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Deregulation of the HOXA10 Homeobox Gene in Endometrial Carcinoma: Role in Epithelial-Mesenchymal Transition

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Deregulation of the HOXA10 Homeobox Gene in Endometrial Carcinoma: Role in Epithelial-Mesenchymal Transition Research Article Deregulation of the HOXA10 Homeobox Gene in Endometrial Carcinoma: Role in Epithelial-Mesenchymal Transition Hiroyuki Yoshida,1 Russell Broaddus,2 Wenjun Cheng,1 SuSu Xie,2 and Honami Naora1 Departments of 1Molecular Therapeutics and 2Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas Abstract normally expressed during early urogenital development, and is expressed in renal tumors (6). PAX2 is thought to promote cell Homeobox genes encode transcription factors that control cell survival, and inhibiting PAX2 expression in cancer cells induces differentiation and play essential roles in developmental apoptosis (7). On the other hand, many homeobox genes that are patterning. Increasing evidence indicates that many homeo- normally expressed in differentiated tissues are lost or down- box genes are aberrantly expressed in cancers, and that their regulated in tumors. Nkx3.1 controls prostate morphogenesis and deregulation significantly contributes to tumor progression. is normally expressed in the prostate during development and in The homeobox gene HOXA10 controls uterine organogenesis the adult (8). NKX3.1 is frequently deleted in prostate cancers (9), during embryonic development and functional endometrial and enforced expression of NKX3.1 in prostate cancer cells differentiation in the adult. We investigated whether HOXA10 inhibits cell growth (10). Many other homeobox genes contribute expression is deregulated in endometrial carcinomas, and to tumor progression by promoting cell growth and/or survival how counteracting this aberrant expression modifies tumor (4, 5). However, given the important role of homeobox genes in behavior. We found that down-regulation of HOXA10 expres- cell differentiation, surprisingly little is known regarding their role sion in endometrial carcinomas strongly correlates with in EMT. increased tumor grade and is associated with methylation of Endometrial carcinoma is the fourth most frequently diagnosed the HOXA10 promoter. Enforced expression of HOXA10 in cancer in women. Grade 1 (G ) endometrioid carcinomas of the endometrial carcinoma cells inhibited invasive behavior 1 endometrium are typically well-differentiated, and are mostly in vitro and tumor dissemination in nude mice. The inhibitory detected while still confined to the uterine corpus (11). Grade 3 effect of HOXA10 on invasive behavior was attributable at (G ) endometrioid carcinomas are mostly solid, whereas uterine least in part to the ability of HOXA10 to induce expression of 3 papillary serous carcinoma (UPSC) is characterized by papillary the epithelial cell adhesion molecule E-cadherin by down- patterns of growth. Although histologically distinct, G endome- regulating expression of Snail, a repressor of E-cadherin gene 3 trioid carcinoma and UPSC share several common features transcription. These findings reveal a novel role for HOXA10 including high-grade nuclear atypia and poor responsiveness to deregulation in the progression of endometrial carcinoma by chemotherapy, radiation, and progestin therapy (11–13). G promoting epithelial-mesenchymal transition. (Cancer Res 3 endometrioid carcinoma and UPSC have greater propensity for 2006; 66(2): 889-97) myometrial and lymphatic/vascular space invasion than G1 tumors (11–13), but the mechanisms underlying the progression of these Introduction high-grade tumors are poorly understood. It is widely recognized that many of the molecular pathways Several studies indicate that the HOXA10 homeobox gene that underlie tumor progression are aberrations of processes that controls uterine organogenesis during embryonic development control normal embryonic development. Epithelial-mesenchymal and functional endometrial differentiation in the adult. HOXA10 transition (EMT) is a dynamic process whereby epithelial cells expression becomes restricted to the uterine primordium during lose polarity and cell-cell adhesion, acquire a migratory pheno- normal mu¨llerian duct differentiation, and is maintained in the type, and switch to a mesenchymal-like gene expression program. adult uterus (14). Female mice with a targeted disruption of This process is essential for normal morphogenesis, and reactiva- Hoxa10 produce normal embryos, but their uteri are unable to tion of the EMT program is regarded as a primary mechanism support embryo implantation (15, 16). Implantation normally underlying carcinoma progression and invasive behavior (1, 2). occurs during the mid-secretory phase of the menstrual cycle, a Homeobox genes have increasingly been thought to also represent period during which the endometrium undergoes extensive important hubs in the intimate relationship between tumor glandular differentiation and HOXA10 expression in the endome- progression and embryogenesis. These genes encode transcription trial glands dramatically increases (14). A role for HOXA10 in factors that control developmental patterning and specify the endometrial differentiation is also supported by our recent findings unique morphologic identities of adult tissues (3, 4). Several that aberrant activation of HOXA10 in ovarian surface epithelium- homeobox genes that are normally expressed in embryonic tissues derived cells gives rise to the endometrial-like features of are activated in tumors (4, 5). One example is PAX2, which is endometrioid ovarian carcinoma (17). Because HOXA10 plays an essential role in endometrial development, we speculated that its expression is deregulated in endometrial carcinomas. In this study, we found that down- regulation of HOXA10 expression in endometrial carcinomas Requests for reprints: Honami Naora, Department of Molecular Therapeutics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, correlates with increased tumor grade and is associated with Box 184, Houston, TX 77030. Phone: 713-563-4222; Fax: 713-563-4235; E-mail: hnaora@ HOXA10 promoter methylation. Enforced expression of HOXA10 in mdanderson.org. I2006 American Association for Cancer Research. endometrial carcinoma cells inhibited invasive behavior, and this doi:10.1158/0008-5472.CAN-05-2828 inhibitory effect was attributable, at least in part, to the ability of www.aacrjournals.org 889 Cancer Res 2006; 66: (2). January 15, 2006 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2006 American Association for Cancer Research. Cancer Research HOXA10 to up-regulate E-cadherin by suppressing the expression Absorbance at 570 nm after MTT addition was measured daily over 5-day of the Snail transcription factor. These findings reveal that time course. The number of trypan blue–excluding cells in replicate plates silencing of HOXA10 expression in the endometrium could were also directly counted by using a hemocytometer. Each assay was done contribute to tumor progression by promoting EMT. in triplicate. Reverse transcription-PCR. Reverse transcription using 1 Ag of DNase I-treated total RNA was done using Superscript II reverse transcriptase Materials and Methods (Invitrogen) in a reaction volume of 20 AL. One microliter of the reverse Cell lines, cDNAs, and antibodies. The endometrial carcinoma cell transcription reaction was used for amplification using Platinum Taq DNA lines SPEC2 and KLE were obtained from Isaiah Fidler (University of polymerase (Invitrogen). Detection of HOXA10 and actin expression has Texas M.D. Anderson Cancer Center, Houston, TX) and American Type been previously described (17). Other primers are as follows: (Snail) sense, Culture Collection (Rockville, MD), respectively. The HOXA10 cDNA clone 5V-TGCGCGAATCGGCGACCC-3V; antisense, 5V-CCTAGAGAAGGCCTTCC- was provided by Corey Largman (University of California VA Medical CGCAG-3V; (Slug) sense, 5V-GCCTCCAAAAAGCCAAACTACAG-3V; antisense, Center, San Francisco, CA). The rabbit polyclonal antibody to HOXA10 has 5V-GTGTGCTACACAGCAGCC-3V. Amplification was done as follows: dena- been previously described (17). Other antibodies used are as follows: actin, turation at 94jC for 1 minute, annealing at 61jC for 1 minute and extension h1 integrin, cadherin-6, Snail (Santa Cruz Biotechnology, Santa Cruz, CA), at 72jC for 2 minutes for 37 cycles to detect Snail expression, and E-cadherin (Zymed Laboratories, San Francisco, CA), vimentin (Neo- denaturation at 95jC for 1 minute, annealing at 58jC for 1 minute and Markers, Fremont, CA), Ki-67 (Vector Laboratories, Burlingame, CA). extension at 72jC for 1 minute for 40 cycles to detect Slug expression. Secondary antibodies were obtained from Kirkegaard & Perry Laboratories Titrations were done to ensure a linear range of amplification. (Gaithersburg, MD). Western blot and immunofluorescence staining. Cell lysates were Tissue microarrays and immunohistochemistry. Tissue microarrays prepared by using M-PER buffer (Pierce, Rockford, IL). Equal amounts of were constructed from core biopsies of endometrial carcinoma specimens protein (20 Ag per lane) were separated by SDS-PAGE and transferred to at the University of Texas M.D. Anderson Cancer Center using a Beecher polyvinylidene difluoride membranes (Amersham Pharmacia Biotech, Instruments (Silver Spring, MD) tissue arrayer. Use of specimens was Piscataway, NJ). Membranes were probed with antibodies to E-cadherin approved by the Institutional Review Board. Cases included the following: (1 Ag/mL), h1 integrin (1:100), cadherin-6 (1:200), and actin (1:100). For cell normal secretory endometrium (n = 10), G1 (n = 26), G2 (n = 37), G3 (n = 58) staining, cells were fixed in 4% paraformaldehyde and permeabilized
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