miR-212 Increases Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Sensitivity in Non-Small Cell Lung Cancer by Targeting the Antiapoptotic Protein PED
ABSTRACT PED/PEA-15 (PED) is a death effector domain family member of 15 kDa with a broad antiapoptotic function found overexpressed in a number of different human tumors, including lung cancer. To date, the mechanisms that regulate PED expression are unknown. Therefore, we address this point by the identification of microRNAs that in non-small cell lung cancer (NSCLC) modulate PED levels. In this work, we identify miR-212 as a negative regulator of PED expression. We also show that ectopic expression of this miR increases tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death in NSCLC cells. In contrast, inhibition of endogenous miR-212 by use of antago-miR results in increase of PED protein expression and resistance to TRAIL treatment. Besides, in NSCLC, we show both in vitro and in vivo that PED and miR-212 expressions are inversely correlated, that is, PED is upregulated and miR-212 is rarely expressed. In conclusion, these findings suggest that miR-212 should be considered as a tumor suppressor because it negatively regulates the antiapoptotic protein PED and regulates TRAIL sensitivity.
- SourceAvailable from: Carlotta A Glackin
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- "miR-1 is known to negatively target cyclin D2, a protein required for cell cycle progression, and also CXCR4 and its ligand SDF1α that are known as important chemotactic proteins in cancer metastasis  . miR-212 is known to negatively target antiapoptotic protein phosphoprotein enriched in diabetes (PED) and transcriptional factor c-Myc. miR-122 is known to negatively target cyclin B1  and miR-34c to negatively target transcriptional factor E2F3 and apoptosis key regulator Bcl2  . miR-200c has been shown to inhibit ZEB1 and ZEB2, which are transcriptional repressors of the E-cadherin gene, whose product is critical in cell adhesion . "
ABSTRACT: Pomegranate juice (PJ) is a natural product that inhibits prostate cancer progression. A clinical trial on patients with recurrent prostate cancer resulted in none of the patients progressing to a metastatic stage during the period of the trial. We have previously found that, in addition to causing cell death of hormone-refractory prostate cancer cells, PJ also markedly increases adhesion and decreases migration of the cells that do not die. However, because PJ is a very complex mixture of components and is found in many different formulations, it is important to identify specific components that are effective in inhibiting growth and metastasis. Here, we show that the PJ components luteolin, ellagic acid, and punicic acid together inhibit growth of hormone-dependent and hormone-refractory prostate cancer cells and inhibit their migration and their chemotaxis toward stromal cell-derived factor 1α (SDF1α), a chemokine that is important in prostate cancer metastasis to the bone. These components also increase the expression of cell adhesion genes and decrease expression of genes involved in cell cycle control and cell migration. Furthermore, they increase several well-known tumor-suppression microRNAs (miRNAs), decrease several oncogenic miRNAs, and inhibit the chemokines receptor type 4 (CXCR4)/SDF1α chemotaxis axis. Our results suggest that these components may be more effective in inhibiting prostate cancer growth and metastasis than simply drinking the juice. Chemical modification of these components could further enhance their bioavailability and efficacy of treatment. Moreover, because the mechanisms of metastasis are similar for most cancers, these PJ components may also be effective in the treatment of metastasis of other cancers.Translational oncology 10/2012; 5(5):344-55. DOI:10.1593/tlo.12190 · 3.40 Impact Factor
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- "Mature miRs regulate the repression of specific target gene translation and/or promote degradation of transcribed mRNAs by binding to the 3 0 -untranslated regions (3 0 -UTR) of the target genes. In the recent past, several reports have indicated that miRs are closely implicated in diverse biological processes, including cell growth, cell differentiation, apoptosis, carcinogenesis , and diabetes     . In osteogenesis, several miRs— such as miR-138, miR-206, and miR-210—regulate osteoblast differentiation   . "
ABSTRACT: MicroRNAs (miRs) regulate several biological functions such as cell growth, cell differentiation, and carcinogenesis, by binding to the 3'-untranslated regions (3'-UTR) of specific target genes, in order to repress translation or promote degradation of the transcribed mRNAs. In the present study, using microRNA array and in silico analyses, we found that miR-370 regulates the expression of bone morphogenetic protein-2 (BMP-2) and V-ets Erythroblastosis Virus E26 Oncogene Homolog 1 (Ets1) in BMP-2-stimulated murine pre-osteoblast MC3T3-E1 cell differentiation. The enforced expression of mature miR-370 in MC3T3-E1 cells or primary osteoblast cells remarkably attenuated BMP-2-induced pre-osteoblast differentiation. To ascertain the mechanisms underlying the regulation of osteoblast differentiation by miR-370, we hypothesized a BMP-2-Ets1-PTHrP feed-forward loop regulatory mechanism.FEBS letters 05/2012; 586(12):1693-701. DOI:10.1016/j.febslet.2012.04.014 · 3.34 Impact Factor
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- "On the contrary, in the majority of lung cancer samples, miR-212 was expressed at low levels, and PED was overexpressed (Incoronato et al., 2010). The protein PED/PEA-15 has been demonstrated to increase cell migration in lung cancer (Zanca et al., 2010), which is also a target of miR-212 (Incoronato et al., 2010). It was concluded that miR-212 should be considered a tumor suppressor, because it negatively regulates the anti-apoptotic protein PED. "
ABSTRACT: Dysexpression of microRNAs has been found in many tumors, including lung cancer. The hedgehog (Hh) signaling pathway plays an important role during normal development, and the abnormal regulation of its members has also been related to many tumors. However, little is known about the relationship between microRNA and the Hh pathway. In this paper, we report microRNA-212 (miR-212) playing a role in non-small cell lung cancer (NSCLC) and targeting PTCH1, a receptor of the Hh pathway. We found that miR-212 was up-regulated when cells were treated with 4ß-12-O-tetradecanoylphorbol-13-acetate (TPA). We ectopically expressed miR-212 in NSCLC cell lines to examine the influence of miR-212 overexpression. The results showed that overexpression of miR-212 in NSCLC cells promoted cell cycle progression and cell proliferation, migration, and invasion. The promoting effects of miR-212 on cell proliferation, migration, and invasion were partially reversed by the miR-212 inhibitor anti-miR-212. These results suggested that miR-212 might have tumor-promoting properties. Potential targets of miR-212 were predicted, and we showed tumor suppressor PTCH1 was a functional target of miR-212. PTCH1 may be responsible for the effect of miR-212 on cell proliferation. Altogether, our results indicated that miR-212 was involved in tumorigenesis, and the oncogenic activity of miR-212 in NSCLC cells was due, in part, to suppression of PTCH1.Molecular biology of the cell 02/2012; 23(8):1423-34. DOI:10.1091/mbc.E11-09-0777 · 5.98 Impact Factor