Signal transducer and activator of transcription 3 (STAT3) signaling is constantly activated in human melanoma, and promotes melanoma metastasis.,The dietary flavonoid apigenin is a bioactive compound that possesses low toxicity and exerts anti-metastatic activity in melanoma.,However, the anti-metastasis mechanism of apigenin has not been fully elucidated.,In the present study, we showed that apigenin suppressed murine melanoma B16F10 cell lung metastasis in mice, and inhibited cell migration and invasion in human and murine melanoma cells.,Further study indicated that apigenin effectively suppressed STAT3 phosphorylation, decreased STAT3 nuclear localization and inhibited STAT3 transcriptional activity.,Apigenin also down-regulated STAT3 target genes MMP-2, MMP-9, VEGF and Twist1, which are involved in cell migration and invasion.,More importantly, overexpression of STAT3 or Twist1 partially reversed apigenin-impaired cell migration and invasion.,Our data not only reveal a novel anti-metastasis mechanism of apigenin but also support the notion that STAT3 is an attractive and promising target for melanoma treatment.
Melanoma is one of the most aggressive skin cancers and is well known for its high metastatic rate.,Studies have shown that epithelial mesenchymal transition (EMT) is essential for melanoma cell metastasis.,However, the molecular mechanisms underlying EMT are still not fully understood.,We have shown that IRGM1, a member of immunity-related GTPase family that regulates immune cell motility, is highly expressed by melanoma cells.,The current study aimed to explore whether and how IRGM1 may regulate melanoma cell metastasis.,To test this, we modified IRGM1 expression in B16 melanoma cells.,We found that over-expression of IRGM1 substantially enhanced pulmonary metastasis in vivo.,In keeping with that, knocking-in IRGM1 strongly enhanced while knocking-down IRGM1 impaired B16 cell migration and invasion ability in vitro.,Interestingly, we observed that IRGM1 enhanced F-actin polymerization and triggers epithelial mesenchymal transition (EMT) through a mechanism involved in PIK3CA mediated Rac1 activation.,Together, these data reveals a novel molecular mechanism that involved in melanoma metastasis.