Many viruses disrupt the host cell cycle to facilitate their own growth. We assessed the mechanism and function of enterovirus 71 (EV71), a primary causative agent for recent hand, foot, and mouth disease outbreaks, in manipulating cell cycle progression. Our results suggest that EV71 infection induces S-phase arrest in diverse cell types by preventing the cell cycle transition from the S phase into the G2/M phase. Similar results were observed for an alternate picornavirus, Coxsackievirus A16. Synchronization in S phase, but not G0/G1 phase or G2/M phase, promotes viral replication. Consistent with its ability to arrest cells in S phase, the expression of cyclin A2, CDK 2, cyclin E1, and cyclin B1 was regulated by EV71 through increasing transcription of cyclin E1, promoting proteasome-mediated degradation of cyclin A2 and regulating the phosphorylation of CDK 2. Finally, a non-structural protein of EV71, the RNA-dependent RNA polymerase 3D, was demonstrated to mediate S-phase cell cycle arrest. These findings suggest that EV71 induces S-phase cell cycle arrest in infected cells via non-structural protein 3D, which may provide favorable conditions for virus production.
Up to date, miR-137 has been demonstrated as a tumor suppressor in many kinds of human malignancies. In the present study, we conducted transfection, western blot and RT-PCR to explore the role of miR-137 in the development of human glioblastoma (GBM). Here, we found that miR-137 expression was obviously down-regulated in GBM tissues and cells rather than matched non-tumor tissues and NHA cells. However, the expression of C-X-C motif ligand 12 (CXCL12) mRNA and protein were up-regulated in GBM tissues and cells. In vitro, miR-137 mimics inhibited GBM cell proliferation, migration and invasion, and the 3′-untranslated regions (3′-UTR) of CXCL12 were a direct target of miR-137. In addition, miR-137 mimics also inhibited the expression of EGFR, Bcl-2 and MMP2/9 proteins, but increased the expression of Bax protein. Notably, CXCL12 over-expression attenuated miR-137-inhibited cell proliferation and invasion, while CXCL12 siRNAs promoted miR-137 inhibition effects. In vivo, miR-137 mimics also suppressed tumor growth in nude mice xenograft model. In conclusion, miR-137 serves as a tumor suppressor by inhibition of CXCL12 in human GBM. Thus, miR-137-CXCL12 can be recommended as a useful and effective target for treatment of GBM.
Primary squamous cell carcinoma of the thyroid is a rare and aggressive type of neoplasm, which is routinely treated with surgery; however, despite this, survival time is not commonly more than six months. Thus, the aim of the present study was to determine the efficacy of pseudolaric acid (PAB) as a therapeutic agent. PAB is an antitubulin agent, and in the present study, inhibition of the SW579 thyroid squamous cell carcinoma cell line by PAB was investigated. PAB was found to inhibit SW579 cell growth in a time- and dose-dependent manner via interference in α-tubulin polymerization. However, the inhibitory role of PAB in SW579 cells was not predominantly due to apoptosis, but was due to the cytostatic status resulting from cell cycle arrest. The present study proposes that this is the underlying mechanism of the antitumor properties of PAB. During cytostatis, autophagy was activated to sustain cell survival and SW579 cell migration was inhibited. Nuclear p53 expression was observed to be reduced, however the role of reduced p53 requires further investigation. Therefore, PAB induced cytostasis, which inhibited SW579 cell growth and therefore may function as an antitubulin therapeutic agent.
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