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

Abstract

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.

MiR‐139‐5p inhibits the tumorigenesis and progression of oral squamous carcinoma cells by targeting HOXA9

“…QRT-PCR results revealed that HOXA9 was upregulated in SAS cells, which was inconsistent with some of the previous studies. Ruiz et al found that HOXA9 was under-expressed in cervical cancer cells and its restoration decreased the proliferation, migration and expression of epithelial-to-mesenchymal transition (EMT) genes [51]. Hwang JA et al detected that HOXA9 inhibits lung cancer cells migration and its hypermethylation is closely linked with the recurrence in non-small cell lung cancer [52].…”

MiR-221 represents an innovative bio-marker in cervical carcinoma detection

“…SHI et al suggested that secreted protein acidic and rich in cysteine (SPARC) may be a potential therapeutic option for cervical cancer patients [23]. Liliana Alvarado-Ruiz et al found that normal cervical cancer from women without cervical lesions expression HOXA9 but controlling HOXA9 expression appears to be a necessary step during cervical cancer development [24]. These data suggested the crucial roles of cancer related molecules in cervical cancers.…”

The association of miR-138 variants with the prognosis of cervical cancer

“…Accumulating evidences have been identi ed that molecular genes may be responsible for tumor initiation, metastasis and recurrence, which playing important role in the detection and treatment of patients with several different cancer types, including cervical cancer [19][20][21][22]. Li et al suggested that fotillin-1 facilitates cervical cancer cell metastasis through Wnt/β-catenin and NF-κB pathway-regulated EMT and the increased fotillin-1 expression is associated with lymph node metastasis and poor prognosis in early-stage cervical cancer [19].…”

“…Li et al suggested that fotillin-1 facilitates cervical cancer cell metastasis through Wnt/β-catenin and NF-κB pathway-regulated EMT and the increased fotillin-1 expression is associated with lymph node metastasis and poor prognosis in early-stage cervical cancer [19]. HOXA9 is found downregulated by Liliana Alvarado-Ruiz et al in cervical cancer and controlling HOXA9 expression appears to be a necessary step during cervical cancer development [20]. Torres-Poveda K et al conducted a case-control study paired by age and found the serum levels of Th2 and Th3 cytokines were higher in cervical cancer cases than the controls, representing a risk allelic load for cervical cancer and can be used as a biomarker of susceptibility to this disease [21].…”