Abstract
Treatment of lung cancer is an unmet need as it accounts for the majority of cancer deaths worldwide. The development of new therapies urges the identification of potential targets. MicroRNAs’ expression is often deregulated in cancer and their modulation has been proposed as a successful strategy to interfere with tumor cell growth and spread. We recently reported on an unbiased high-content approach to identify miRNAs regulating cell proliferation and tumorigenesis in non-small cell lung cancer (NSCLC). Here we studied the oncogenic role of miR-663 in NSCLC biology and analyzed the therapeutic potential of miR-663 targeting. We found that miR-663 regulates apoptosis by controlling mitochondrial outer membrane permeabilization (MOMP) through the expression of two novel direct targets PUMA/BBC3 and BTG2. Specifically, upon miR-663 knockdown the BH3-only protein PUMA/BBC3 directly activates mitochondrial depolarization and cell death, while BTG2 accumulation further enhances this effect by triggering p53 mitochondrial localization. Moreover, we show that miR-663 depletion is sufficient to elicit cell death in NSCLC cells and to impair tumor growth in vivo.
Highlights
Lung cancer is a disease with enormous implications on public health as it is nowadays the foremost cause of cancer-related death[1]
It is a heterogeneous disease that can be divided into two subtypes: small cell lung cancer (SCLC), a highly malignant tumor developed from neuroendocrine cells and non-small cell lung cancer (NSCLC)
We have recently investigated the role of all known miRNAs in NSCLC through the neutralization of their function, taking advantage of a locked nucleic acid (LNA)based anti-miRNA library[12]
Summary
Lung cancer is a disease with enormous implications on public health as it is nowadays the foremost cause of cancer-related death[1]. It is a heterogeneous disease that can be divided into two subtypes: small cell lung cancer (SCLC), a highly malignant tumor developed from neuroendocrine cells and non-small cell lung cancer (NSCLC). The study of the molecular basis of lung cancer, aimed at the identification of novel therapeutic targets is a major need to fight this devastating disease[4]. MicroRNAs (miRs) are a class of highly conserved nonprotein-coding RNAs, involved in the regulation of gene expression[5]. Single-stranded miRs bind to partially complementary target sequences on specific mRNAs (usually in the 3′ untranslated region -3′ UTR)
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