Abstract
BackgroundExpression of the microRNA miR-21 has been found to be altered in almost all types of cancers and it has been classified as an oncogenic microRNA or oncomir. Due to the critical functions of its target proteins in various signaling pathways, miR-21 is an attractive target for genetic and pharmacological modulation in various cancers. Cervical cancer is the second most common cause of death from cancer in women worldwide and persistent HPV infection is the main etiologic agent. This malignancy merits special attention for the development of new treatment strategies. In the present study we analyze the role of miR-21 in cervical cancer cells.MethodsTo identify the downstream cellular target genes of upstream miR-21, we silenced endogenous miR-21 expression in a cervical intraepithelial neoplasia-derived cell lines using siRNAs. The effect of miR-21 on gene expression was assessed in cervical cancer cells transfected with the siRNA expression plasmid pSIMIR21. We identified the tumor suppressor gene PTEN as a target of miR-21 and determined the mechanism of its regulation throughout reporter construct plasmids. Using this model, we analyzed the expression of miR-21 and PTEN as well as functional effects such as autophagy and apoptosis induction.ResultsIn SiHa cells, there was an inverse correlation between miR-21 expression and PTEN mRNA level as well as PTEN protein expression in cervical cancer cells. Transfection with the pSIMIR21 plasmid increased luciferase reporter activity in construct plasmids containing the PTEN-3′-UTR microRNA response elements MRE21-1 and MRE21-2. The role of miR-21 in cell proliferation was also analyzed in SiHa and HeLa cells transfected with the pSIMIR21 plasmid, and tumor cells exhibited markedly reduced cell proliferation along with autophagy and apoptosis induction.ConclusionsWe conclude that miR-21 post-transcriptionally down-regulates the expression of PTEN to promote cell proliferation and cervical cancer cell survival. Therefore, it may be a potential therapeutic target in gene therapy for cervical cancer.
Highlights
Expression of the microRNA miR-21 has been found to be altered in almost all types of cancers and it has been classified as an oncogenic microRNA or oncomir
Results small interference RNAs (siRNAs) expression plasmids for miR-21 induce silencing of human microRNA miR-21 The effect of siRNAs on miR-21 can be influenced by secondary structure and positioning of the cognate sequence within the pre-miR-21 molecule
The RNU6 RNA expression level did not show any changes under these same conditions. These data suggest that pSIMIR21 is a siRNA expression plasmid specific for miR-21, which has the ability to induce selective and specific silencing of miR-21 microRNA in human cervical cancer cells infected with HPV16
Summary
Expression of the microRNA miR-21 has been found to be altered in almost all types of cancers and it has been classified as an oncogenic microRNA or oncomir. Cervical cancer is the second most common cause of death from cancer in women worldwide and persistent HPV infection is the main etiologic agent. This malignancy merits special attention for the development of new treatment strategies. There are few microRNAs whose physiologic function has been elucidated in vivo and whose gene targets are known. Among these is miR-21, located at chromosome 17q23.2 locus, which codes for pri-miR-21 located within the intronic region of the protein-coding gene TMEM49 [25]. The functional activity of miR-21 in cervical cancer cells remains largely unknown, and far, few miR-21 gene targets in cervical cells have been reported
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