Abstract
Lung cancer represents the leading cause of cancer-related death in developed countries. Despite the advances in diagnostic and therapeutic techniques, the 5-year survival rate remains low. The research for novel therapies directed to biological targets has modified the therapeutic approach, but the frequent engagement of resistance mechanisms and the substantial costs, limit the ability to reduce lung cancer mortality. MicroRNAs (miRNAs) are small noncoding RNAs with known regulatory functions in cancer initiation and progression. In this study we found that mir-660 expression is downregulated in lung tumors compared with adjacent normal tissues and in plasma samples of lung cancer patients with poor prognosis, suggesting a potential functional role of this miRNA in lung tumorigenesis. Transient and stable overexpression of mir-660 using miRNA mimics reduced migration, invasion, and proliferation properties and increased apoptosis in p53 wild-type lung cancer cells (NCI-H460, LT73, and A549). Furthermore, stable overexpression using lentiviral vectors in NCI-H460 and A549 cells inhibited tumor xenograft growth in immunodeficient mice (95 and 50% reduction compared with control, respectively), whereas the effects of mir-660 overexpression were absent in H1299, a lung cancer cell line lacking p53 locus, both in in vitro and in vivo assays. We identified and validated mouse double minute 2 (MDM2) gene, a key regulator of the expression and function of p53, as a new direct target of mir-660. In addition, mir-660 expression reduced both mRNA and protein expression of MDM2 in all cell lines and stabilized p53 protein levels resulting in an upregulation of p21WAF1/CIP1 in p53 wild-type cells. Our finding supports that mir-660 acts as a tumor suppressor miRNA and we suggest the replacement of mir-660 as a new therapeutic approach for p53 wild-type lung cancer treatment.
Highlights
Tyrosine kinase inhibitors, represent roughly 10%, whereas the subgroup of tumors with anaplastic lymphoma kinase (ALK) rearrangements, targeted by ALK inhibitors, is only ~ 5%.7 the majority of lung tumors lack effective treatment and novel therapeutic strategies are still needed
Among those miRNAs significantly deregulated between patients and controls, we found that mir-660 was progressively downmodulated in patients with good prognosis, and patients with poor prognosis (Figure 1a) compared with disease-free subjects
To analyze mir-660 expression in lung tissue samples, 20 pairs of tumor and distant normal lung tissues obtained from lung cancer patients identified in the Multicentric Italian Lung Detection (MILD) trial[45] were selected (Supplementary Table 1)
Summary
Tyrosine kinase inhibitors, represent roughly 10%, whereas the subgroup of tumors with ALK rearrangements, targeted by ALK inhibitors, is only ~ 5%.7 the majority of lung tumors lack effective treatment and novel therapeutic strategies are still needed. MiRNAs are actively released by various cell types and can be detected in biological fluids, such as plasma and serum, making them suitable as circulating biomarkers in NSCLC.[20,21]. There is limited evidence of mir-660 deregulation in cancer and little is known about its role in lung tumorigenesis and its putative target genes. Received 10.9.14; revised 10.10.14; accepted 21.10.14; Edited by G Melino mir-660 was one of the 24 miRNAs deregulated in plasma samples of NSCLC patients identified in a low-dose computed tomography (LDCT) screening trial.[20]
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