Abstract
Homeobox C6 (HOXC6) is a transcription factor that plays a role in the malignant progression of various cancers. However, the roles of HOXC6 and its regulatory mechanism remain unclear. In this study, we used microRNA (miRNA) regulatory networks to identify key regulatory interactions responsible for HOXC6-mediated cancer progression. In microarray profiling of miRNAs, the levels of miRNAs such as hsa-miR-188-5p, hsa-miR-8063, and hsa-miR-8064 were significantly increased in HOXC6-overexpressing cells. Higher positive expression rates of HOXC6 and miR-188-5p were observed in malignant cancer. We also found that HOXC6 significantly upregulated miR-188-5p expression. The underlying function of HOXC6-mediated miR-188-5p expression was predicted through TargetScan and the MiRNA Database. Overexpression of mir-188-5p inhibited the expression of forkhead box N2 (FOXN2), a tumor suppressor gene. Furthermore, in the luciferase assay, miR-188-5p bound to the 3′-UTR of FOXN2 and was mainly responsible for the dysregulation of FOXN2 expression. Silencing FOXN2 induced cell migration, and the effect of FOXN2 silencing was enhanced when the HOXC6/miR-188-5p axis was induced. These results suggest that HOXC6/miR-188-5p may induce malignant progression in cancer by inhibiting the activation of the FOXN2 signaling pathway.
Highlights
Human homeobox C6 (HOXC6) is a member of the highly conserved homeobox family of transcription factors that play critical roles in embryonic development, cell morphogenesis, angiogenesis, and differentiation [1]
To investigate whether miRNA expression is influenced by HOXC6, miRNAs were profiled in FaDu cells using human microRNA arrays and quantitative polymerase chain reaction (PCR) analysis
We demonstrated that the forkhead box N2 (FOXN2) mRNA and protein levels were significantly inhibited in FaDu cells transfected with pSUPER/miR-155 compared with control cells (Figure 3F,G)
Summary
Human homeobox C6 (HOXC6) is a member of the highly conserved homeobox family of transcription factors that play critical roles in embryonic development, cell morphogenesis, angiogenesis, and differentiation [1]. It has been reported that oral squamous cell carcinoma (OSCC) patients have a high expression of HOXC6 [8], suggesting a role of aberrant HOX gene expression in the development of OSCC. Recent studies have demonstrated that miRNAs can be aberrantly expressed in various cancers [15] and function as oncogenes and/or tumor suppressor genes through the transcription of a target [16]. Much evidence suggest that miRNAs play a critical role in regulating cancer initiation, progression, and metastasis; this evidence was obtained from the microRNA profile analysis of various cancers, in relation to the pathological characteristics and prognosis of the tumor [16,17,18]. Our novel observation of increased HOXC6/miR-188-5p expression and its oncogenic activity in cancer cells suggests that HOXC6/miR-188-5p may serve as a diagnostic and, a therapeutic tool for the effective clinical management of metastatic cancers
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