Circ_0005576 Exerts an Oncogenic Role in Cervical Cancer via miR-1305-Dependent Regulation of PAIP1.

Cervical cancer (CC) is a leading cause of high morbidity and mortality in women worldwide. Circular RNAs (circRNAs) are considered to be essential regulators of various cancers, including CC. The purpose of this study was to investigate the role and mechanism of circ_0005576 in CC progression. The levels of circ_0005576, miR-1305, and poly(A)-binding protein-interacting protein 1 (PAIP1) were detected by quantitative real-time PCR (qRT-PCR) or western blot assay. The stability and location of circ_0005576 were determined by ribonuclease R (RNase R) assay and subcellular fractionation distribution assay, respectively. Cell proliferation was evaluated by CCK-8 assay, EDU incorporation assay, and colony formation assay. Cell migration and invasion were assessed by transwell assay. The interactions between miR-1305 and circ_0005576 or PAIP1 were validated by dual-luciferase reporter assay. The protein expression of cyclin D1, vimentin, and matrix metallopeptidase 9 (MMP9) was tested by western blot. Moreover, mice xenograft models were constructed to analyze tumor growth in vivo. Circ_0005576 and PAIP1 were upregulated, while miR-1305 was downregulated in CC tissues and cells. Circ_0005576 was a stable circRNA that was mainly distributed in the cytoplasm of cells. Knockdown of circ_0005576 suppressed the proliferation, migration, and invasion of CC cells, while the silence of miR-1305 facilitated the development of CC cells. Meanwhile, circ_0005576 could sponge miR-1305 to promote PAIP1 expression. Furthermore, PAIP1 overexpression relieved the influence of circ_0005576 silence on the growth of CC cells. Additionally, circ_0005576 silence hindered CC tumor growth in vivo. Circ_0005576 depletion suppressed tumor development in CC by regulating the miR-1305/PAIP1 axis, suggesting that circ_0005576 might be a potential biomarker for CC treatment.

A chromatin modifier regulates Sertoli cell response to mono-(2-ethylhexyl) phthalate (MEHP) via tissue inhibitor of metalloproteinase 2 (TIMP2) signaling.

Epigenetic silencing mechanisms are essential for regulating germ cell apoptosis in response to different stimuli during complicated spermatogenesis. Herein, we report the potential signaling events related to up-regulation of metastasis associated protein 1 (Mta1), a master chromatin modifier, during mono-(2-ethylhexyl) phthalate (MEHP)-induced Sertoli cells (SCs) injury. Mta1 up-regulation correlated to the gradual increases of MYC expression in MEHP-treated SCs. Selective knockdown of MYC abolished MEHP-induced activation of Mta1, suggesting that MYC may regulate the Mta1 signaling following MEHP injury. Furthermore, MTA1 acted as a specific corepressor of tissue inhibitor of metalloproteinase 2 (Timp2) during SCs injury. Mta1 repressed Timp2 expression either directly by recruiting histone deacetylase 2 onto the Timp2 promoter or indirectly by enhancing NF-κB-mediated inflammatory responses during MEHP injury. This transcriptional and post-translational down-regulation of Timp2/TIMP2 expression consequently resulted in the stimulated activation of matrix metalloproteinase 2 (MMP2) in SCs, which should ultimately promote germ cell death upon MEHP insult. From a functional standpoint, inhibition of endogenous Mta1 expression along with anti-inflammation treatment in cultured SCs could rescue MEHP-inhibited TIMP2 and subsequently rebalanced MMP2 activity to the control level. Together with the recently reported essential role of TIMP2/MMP2 signaling in MEHP-induced specific disruption of junctional complexes in the seminiferous epithelium, our results further substantiate a critical role of Mta1 in the control of SCs response to MEHP stimulation. The MYC/Mta1/TIMP2 circuit may serve as an important scavenger mechanism to help to maintain the capacity of damaged SCs to support germ cell development following MEHP injury.