Elevation of miR-27b by HPV16 E7 inhibits PPARγ expression and promotes proliferation and invasion in cervical carcinoma cells

Abstract

MicroRNAs (miRNAs) have been reported to be involved in multiple biological pathways that can influence tumor progression and metastasis. High-risk human papillomavirus (HR-HPVs) is aetiologically correlated to cervical cancer. Recently, miRNAs were reported to be regulated by virus and play pivotal roles in HPV-related tumor progression. However, the underlying mechanism remains poorly understood. In the present study, we report that HPV16 E7 upregulated miR-27b to promote proliferation and invasion in cervical cancer. The results showed that PPARγ, as a target of miR-27b, played a significant role in suppressing cervical cancer progression by downregulating the sodium-hydrogen exchanger isoform 1 (NHE1). It was also shown that the inhibition of miR-27b diminished the ability of HPV16 E7 to suppress PPARγ or activate NHE1 expression. In addition, we observed high expression of miR-27b and NHE1, but low expression of PPARγ in HPV16-positive cervical cancer tissues. In summary, the present study revealed that miR-27b is upregulated by HPV16 E7 to inhibit PPARγ expression and promotes proliferation and invasion in cervical carcinoma cells.

The human papillomavirus E7 oncoprotein as a regulator of transcription

“…The molecular interactions that result in the activation or inhibition of the transcriptional process are complex and have been extensively reviewed by others (Li, Carey et al 2007; Lenhard, Sandelin et al 2012; Allen and Taatjes 2015; Zhang, Cooper et al 2015), so we will give only a brief outline here. The pattern of modifications on histone proteins is thought to comprise a complex, interactive “histone code,” which serves both to communicate information to transcriptional regulatory proteins and to physically alter the structure of the chromatin in order to increase or decrease promoter activity (Zhang, Cooper et al 2015). Enzymes that modify histones and other chromatin components are designated “writer” proteins, and include HATs, methyltransferases, ubiquitin ligases, and others.…”

“…Reader proteins bind to the modified histone moieties and recruit other proteins to the growing transcriptional complex. Finally, “eraser” enzymes remove modifying groups from the histones (Zhang, Cooper et al 2015). Erasers include HDACs, demethylases, deubiquitinases, and so forth (Li, Carey et al 2007).…”

“…The best known enzymes that promote chromatin accessibility are the HATs, which acetylate histone tails. Transcriptionally active chromatin is characterized by high levels of histone acetylation, which is thought to reduce interactions between nucleosomes to promote chromatin accessibility, as well as providing recognition sites for reader proteins (Zhang, Cooper et al 2015). As more modifications occur, reader proteins are recruited, which interact to promote binding of additional transcriptional effectors (Zhang, Cooper et al 2015).…”

The expression of miR-21 and miR-143 is deregulated by the HPV16 E7 oncoprotein and 17β-estradiol

“…The HR-HPV16 E7 oncoprotein upregulates the expression of miR-15b and miR-27b (30,31). E 2 has also been involved in regulating the expression of microRNAs with tumor suppressor and oncogenic functions.…”

Promising therapeutic role of miR-27b in tumor

“…NHE1 is an oncogenic factor and a downstream molecule of PPARγ. PPARγ reduces NHE1 expression in breast 71 and cervical cancer, 72 while activates NHE1 expression in neuroblastoma. 51 Hence, PPARγ functions as a tumor suppressor in breast and cervical cancer and an oncogene in neuroblastomas.…”