MicroRNAs (miRNAs) are 21–23-nucleotide, short, non-coding RNAs that play important roles in virtually all biological pathways in mammals and other multicellular organisms. The association of miR-221 and miR-222 (miR-221/222) for breast cancer is critical, but their detailed roles in its development and progression remain unclear. In the present study, we found that miR-221/222 were consistently up-regulated in breast cancer tissues. We then investigated the molecular mechanisms by which miR-221/222 contributed to breast cancer and identified growth arrest–specific transcript 5 (GAS5) as a direct target gene of miR-221/222. In contrast with the up-regulated expression levels of miR-221/222, GAS5 levels were significantly down-regulated and negatively correlated with miR-221/222 in breast cancer tissues. In addition, we showed that miR-221/222 inhibitors increased cellular apoptosis, miR-221/222 mimics decreased the cell apoptosis in breast cancer cells, and restoration of GAS5 expression attenuated the anti-apoptotic effects of miR-221/222 in breast cancer cells, indicating that GAS5 was a direct mediator of miR-221/222 function. Finally, we showed that miR-221/222 suppressed GAS5 expression significantly and enhanced tumor growth in a mouse model of breast cancer xenografts. The present study highlighted the important role of miR-221/222 as oncomiRs in breast cancer, which inhibited GAS5 translation. These findings may provide a new perspective for the molecular mechanism of breast carcinogenesis and provide a novel approach to the treatment of breast cancer.
Melanoma is inherently heterogeneous, providing resistance to apoptosis. Anoikis resistance is a hallmark feature of metastatic melanoma to escape apoptosis when cells lose contact with adjacent cells or extracellular matrix. The yes-associated protein transcription co-activator is the effector of Hippo pathway. Herein, we investigated the function of yes-associated protein in anoikis resistance of melanoma cells. When melanoma cells were grown under anchorage-independent condition, anoikis-resistant cells displayed higher levels of yes-associated protein activation than the cells that were attached to the basement membrane, as evidenced by downregulated phosphorylated yes-associated protein at Ser127 and higher expression of downstream genes BCL2 and MCL-1. Yes-associated protein overexpression directly enhanced the anoikis resistance and metastatic potential of melanoma cells. Conversely, yes-associated protein inhibitor CA3 exhibited Dose-dependent induction of anoikis in resistant melanoma cells and exerted great inhibition on cell migration. Knockdown of yes-associated protein expression by shRNA also rendered melanoma cells susceptible to anoikis and interrupted cell invasiveness. Yes-associated protein inhibition in anoikis-resistant cells also reduced the number of metastatic nodules in the lung sections of SCID mice. Clinically, higher yes-associated protein level in the lung metastasis tissues correlated with higher BCL2 and MCL1 expressions compared with the non-metastasis tissues. Overall, our finding suggests that the aberrant activation of yes-associated protein exerts important role on anoikis resistance and metastatic capability of melanoma cells.
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