ABSTRACT
Cervical cancer (CxCa) is the fourth most frequent cancer in women. This study aimed to determine the role and underlying mechanism of fibronectin type III domain-containing protein 5 (FNDC5) in inhibiting CxCa growth. Experiments were performed in human CxCa tissues, human CxCa cell lines (HeLa and SiHa), and xenograft mouse model established by subcutaneous injection of SiHa cells in nude mice. Bioinformatics analysis showed that CxCa patients with high FNDC5 levels have a longer overall survival period. FNDC5 expression was increased in human CxCa tissues, HeLa and SiHa cells. FNDC5 overexpression or FNDC5 protein not only inhibited proliferation, but also restrained invasion and migration of HeLa and SiHa cells. The effects of FNDC5 were prevented by inhibiting integrin with cilengitide, activating PI3K with recilisib or activating Akt with SC79. FNDC5 inhibited the phosphorylation of PI3K and Akt, which was attenuated by recilisib. PI3K inhibitor LY294002 showed similar effects to FNDC5 in HeLa and SiHa cells. Intravenous injection of FNDC5 (20 µg/day) for 14 days inhibited the tumor growth, and reduced the proliferation marker Ki67 expression and the Akt phosphorylation in the CxCa xenograft mouse model. These results indicate that FNDC5 inhibits the malignant phenotype of CxCa cells through restraining PI3K/Akt signaling. Upregulation of FNDC5 may play a beneficial role in retarding the tumor growth of CxCa.
Subject(s)
Cell Proliferation , Fibronectins , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Signal Transduction , Uterine Cervical Neoplasms , Animals , Female , Humans , Mice , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Fibronectins/metabolism , Fibronectins/genetics , Gene Expression Regulation, Neoplastic/drug effects , HeLa Cells , Mice, Inbred BALB C , Mice, Nude , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol 3-Kinases/genetics , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Uterine Cervical Neoplasms/pathology , Uterine Cervical Neoplasms/genetics , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/drug therapy , Xenograft Model Antitumor Assays , Integrins/metabolism , Disease ProgressionABSTRACT
Enhanced proliferation and migration of vascular smooth muscle cells (VSMCs) contributes to vascular remodeling in hypertension. Adventitial fibroblasts (AFs)-derived extracellular vesicles (EVs) modulate vascular remodeling in spontaneously hypertensive rat (SHR). This study shows the important roles of EVs-mediated miR-21-3p transfer in VSMC proliferation and migration and underlying mechanisms in SHR. AFs and VSMCs were obtained from aorta of Wistar-Kyoto rat (WKY) and SHR. EVs were separated from AFs culture with ultracentrifugation method. MiR-21-3p content in the EVs of SHR was increased compared with those of WKY. MiR-21-3p mimic promoted VSMC proliferation and migration of WKY and SHR, while miR-21-3p inhibitor attenuated proliferation and migration only in the VSMCs of SHR. EVs of SHR stimulated VSMC proliferation and migration, which were attenuated by miR-21-3p inhibitor. Sorbin and SH3 domain containing 2 (SORBS2) mRNA and protein levels were reduced in the VSMCs of SHR. MiR-21-3p mimic inhibited, while miR-21-3p inhibitor promoted SORBS2 expressions in the VSMCs of both WKY and SHR. EVs of SHR reduced SORBS2 expression, which was prevented by miR-21-3p inhibitor. EVs of WKY had no significant effect on SORBS2 expressions. SORBS2 overexpression attenuated the roles of miR-21-3p mimic and EVs of SHR in promoting VSMC proliferation and migration of SHR. Overexpression of miR-21-3p in vivo promotes vascular remodeling and hypertension. These results indicate that miR-21-3p in the EVs of SHR promotes VSMC proliferation and migration via negatively regulating SORBS2 expression.
Subject(s)
Extracellular Vesicles , Hypertension , MicroRNAs , Rats , Animals , Rats, Inbred SHR , Muscle, Smooth, Vascular/metabolism , Rats, Inbred WKY , Vascular Remodeling , Extracellular Vesicles/metabolism , MicroRNAs/metabolism , Cell Proliferation , Fibroblasts/metabolism , Cells, Cultured , Myocytes, Smooth Muscle/metabolismABSTRACT
Salt stress induced Gamma-aminobutyric acid (GABA) accumulation in maize plants. The germination of maize seeds was inhibited seriously by NaCl treatment, while exogenous GABA reduced the inhibition of NaCl on the seeds germination. Effects on SOD, POD and CAT activity of GABA were detected. 1-2 mmol/L GABA induced the increase of the activity of SOD, POD and CAT about 20%. Because of SOD, CAT and POD are important protective enzymes which can eliminate active oxygen, so GABA can alleviate the damage of salt stress through promoting the activity of the protective enzyme system.
