MicroRNA-379 inhibits metastasis and epithelial-mesenchymal transition via targeting FAK/AKT signaling in gastric cancer

Abstract

Accumulating evidence demonstrates that aberrant miRNAs contribute to gastric cancer (GC) development and progression. However, the roles of various miRNAs in GC remain to be determined. In the present study, we confirmed that a reduced miR-379 expression was present in GC tissues and cell lines. Our clinical analysis revealed that the downregulated miR-379 expression was significantly correlated with poor prognostic features including lymph node metastasis and advanced TNM stage. Moreover, we confirmed that miR-379 was a novel independent prognostic marker for predicting 5-year survival of GC patients. The ectopic overexpression of miR-379 inhibited cell migration, invasion and EMT progress, while downregulated miR-379 reversed the effect. In addition, miR-379 regulated the focal adhesion kinase (FAK) by directly binding to its 3'-UTR, resulting in suppression of AKT signaling. In clinical samples of GC, miR-379 inversely correlated with FAK, which was upregulated in GC. Alteration of FAK expression or activating AKT signaling at least partially abolished the migration, invasion and EMT progress effects of miR-379 on GC cells. In conclusion, our results indicated that miR-379 functioned as a tumor suppressor gene in regulating the EMT and metastasis of GC via targeting FAK/AKT signaling, and may represent a novel potential therapeutic target and prognostic marker for GC.

MicroRNA‐379 inhibits laryngeal carcinoma cell proliferation and invasion through directly targeting TCF‐4

“…Many targets of miR‐379 have been confirmed. For example, FAK was found in gastric cancer and hepatocellular carcinoma, cyclin B1 in breast cancer, and MDM2 in bladder cancer . In the present study, TCF‐4 was detected as a direct target of miR‐379 in laryngeal carcinoma and validated by luciferase reporter assay.…”

“…Many targets of miR-379 have been confirmed. For example, FAK was found in gastric cancer 31 and hepatocellular carcinoma, 29 cyclin B1 in breast cancer, 18 and MDM2 in bladder cancer. 32 In the present F I G U R E 4 TCF-4 overexpression rescued the tumor-suppressing roles of miR-379 on laryngeal carcinoma cells.…”

“…15 MiR-379, located at chromosome 14q32. 31, is differentially expressed in many kinds of cancers, [16][17][18][19] suggesting that miR-379 may exert key functions in cancer development. Nevertheless, little is reported about the biological functions of miR-379 in laryngeal carcinoma.…”

MicroRNAs and the PTEN/PI3K/Akt pathway in gastric cancer (Review)

“…The miR-29 family, consisting of miR-29a, miR-29b and miR-29c, was able to restrain Akt2 expression and subsequently inactivate GSK3β, leading to the impaired invasive ability of GC cells (62). Focal adhesion kinase (FAK) is a crucial transducer of integrin-mediated signaling to downstream pathways, including the PI3K/Akt pathway (63). The activated FAK by integrins may form a binding site for the SH2 domain of p85 subunit and phosphorylate it, which may subsequently activate the p110 catalytic subunit of PI3K (63).…”

“…The activated FAK by integrins may form a binding site for the SH2 domain of p85 subunit and phosphorylate it, which may subsequently activate the p110 catalytic subunit of PI3K (63). Xu et al (63) identified that miR-379 inactivated Akt signaling by suppressing FAK expression, thus leading to inhibition of cell migration, invasion and EMT process. Cullin 4B, a scaffold protein, directly binds to the S2 region of the miR-125a promoter and transcriptionally represses miR-125a, through which it promotes HER2 expression, thus stimulating downstream PI3K/Akt signaling and the migration of GC cells.…”