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HOXA9 is Underexpressed in Cervical Cancer Cells and its Restoration Decreases Proliferation, Migration and Expression of Epithelial-to-Mesenchymal Transition Genes
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 Title & Authors
HOXA9 is Underexpressed in Cervical Cancer Cells and its Restoration Decreases Proliferation, Migration and Expression of Epithelial-to-Mesenchymal Transition Genes
Alvarado-Ruiz, Liliana; Martinez-Silva, Maria Guadalupe; Torres-Reyes, Luis Alberto; Pina-Sanchez, Patricia; Ortiz-Lazareno, Pablo; Bravo-Cuellar, Alejandro; Aguilar-Lemarroy, Adriana; Jave-Suarez, Luis Felipe;
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HOX transcription factors are evolutionarily conserved in many different species and are involved in important cellular processes such as morphogenesis, differentiation, and proliferation. They have also recently been implicated in carcinogenesis, but their precise role in cancer, especially in cervical cancer (CC), remains unclear. In this work, using microarray assays followed by the quantitative polymerase chain reaction (qPCR), we found that the expression of 25 HOX genes was downregulated in CC derived cell lines compared with non-tumorigenic keratinocytes. In particular, the expression of HOXA9 was observed as down-modulated in CC-derived cell lines. The expression of HOXA9 has not been previously reported in CC, or in normal keratinocytes of the cervix. We found that normal CC from women without cervical lesions express HOXA9; in contrast, CC cell lines and samples of biopsies from women with CC showed significantly diminished HOXA9 expression. Furthermore, we found that methylation at the first exon of HOXA9 could play an important role in modulating the expression of this gene. Exogenous restoration of HOXA9 expression in CC cell lines decreased cell proliferation and migration, and induced an epithelial-like phenotype. Interestingly, the silencing of human papilloma virus (HPV) E6 and E7 oncogenes induced expression of HOXA9. In conclusion, controlling HOXA9 expression appears to be a necessary step during CC development. Further studies are needed to delineate the role of HOXA9 during malignant progression and to afford more insights into the relationship between downmodulation of HOXA9 and viral HPV oncoprotein expression during cercical cancer development.
Cervical cancer;HOX genes;HOXA9;proliferation;migration;epithelial-mesenchymal transition;
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Acampora D, D'Esposito M, Faiella A, et al (1989). The human HOX gene family. Nucleic Acids Res, 17, 10385-402. crossref(new window)

Alami Y, Castronovo V, Belotti D, et al (1999). HOXC5 and HOXC8 expression are selectively turned on in human cervical cancer cells compared to normal keratinocytes. Biochem Biophys Res Commun, 257, 738-45. crossref(new window)

Bai Y, Fang N, Gu T, et al (2014). HOXA11 gene is hypermethylation and aberrant expression in gastric cancer. Cancer Cell Int, 14, 79. crossref(new window)

Barresi V, Ieni A, Cardia R, et al (2015). HOXB13 as an immunohistochemical marker of prostatic origin in metastatic tumors. APMIS.

Bosch FX, Munoz N (2002). The viral etiology of cervical cancer. Virus Res, 89, 183-90. crossref(new window)

Brunskill EW, Potter SS (2012). RNA-Seq defines novel genes, RNA processing patterns and enhancer maps for the early stages of nephrogenesis: HOX supergenes. Dev Biol, 368, 4-17. crossref(new window)

Burel A, Mouchel T, Odent S, et al (2006). Role of HOXA7 to HOXA13 and PBX1 genes in various forms of MRKH syndrome (congenital absence of uterus and vagina). J Negat Results Biomed, 5, 4. crossref(new window)

Cantile M, Scognamiglio G, Anniciello A, et al (2012). Increased HOX C13 expression in metastatic melanoma progression. J Transl Med, 10, 91. crossref(new window)

Castelli-Gair J (1998). Implications of the spatial and temporal regulation of HOX genes on development and evolution. Int J Dev Biol, 42, 437-44.

Collins CT, Hess JL (2015). Role of HOXA9 in leukemia: dysregulation, cofactors and essential targets. Oncogene.

Conway K, Edmiston SN, May R, et al (2014). DNA methylation profiling in the Carolina Breast Cancer Study defines cancer subclasses differing in clinicopathologic characteristics and survival. Breast Cancer Res, 16, 450. crossref(new window)

Coutlee F, Rouleau D, Petignat P, et al (2006). Enhanced detection and typing of human papillomavirus (HPV) DNA in anogenital samples with PGMY primers and the Linear array HPV genotyping test. J Clin Microbiol, 44, 1998-2006. crossref(new window)

Cribier B, Worret WI, Braun-Falco M, et al (2006). Expression patterns of hair and epithelial keratins and transcription factors HOXC13, LEF1, and beta-catenin in a malignant pilomatricoma: a histological and immunohistochemical study. J Cutan Pathol, 33, 1-9.

Chen JL, Li J, Kiriluk KJ, et al (2012). Deregulation of a HOX protein regulatory network spanning prostate cancer initiation and progression. Clin Cancer Res, 18, 4291-302. crossref(new window)

Duluc I, Lorentz O, Fritsch C, et al (1997). Changing intestinal connective tissue interactions alters homeobox gene expression in epithelial cells. J Cell Sci, 110, 1317-24.

Ferlay J, Soerjomataram I, Dikshit R, et al (2015). Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer, 136, 359-86. crossref(new window)

Gilbert PM, Mouw JK, Unger MA, et al (2010). HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. J Clin Invest, 120, 1535-50. crossref(new window)

Gonzalez-Herrera A, Salgado-Bernabe M, Velazquez-Velazquez C, et al (2015). Increased expression of HOXB2 and HOXB13 proteins is associated with HPV infection and cervical cancer progression. Asian Pac J Cancer Prev, 16, 1349-53. crossref(new window)

Gravitt PE, Peyton CL, Alessi TQ, et al (2000). Improved amplification of genital human papillomaviruses. J Clin Microbiol, 38, 357-61.

Guerrero-Preston R, Michailidi C, Marchionni L, et al (2014). Key tumor suppressor genes inactivated by "greater promoter" methylation and somatic mutations in head and neck cancer. Epigenetics, 9, 1031-46. crossref(new window)

Guerrero-Preston R, Soudry E, Acero J, et al (2011). NID2 and HOXA9 promoter hypermethylation as biomarkers for prevention and early detection in oral cavity squamous cell carcinoma tissues and saliva. Cancer Prev Res (Phila), 4, 1061-72. crossref(new window)

Hsieh-Li HM, Witte DP, Weinstein M, et al (1995). HOXA 11 structure, extensive antisense transcription, and function in male and female fertility. Development, 121, 1373-85.

Hung YC, Ueda M, Terai Y, et al (2003). Homeobox gene expression and mutation in cervical carcinoma cells. Cancer Sci, 94, 437-41. crossref(new window)

Hwang JA, Lee BB, Kim Y, et al (2015). HOXA9 inhibits migration of lung cancer cells and its hypermethylation is associated with recurrence in non-small cell lung cancer. Mol Carcinog, 54, 72-80. crossref(new window)

Hyland PL, McDade SS, McCloskey R, et al (2011). Evidence for alteration of EZH2, BMI1, and KDM6A and epigenetic reprogramming in human papillomavirus type 16 E6/E7-expressing keratinocytes. J Virol, 85, 10999-1006. crossref(new window)

Jave-Suarez LF, Winter H, Langbein L, et al (2002). HOXC13 is involved in the regulation of human hair keratin gene expression. J Biol Chem, 277, 3718-26. crossref(new window)

Karamboulas C, Ailles L (2013). Developmental signaling pathways in cancer stem cells of solid tumors. Biochim Biophys Acta, 1830, 2481-95. crossref(new window)

Kasiri S, Ansari KI, Hussain I, et al (2013). Antisense oligonucleotide mediated knockdown of HOXC13 affects cell growth and induces apoptosis in tumor cells and over expression of HOXC13 induces 3D-colony formation. RSC Adv, 3, 3260-9. crossref(new window)

Kim YJ, Yoon HY, Kim JS, et al (2013). HOXA9, ISL1 and ALDH1A3 methylation patterns as prognostic markers for nonmuscle invasive bladder cancer: array-based DNA methylation and expression profiling. Int J Cancer, 133, 1135-42. crossref(new window)

Ko SY, Naora H (2014). HOXA9 promotes homotypic and heterotypic cell interactions that facilitate ovarian cancer dissemination via its induction of P-cadherin. Mol Cancer, 13, 170. crossref(new window)

Lappin TR, Grier DG, Thompson A, et al (2006). HOX genes: seductive science, mysterious mechanisms. Ulster Med J, 75, 23-31.

Li LC, Dahiya R (2002). MethPrimer: designing primers for methylation PCRs. Bioinformatics, 18, 1427-31. crossref(new window)

Lopez R, Garrido E, Pina P, et al (2006a). HOXB homeobox gene expression in cervical carcinoma. Int J Gynecol Cancer, 16, 329-35. crossref(new window)

Lopez R, Garrido E, Vazquez G, et al (2006b). A subgroup of HOX Abd-B gene is differentially expressed in cervical cancer. Int J Gynecol Cancer, 16, 1289-96. crossref(new window)

Marcinkiewicz KM, Gudas LJ (2014a). Altered epigenetic regulation of homeobox genes in human oral squamous cell carcinoma cells. Exp Cell Res, 320, 128-43. crossref(new window)

Marcinkiewicz KM, Gudas LJ (2014b). Altered histone mark deposition and DNA methylation at homeobox genes in human oral squamous cell carcinoma. J Cell Physiol, 229, 1405-16. crossref(new window)

Mehrazarin S, Chen W, Oh JE, et al (2015). The p63 Gene Is Regulated by Grainyhead-like 2 (GRHL2) through Reciprocal Feedback and Determines the Epithelial Phenotype in Human Keratinocytes. J Biol Chem, 290, 19999-20008. crossref(new window)

Milne TA, Kim J, Wang GG, et al (2010). Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis. Mol Cell, 38, 853-63. crossref(new window)

Perez-Plasencia C, Duenas-Gonzalez A, Alatorre-Tavera B (2008). Second hit in cervical carcinogenesis process: involvement of wnt/beta catenin pathway. Int Arch Med, 1, 10. crossref(new window)

Qi Z, Xu X, Zhang B, et al (2010). Effect of simultaneous silencing of HPV-18 E6 and E7 on inducing apoptosis in HeLa cells. Biochem Cell Biol, 88, 697-704. crossref(new window)

Raines AM, Adam M, Magella B, et al (2013). Recombineering-based dissection of flanking and paralogous HOX gene functions in mouse reproductive tracts. Development, 140, 2942-52. crossref(new window)

Rauch T, Wang Z, Zhang X, et al (2007). Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay. Proc Natl Acad Sci USA, 104, 5527-32. crossref(new window)

Rossig L, Urbich C, Bruhl T, et al (2005). Histone deacetylase activity is essential for the expression of HOXA9 and for endothelial commitment of progenitor cells. J Exp Med, 201, 1825-35. crossref(new window)

Sasagawa T, Takagi H, Makinoda S (2012). Immune responses against human papillomavirus (HPV) infection and evasion of host defense in cervical cancer. J Infect Chemother, 18, 807-15. crossref(new window)

Shah N, Sukumar S (2010). The HOX genes and their roles in oncogenesis. Nat Rev Cancer, 10, 361-71. crossref(new window)

Sun X, Liu B, Ji W, et al (2013). The role of HOXA9 in human laryngeal squamous cell carcinoma. Oncol Res, 20, 467-72.

Svingen T, Tonissen KF (2006). HOX transcription factors and their elusive mammalian gene targets. Heredity (Edinb), 97, 88-96. crossref(new window)

Torres-Reyes LA, Alvarado-Ruiz L, Pina-Sanchez P, et al (2014). Expression of transcription factor grainyhead-like 2 is diminished in cervical cancer. Int J Clin Exp Pathol, 7, 7409-18.

Uchida K, Veeramachaneni R, Huey B, et al (2014). Investigation of HOXA9 promoter methylation as a biomarker to distinguish oral cancer patients at low risk of neck metastasis. BMC Cancer, 14, 353. crossref(new window)

Wu Q, Lothe RA, Ahlquist T, et al (2007). DNA methylation profiling of ovarian carcinomas and their in vitro models identifies HOXA9, HOXB5, SCGB3A1, and CRABP1 as novel targets. Mol Cancer, 6, 45. crossref(new window)

Zhu JY, Sun QK, Wang W, et al (2014). High-level expression of HOXB13 is closely associated with tumor angiogenesis and poor prognosis of hepatocellular carcinoma. Int J Clin Exp Pathol, 7, 2925-33.