MicroRNA-21 inhibits p57Kip2 expression in prostate cancer

Abstract

Backgroundp57Kip2, a cyclin-dependent kinase inhibitor, is considered to be a candidate tumor suppressor gene that has been implicated in Beckwith-Wiedemann syndrome and sporadic cancers. In addition, decreased expression of p57Kip2 protein has been frequently observed in pancreatic, lung, breast, bladder, gastrointestinal tract and prostate cancers. However, p57Kip2 gene mutations are rare in these cancers suggesting that other unknown mechanisms might be at play in reducing its expression. The aim of this study was to investigate the molecular mechanism of down-regulation of p57Kip2 in prostate cancer.FindingsWe observed a significant negative correlation between the expression of p57Kip2 and microRNA-21 (miR-21) in prostate cancer samples and after androgen deprivation with castration in the CWR22 human prostate cancer xenograft model. We report that miR-21 targeted the coding region and decreased p57Kip2 mRNA and protein levels in prostate cancer cells. Conversely, inhibition of endogenous miR-21 by an anti-miR-21 inhibitor strongly induced p57Kip2 expression. Furthermore, we found that knockdown of p57Kip2 reversed the effects of the anti-miR-21 inhibitor on cell migration and anchorage-independent cell growth.ConclusionsOur results indicate that miR-21 is able to downregulate p57Kip2 expression by targeting the coding region of the gene and is also able to attenuate p57Kip2 mediated functional responses. This is the first report demonstrating that p57Kip2 is a novel target of miR-21 in prostate cancer and revealing a novel oncogenic function of this microRNA.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-212) contains supplementary material, which is available to authorized users.

Exosomes of pasteurized milk: potential pathogens of Western diseases

“…miR-21, a signature miR of dairy milk, is overexpressed in PCa cells [304,305], in blood serum [304,306], PBMCs [307], serum exosomes [308] well as urinary exosomes of PCa patients [309,310]. miR-21 is regarded as an oncomir, that inhibits pivotal tumor suppressor genes such as PTEN, p57kip2 (CDKN1C), PDCD4, MARCKS and others [240,[311][312][313][314]. Loss of function of the PTEN tumor suppressor, upregulating the phosphoinositide 3-kinase (PI3K)-AKT signaling network, is recognized as one of the most common driving events in PCa development [311].…”

Milk—A Nutrient System of Mammalian Evolution Promoting mTORC1-Dependent Translation

“…Importantly, daily milk consumption during adolescence ( vs. less than daily), but not in midlife or currently, was associated with a 3.2-fold risk of advanced prostate cancer [ 253 ], pointing to a critical signaling magnitude of mTORC1-dependent prostate branching morphogenesis during adolescence [ 254 ], the prostate’s period of sexual maturation [ 246 ]. There is accumulating evidence that microRNA-21 contributes to prostate cancer pathogenesis interfering with multiple pathways including mTORC1-dependent translation and cell proliferation [ 255 , 256 , 257 , 258 ]. In fact, addition of commercial cows' milk to LNCaP prostate cancer cells stimulated growth of prostate cancer cells and increased the growth rate of the tumor cells over 30% [ 259 ].…”

“…Depletion of p57Kip2 but not p21Cip1 rendered IGF-1 or insulin sufficient to induce cellular proliferation in the absence of EGF. Remarkably, microRNA-21, a major microRNA of commercial milk [ 111 , 117 ], has recently been shown to target p57Kip2 in prostate cancer cells [ 256 ]. Increased levels of microRNA-21 have been found in serum and mammary tumor tissue of breast cancer patients [ 273 , 274 , 275 , 276 ].…”

The novel role of miRNAs for tamoxifen resistance in human breast cancer

“…Interestingly, miR-21 was identified as one of the oncomiRs whose expression was found to be upregulated in many types of cancer, including both solid tumors and breast cancer [70]. Mechanistically, upregulation of miR-21 expression leads to the suppression of several key tumor suppressor genes, such as p57 Kip2 , tropomyosin 1 (TPM1), programmed cell death protein 4 (PDCD4) and PTEN [71][72][73][74]. Indeed, it was also confirmed that miR-21 antisense oligos inhibited the proliferation and invasion of primary stromal cells of phyllodes tumors [70].…”