MicroRNA-155 Regulates Cell Survival, Growth, and Chemosensitivity by Targeting FOXO3a in Breast Cancer

Abstract

Breast cancer is the second leading cause of cancer death in women. Despite improvement in treatment over the past few decades, there is an urgent need for development of targeted therapies. miR-155 (microRNA-155) is frequently up-regulated in breast cancer. In this study, we demonstrate the critical role of miR-155 in regulation of cell survival and chemosensitivity through down-regulation of FOXO3a in breast cancer. Ectopic expression of miR-155 induces cell survival and chemoresistance to multiple agents, whereas knockdown of miR-155 renders cells to apoptosis and enhances chemosensitivity. Further, we identified FOXO3a as a direct target of miR-155. Sustained overexpression of miR-155 resulted in repression of FOXO3a protein without changing mRNA levels, and knockdown of miR-155 increases FOXO3a. Introduction of FOXO3a cDNA lacking the 3-untranslated region abrogates miR-155-induced cell survival and chemoresistance. Finally, inverse correlation between miR-155 and FOXO3a levels were observed in a panel of breast cancer cell lines and tumors. In conclusion, our study reveals a molecular link between miR-155 and FOXO3a and presents evidence that miR-155 is a critical therapeutic target in breast cancer. MicroRNAs (miRs)3 are short single-stranded RNAs that have become known as important regulators of various cellular processes by controlling gene expression at the post-transcriptional level (1-4). Deregulated microRNAs in cancer function as either tumor suppressors (5-7) or oncogenes (8 -11) and play a central role in carcinogenesis. Accumulating evidence shows that miR-155 is an oncogenic microRNA. First, microRNA profiling studies indicated frequent increase of miR-155 in various types of human malignancy, including different forms of B cell lymphoma and carcinoma of breast, lung, colon, head/neck, and kidney (9,(11)(12)(13)(14)(15)(16) FKHRL1 (FOXO3a) is a major member of the forkhead transcriptional factor family (24). Members of this family are characterized by a distinctive forkhead DNA binding domain, which is negatively regulated by protein kinases Akt, SGK, and IKK␤ (25-28). The phosphorylation of FOXO3a by these kinases leads to its translocation from the nucleus to the cytoplasm and loss of the proapoptotic function. In the unphosphorylated active form, FOXO3a resides in the nucleus and induces cell death by up-regulation of apoptotic proteins, such as BIM, p27, BNIP3, and 24p3 (29 -32) and repression of antiapoptotic molecule FLIP and BCL-XL (33, 34).To date, the majority of validated miR-155 functional biology and protein targets define the importance of miR-155 in immunology (23,(35)(36)(37)(38)(39) and various forms of lymphoma (9,11,40,41); however, the role of miR-155 in human breast cancer remains elusive. Here, we report that miR-155 induces cell survival and plays an important role in chemoresistance in breast cancer. Its anti-apoptotic function is mediated by direct inhibition of FOXO3a. Thus, our findings not only demonstrate regulation of FOXO3a at post-transcriptional levels but also i...

Resveratrol Ameliorates Cardiac Hypertrophy by Down‐regulation of miR‐155 Through Activation of Breast Cancer Type 1 Susceptibility Protein

“…demonstrated that myocardin expression can be stimulated by ROS, and FoxO3a negatively regulates myocardin expression through controlling ROS levels 27. Recently, there were several reports suggesting that FoxO3a was closely controlled by miR‐155 28, 29. In this current study, we provide the evidence that transient transfection with miR‐155 obviously reduced the protein level of FoxO3a.…”

“…The down‐regulated FoxO3a was verified to be associated with knockdown of BRCA1 (Figure 7C). Recently, there were several reports suggesting that FoxO3a was closely controlled by miR‐155 28, 29. We set out to speculate whether miR‐155 targeted the FoxO3a gene to influence the pathological process in cardiac hypertrophy.…”

The forkhead transcription factor FOXO1 mediates cisplatin resistance in gastric cancer cells by activating phosphoinositide 3-kinase/Akt pathway

“…We have previously shown that phosphorylated FOXO1 is overexpressed in gastric cancer specimens and that FOXO1 inactivation is related to better prognosis of gastric cancer patients [18]. Although FOXO proteins, especially FOXO1 and FOXO3, have been reported to be related to chemoresistance in various cancer cells [8][9][10][19][20][21], their involvement in chemoresistance of gastric cancer cells has not been reported. In the present study, we used two gastric cancer cell lines, MKN45 and SNU-601, with constitutive FOXO1 expression and found that CDDP treatment increased the levels of FOXO1 protein expression and activation.…”

Mutant p53 drives invasion in breast tumors through up-regulation of miR-155

“…In fact, findings from Xiang et al suggest that miR-155 suppresses the ability of 4T1 cells to undergo EMT. Indeed, it appears that the biological activity of miR-155 in human cell lines (10,24) is vastly different to that observed upon miR-155 expression in mammary cell lines that originate from mice (25,26), suggesting a lack of conservation of miR-155 seed sequences in its target 3'UTRs across these two species.…”