miR-34a as a prognostic marker of relapse in surgically resected non-small-cell lung cancer

Abstract

MicroRNAs (miRNAs) have been identified as promising prognostic markers in non-small-cell lung cancer (NSCLC) since they play an important role in oncogenesis. The miR-34 family is composed of three miRNAs (miR-34a, miR-34b and miR-34c) that are part of the p53 network and whose expression is directly induced by p53 in response to DNA damage or oncogenic stress. We have analyzed the impact of miR-34 expression on relapse and overall survival in surgically resected NSCLC patients. For this purpose, we used stem-loop reverse transcription-polymerase chain reaction to analyze the expression of the miR-34 family in paired tumor and normal tissue from 70 surgically resected NSCLC patients who received no postsurgical treatment until relapse. In addition, in patients with sufficient tumor tissue, we assessed p53 mutations and the methylation status of the MIRN34A gene promoter region and correlated these findings with miR-34a expression. Molecular findings were correlated with relapse and overall survival. The miR-34 family was downregulated in tumor compared with normal tissue, and low levels of miR-34a expression were correlated with a high probability of relapse (P = 0.04). A relation was also found between MIRN34A methylation and miR-34a expression (P = 0.008). Patients with both p53 mutations and low miR-34a levels had the highest probability of relapse (P = 0.001). In the multivariate analysis, miR-34a expression emerged as an independent prognostic marker for relapse. In summary, we have identified miR-34a as a novel prognostic marker in NSCLC patients, providing a potential mechanism for estimating a patient's risk of disease recurrence and a useful tool to help guide treatment decisions.

Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer

“…While no significant correlation between miR expression levels and patients' clinico-pathological characteristics (gender, age, tumor size, lymph nodal status and clinical stage) was found, survival analysis indicated a positive association towards a longer survival for those patients with miR-34 upregulation. This is in line with recent results indicating miR-34 as a prognostic factor in NSCLC (Gallardo et al, 2009), and further confirm its putative role as a tumor suppressor miR in lung cancer. Interestingly, a comparably lower level of regulation (that is, expression) in squamous, as compared with non-squamous tumors, has been observed for all the three miRs.…”

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

“…Mirna Therapeutics is currently developing let-7 as a potential miRNA replacement treatment for cancer [168]. miR-34 is another master tumour suppressor miRNA, the downregulation of which is largely investigated in lung cancer [178,179]. miR-34 family members (a, b and c) are responsible for cell cycle control, apoptosis and cell senescence via the repression of several targets involved in carcinogenesis like BCL2, MYC and MET genes [180].…”

Effect of miRNAs in lung cancer suppression and oncogenesis

“…The miR-34/449 family however were found to control apoptosis and cell cycle arrest in lung cancer cell lines by directly regulating transcription factors p53 and E2F [31,32]. As an example, inactivated miR-34a may cause transcription silence in lung cancer through CpG methylation, which indicates that miR-34a may be used as a biomarker for NSCLC [33,34]. Based on these directly miR-15a and miR-16-1 together with miR-15b and miR-16-2 belong to the cluster of miR-15/16, and when the deletion or downregulation of miR-15 and miR-16 occurs, many phases of lung cancer development -including proliferation, invasion and cell survival -are inhibited [39].…”