miR-194 regulated AGK and inhibited cell proliferation of oral squamous cell carcinoma by reducing PI3K-Akt-FoxO3a signaling.

Growing evidence supports that microRNAs (miRNAs) play crucial roles in cancer progression by directly downregulating multiple targets. However, the underlying mechanisms of miRNAs in oral squamous cell carcinoma (OSCC) are poorly understood. In the current study, we found that miR-194 expression was markedly downregulated in both clinical OSCC tissues and OSCC cell lines, compared with adjacent non-cancerous tissues and normal tongue epithelial cell TEC, respectively. Overexpression of miR-194 suppressed, whereas miR-194-in promoted OSCC cell proliferation. Furthermore, we demonstrated that miR-194 could reduce the phosphoinositide 3-kinase (PI3K)/AKT/FoxO3a signaling pathway by suppressing acylglycerol kinase (AGK) directly, resulting in decreasing cyclin D1 expression and increasing expression of p21 in OSCC. In sum, our data provide compelling evidence that miR-194 functions as a potential tumor suppressor by inhibiting the PI3K/AKT/FoxO3a signaling pathway and might sever as a potential therapeutic target for OSCC patients.

Chi H 《-》

Acylglycerol kinase promotes the proliferation and cell cycle progression of oral squamous cell carcinoma.

Liu G ，Ren X ，Gao C ，Zhang W ... -  《-》

OSCC Exosomes Regulate miR-210-3p Targeting EFNA3 to Promote Oral Cancer Angiogenesis through the PI3K/AKT Pathway.

This study is aimed at determining how oral squamous cell carcinoma (OSCC) regulates the angiogenesis of HUVECs through miR-210-3p expression and exploring the relationship among miR-210-3p, its target protein, and the possible mechanism of angiogenesis regulation. miR-210-3p expression was detected in OSCC tissues and juxta cancerous tissues (JCT), and the relationship among miR-210-3p, microvessel density (MVD), and histopathologic features was analyzed. A conditioned medium (CM) of the OSCC cell line CAL27 was collected to stimulate human umbilical vein endothelial cells (HUVECs), and the miR-210-3p levels and tube formation capability of HUVECs were measured. The target protein level of miR-210-3p was altered; then, PI3K/AKT pathway activation in HUVECs was detected. miR-210-3p was tested in exosomes separated from CAL27 CM, and the transfer of miR-210-3p from OSCC exosomes to HUVECs was verified. Then, we found that the OSCC tissues had higher miR-210-3p levels than the JCT, and miR-210-3p level was positively correlated with MVD and tumor grade. CAL27 CM was able to elevate miR-210-3p levels in HUVECs and promoted tube formation. EFNA3 was the target gene of miR-210-3p, and ephrinA3 protein level was able to influence the migration and proliferation of HUVECs. The levels of phosphorylated AKT in the HUVECs increased when ephrinA3 was downregulated, and the upregulation of ephrinA3 resulted in the suppression of the PI3K/AKT pathway. miR-210-3p was detected in exosomes isolated from the CM of CAL27 cells, and miR-210-3p level in the HUVECs was elevated after absorbing the OSCC exosomes. In conclusion, miR-210-3p was more overexpressed in OSCC tissues than in the JCT. The exosomes secreted by OSCC cells were able to upregulate miR-210-3p expression and reduce ephrinA3 expression in HUVECs and promoted tube formation through the PI3K/AKT signaling pathway.

Wang H ，Wang L ，Zhou X ，Luo X ，Liu K ，Jiang E ，Chen Y ，Shao Z ，Shang Z ... -  《-》

MicroRNA-16 functions as a tumor-suppressor gene in oral squamous cell carcinoma by targeting AKT3 and BCL2L2.

Aberrant expressions of microRNAs have been reported to be strongly associated with the progression and prognosis of various tumors, including oral squamous cell carcinoma (OSCC). Recent studies on miRNA expression profiling have suggested that microRNA-16 (miR-16) may be dysregulated in OSCC. However, the tumorigenic roles and mechanisms of miR-16 in OSCC are still largely unknown. In this study, we demonstrated that miR-16 was specifically downregulated in both OSCC patients and cancer cell lines. In addition, functional roles of miR-16 in vitro suggested that the miR-16 mimic inhibited cell proliferation and induced apoptosis, whereas miR-16 inhibitor displayed the opposite effects. Luciferase reporter assay and correlation analysis showed that AKT3 and BCL2L2 were directly targeted by miR-16 and were inversely expressed with miR-16 in OSCC. Moreover, restoration of AKT3 and BCL2L2 expression could partially reverse the cell proliferation inhibition and apoptosis induction caused by miR-16. In xenograft nude mice, miR-16 mimics decreased the expression of AKT3 and BCL2L2 and reduced the tumors volumes and weights, whereas the miR-16 inhibitor exhibited adverse effects in the derived xenografts. In conclusion, the findings suggested that miR-16 functions as a tumor suppressor miRNA to inhibit cell proliferation and induce apoptosis in OSCC through decreasing the oncogenes AKT3 and BCL2L2 and that miR-16 could be a potential therapeutic target for OSCC.

Wang X ，Li GH 《-》

Akt-FOXO3a signaling axis dysregulation in human oral squamous cell carcinoma and potent efficacy of FOXO3a-targeted gene therapy.

Phosphoinositide-3-kinase (PI3K)/Akt pathway has been shown to be activated in oral squamous cell carcinoma (OSCC). Activation of Akt suppresses FOXO transcription factor-mediated growth arrest and apoptosis in various cancers. We investigated FOXO3a and phosphor(p)-Akt expression and potential efficacy of FOXO3a-targeted gene therapy in OSCC. Low expression of FOXO3a was negatively associated with overexpression of p-Akt and histological grade using immunohistochemistry. Akt-FOXO3a axis was also examined by detection of FOXO3a expression after induction or inhibition of Akt activity in Tca8113 OSCC cells. Transfection of a constitutively active form of FOXO3a (FOXO3a(3A)) in OSCC cells induced significant G₁-phase arrest and apoptosis as compared with control and transfection of a wild-type FOXO3a (FOXO3a(WT)). Stable FOXO3a(3A) transfectant OSCC cells also revealed the most potent growth inhibition effect in vivo. Furthermore, the downstream effects of FOXO3a activation were found to be inhibition of CDK4/6 and cyclin D1, and accumulation of p27 and Bim. We also found that transcription of FOXO1 and FOXO4 were stimulated by FOXO3a. Our results suggest that FOXO3a activity may be important in tumorigenesis and development of OSCC. Akt-FOXO3a axis inhibition-mediated constitutively active FOXO3a induces significant growth inhibition and FOXO3a activation may present a potent target-based therapeutic strategy for OSCC therapy.

Fang L ，Wang H ，Zhou L ，Yu D ... -  《-》