Increased Expression of HOXB2 and HOXB13 Proteins is Associated with HPV Infection and Cervical Cancer Progression

Gonzalez-Herrera, A.L.; Salgado-Bernabé, Manuel Eduardo; Velazquez-Velazquez, Cindy K; Salcedo-Vargas, Mauricio; Andrade-Manzano, Alejandro; Ávila‐Moreno, Federico; Piña‐Sánchez, Patricia

doi:10.7314/apjcp.2015.16.4.1349

Cited by 26 publications

(16 citation statements)

References 35 publications

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“…In recent years, abnormal expression of these genes has been linked with the emergence of various, solid and hematopoietic malignancies (16)(17)(18)(19)(20). In CC, there are evidences concerning the overexpression or downregulation of HOX members, indicating its possible role during cervical carcinogenesis (Lopez et al, 2006b;Gonzalez-Herrera et al, 2015). In order to underscore differences in HOX genes expression in CC and to corroborate and complement previous findings, we performed a comparison by microarray of the mRNA expression profile of two cell lines: one derived from CC (HeLa), and the other, from non-tumorigenic keratinocytes (HaCaT).…”

Section: Discussionmentioning

confidence: 81%

“…Thus, in recent years, much effort has been devoted to the study of HOX genes and proteins and their link with cancer (Shah and Sukumar, 2010). In cervix, despite some evidences of HOX member modulation (Alami et al, 1999;Hung et al, 2003;Lopez et al, 2006b;Gonzalez-Herrera et al, 2015), the participation of these transcription factors in cervical carcinogenesis has not been explored in depth. In this work, we evaluated HOX gene deregulation in CC; in particular, we focused on HOXA9 modulation and whether this phenomenon results in an advantage for the CC cell.…”

Section: Introductionmentioning

confidence: 99%

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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

Alvarado-Ruíz¹,

Martínez-Silva²,

Torres-Reyes³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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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 nontumorigenic keratinocytes. In particular, the expression of HOXA9 was observed as down-modulated in CCderived 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.

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Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

HOXA9 is Underexpressed in Cervical Cancer Cells and its Restoration Decreases Proliferation, Migration and Expression of Epithelial-to-Mesenchymal Transition Genes

Alvarado-Ruíz¹,

Martínez-Silva²,

Torres-Reyes³

et al. 2016

Asian Pacific Journal of Cancer Prevention

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“…Several studies have demonstrated that the clustered homeobox (HOX) genes are important factors in cancer pathogenesis. Numerous examples of deregulated HOX expression have been found in solid tumors, such as acute myeloid leukemia [20], head and neck squamous cell carcinoma [21], and cervical cancer [22]. Deregulation of HOX genes influences tumorigenesis and cancer cell biology through differentiation, apoptosis, receptor signaling, and other unknown mechanisms [23].…”

Section: Introductionmentioning

confidence: 99%

EGR1 mediates miR-203a suppress the hepatocellular carcinoma cells progression by targeting HOXD3 through EGFR signaling pathway

et al. 2016

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EGR1 plays a critical role in cancer progression. However, its precise role in hepatocellular carcinoma has not been elucidated. In this study, we found that the overexpression of EGR1 suppresses hepatocellular carcinoma cell proliferation and increases cell apoptosis by binding to the miR-203a promoter sequence. In addition, we investigated the function of miR-203a on progression of HCC cells. We verified that the effect of overexpression of miR-203a is consistent with that of EGR1 in regulation of cell progression. Through bioinformatic analysis and luciferase assays, we confirmed that miR-203a targets HOXD3. Silencing HOXD3 could block transition of the G2/M phase, increase cell apoptosis, decrease the expression of cell cycle and apoptosis-related proteins, EGFR, p-AKT, p-ERK, CCNB1, CDK1 and Bcl2 by targeting EGFR through EGFR/AKT and ERK cell signaling pathways. Likewise, restoration of HOXD3 counteracted the effects of miR-203a expression.In conclusion, our findings are the first to demonstrate that EGR1 is a key player in the transcriptional control of miR-203a, and that miR-203a acts as an anti-oncogene to suppress HCC tumorigenesis by targeting HOXD3 through EGFR-related cell signaling pathways.

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“…Such activation of HOX cluster members are closely linked to the process of Epithelial-Mesenchymal Transition (EMT) [22–24]. However, studies on expression profiling of HOX cluster genes in cervical cancers are mostly based on cell lines [25–28], with only a couple of studies employing global gene expression profiling of cervical tissues [29–30]. However, none of these studies on cervical cancer cell lines or tissues, have taken into account the presence of HPV or expression of viral oncogenes.…”

Section: Introductionmentioning

confidence: 99%

Expression signatures of HOX cluster genes in cervical cancer pathogenesis: Impact of human papillomavirus type 16 oncoprotein E7

et al. 2017

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The Homeobox (HOX) genes encode important transcription factors showing deregulated expression in several cancers. However, their role in cervical cancer pathogenesis, remains largely unexplored. Herein, we studied their association with Human Papillomavirus type 16 (HPV16) mediated cervical cancers. Our previously published gene expression microarray data revealed a significant alteration of 12 out of 39 HOX cluster members among cervical cancer cases, in comparison to the histopathologically normal controls. Of these, we validated seven (HOXA10, HOXA13, HOXB13, HOXC8, HOXC9, HOXC11 and HOXD10) by quantitative real-time PCR. We identified decreased HOXA10 expression as opposed to the increased expression of the rest. Such decrease was independent of the integration status of HPV16 genome, but correlated negatively with E7 expression in clinical samples, that was confirmed in vitro. HOXA10 and HOXB13 revealed association with Epithelial-Mesenchymal Transition (EMT). While HOXA10 expression correlated positively with E-Cadherin and negatively with Vimentin expression, HOXB13 showed the reverse trend. Chromatin immunoprecipitation study in vitro revealed the ability of E7 to increase HOX gene expression by epigenetic regulation, affecting the H3K4me3 and H3K27me3 status of their promoters, resulting from a loss of PRC2-LSD1 complex activity. Thus, besides identifying the deregulated expression of HOX cluster members in HPV16 positive cervical cancer and their association with EMT, our study highlighted the mechanism of HPV16 E7-mediated epigenetic regulation of HOX genes in such cancers, potentially serving as bedrock for functional studies in the future.

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Increased Expression of HOXB2 and HOXB13 Proteins is Associated with HPV Infection and Cervical Cancer Progression

Cited by 26 publications

References 35 publications

HOXA9 is Underexpressed in Cervical Cancer Cells and its Restoration Decreases Proliferation, Migration and Expression of Epithelial-to-Mesenchymal Transition Genes

HOXA9 is Underexpressed in Cervical Cancer Cells and its Restoration Decreases Proliferation, Migration and Expression of Epithelial-to-Mesenchymal Transition Genes

EGR1 mediates miR-203a suppress the hepatocellular carcinoma cells progression by targeting HOXD3 through EGFR signaling pathway

Expression signatures of HOX cluster genes in cervical cancer pathogenesis: Impact of human papillomavirus type 16 oncoprotein E7

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