Abstract
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.
Highlights
Growth arrest–specific transcript 5 (GAS5), which is a long non-coding RNA, is a tumor-suppressor gene located on 1q25.1
Several studies have reported that GAS5 expression is decreased in various tumor types, including prostate cancer [2], lung cancer [3], bladder cancer [4], liver cancer [5], colon cancer [6], pancreatic cancer [7], and breast cancer [8]
We identified potential target genes of miR-221/222 and found that miR-221/222 inhibited the apoptosis of breast cancer cells by directly targeting an important tumor suppressor, GAS5
Summary
Growth arrest–specific transcript 5 (GAS5), which is a long non-coding RNA (lncRNA), is a tumor-suppressor gene located on 1q25.1. Several studies have reported that GAS5 expression is decreased in various tumor types, including prostate cancer [2], lung cancer [3], bladder cancer [4], liver cancer [5], colon cancer [6], pancreatic cancer [7], and breast cancer [8]. Most cellular studies have shown that GAS5 is mainly involved in regulating the apoptosis of tumors. Zhang et al [9] reported that miR-21 negatively regulated GAS5 in its role in cancer progression. The exact mechanisms of GAS5 in breast cancer remain complex and obscure
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