, as a novel protein with poorly fect the invasive property of PC3 and DU145 prostate cancer cells characterized functions, it is currently difficult to speculate what (22).3 Interestingly, decreased nuclear staining of MTDH/AEG-1 kind of small molecule inhibitors can be used to block the intra- was associated with increased Gleason grade and shorter survival cellular function of MTDH/AEG-1. Further functional character- of patients (11). MTDH may have a nuclear function in normal ization of MTDH/AEG-1 is urgently needed to realize its full prostate tissue and is lost in tumorigenesis. therapeutic potential.

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MTDH/AEG-1 in Tumor Progression

α CIP Conclusions BCCIP , a cofactor for tumor suppressors BRCA2 and p21 (37). Additional interacting partners for MTDH/AEG-1, particu- As a relatively novel gene, MTDH/AEG-1 has emerged as an larly its adhesion receptor in endothelial cells, still need to be important regulator in multiple aspects of cancer development identified. Further studies to clarify the normal physiological and progression. Clinical and functional analyses have estab- roles of MTDH/AEG-1, the function of its various isoforms, as lished this multifunctional gene as a potentially valuable target well as the regulation of its cellular localization will facilitate in cancer treatments. However, the functional mechanisms of the development of novel cancer treatments through molecular MTDH/AEG-1 in regulating oncogenic signaling pathways re- targeting of MTDH/AEG-1. main poorly understood and some of the findings need to be validated in a broader collection of model systems. In addition to Disclosure of Potential Conflicts of Interest its direct interaction with p65 and CBP, MTDH/AEG-1 was recently found by a yeast hybrid screen to interact and destabilize Y. Kang, commercial research grant, Johnson & Johnson.

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The Multifaceted Role of MTDH/AEG-1 in Cancer Progression

Guohong Hu, Yong Wei and Yibin Kang

Clin Cancer Res Published OnlineFirst September 1, 2009.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-09-0049

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