miR-212 Increases Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Sensitivity in Non-Small Cell Lung Cancer by Targeting the Antiapoptotic Protein PED

Fondazione IRCCS SDN, Naples, Italy.
Cancer Research (Impact Factor: 9.28). 04/2010; 70(9):3638-46. DOI: 10.1158/0008-5472.CAN-09-3341
Source: PubMed

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.

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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 [39] [40]. 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 [41] and miR-34c to negatively target transcriptional factor E2F3 and apoptosis key regulator Bcl2 [42] [43]. 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 [44]. "
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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 [4] [5] [6] [7] [8]. In osteogenesis, several miRs— such as miR-138, miR-206, and miR-210—regulate osteoblast differentiation [9] [10] [11]. "
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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. "
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