Abstract
BackgroundHOTTIP, a long non-coding RNA located in the HOXA cluster, plays a role in the patterning of tissues with mesodermal components, including the lung. Overexpression of HOXA genes, including HOTTIP, has been associated with a more aggressive phenotype in several cancers. However, the prognostic impact of HOTTIP has not yet been explored in non-small-cell lung cancer (NSCLC). We have correlated HOTTIP expression with time to relapse (TTR) and overall survival (OS) in early-stage NSCLC patients.MethodsNinety-nine early-stage NSCLC patients who underwent surgical resection in our center from June 2007 to November 2013 were included in the study. Mean age was 66; 77.8% were males; 73.7% had stage I disease; and 55.5% had adenocarcinoma. A validation data set comprised stage I-II patients from The Cancer Genome Atlas (TCGA) Research Network.ResultsHOTTIP was expressed in all tumor samples and was overexpressed in squamous cell carcinoma (p = 0.007) and in smokers (p = 0.018). Patients with high levels of HOTTIP had shorter TTR (78.3 vs 58 months; p = 0.048) and shorter OS (81.2 vs 61 months; p = 0.023) than those with low levels. In the multivariate analysis, HOTTIP emerged as an independent prognostic marker for TTR (OR: 2.05, 95%CI: 1–4.2; p = 0.05), and for OS (OR: 2.31, 95%CI: 1.04–5.1; p = 0.04). HOTTIP was validated as a prognostic marker for OS in the TCGA adenocarcinoma cohort (p = 0.025). Moreover, we identified a 1203-mRNA and a 61-miRNA signature that correlated with HOTTIP expression.ConclusionsThe lncRNA HOTTIP can be considered a prognostic biomarker in early-stage NSCLC.
Highlights
HOTTIP, a long non-coding RNA located in the HOXA cluster, plays a role in the patterning of tissues with mesodermal components, including the lung
Since regulatory interactions between long ncRNAs (lncRNAs), mRNAs and miRNAs have been described [38], we explored a possible association between the mRNAs and miRNAs whose expression correlated with HOTTIP according to TGCA data on adenocarcinoma non-small-cell lung cancer (NSCLC) analyzed with TANRIC
Our findings provide the first indication that HOTTIP may be a prognostic biomarker in NSCLC
Summary
HOTTIP, a long non-coding RNA located in the HOXA cluster, plays a role in the patterning of tissues with mesodermal components, including the lung. The prognostic impact of HOTTIP has not yet been explored in non-small-cell lung cancer (NSCLC). Up to 70% of our genome is transcribed into non-coding RNAs (ncRNAs) that do not serve as templates for proteins. These ncRNAs are subdivided into two major groups: small ncRNAs (< 200 nt) and long ncRNAs (lncRNAs) (> 200 nt) [4]. Small ncRNAs, especially microRNAs (miRNAs), have been the most extensively studied [5], lncRNAs have recently emerged as worthy biomarkers, since their expression is highly cell type- and tissue-specific [6]. In NSCLC, several lncRNAs are involved in the carcinogenesis process, some of which have been associated with patient survival [7,8,9]
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