Abstract
Lung cancer is a leading cause of cancer death worldwide. Several alterations in RNA metabolism have been found in lung cancer cells; this suggests that RNA metabolism-related molecules are involved in the development of this pathology. In this study, we searched for RNA metabolism-related genes that exhibit different expression levels between normal and tumor lung tissues. We identified eight genes differentially expressed in lung adenocarcinoma microarray datasets. Of these, seven were up-regulated whereas one was down-regulated. Interestingly, most of these genes had not previously been associated with lung cancer. These genes play diverse roles in mRNA metabolism: three are associated with the spliceosome (ASCL3L1, SNRPB and SNRPE), whereas others participate in RNA-related processes such as translation (MARS and MRPL3), mRNA stability (PCBPC1), mRNA transport (RAE), or mRNA editing (ADAR2, also known as ADARB1). Moreover, we found a high incidence of loss of heterozygosity at chromosome 21q22.3, where the ADAR2 locus is located, in NSCLC cell lines and primary tissues, suggesting that the downregulation of ADAR2 in lung cancer is associated with specific genetic losses. Finally, in a series of adenocarcinoma patients, the expression of five of the deregulated genes (ADAR2, MARS, RAE, SNRPB and SNRPE) correlated with prognosis. Taken together, these results support the hypothesis that changes in RNA metabolism are involved in the pathogenesis of lung cancer, and identify new potential targets for the treatment of this disease.
Highlights
Lung cancer is one of the most common human cancers and a leading cause of cancer death worldwide [1,2]
To corroborate the validity of this selection, additional in silico validation was performed with a fourth independent cohort of lung adenocarcinoma patients [25], and the results confirmed the findings of the initial experiment (Table S2)
We investigated whether expression of the differentially expressed RNA metabolism-related genes was associated with clinical outcomes in patients with lung adenocarcinoma using a publicly available microarray data [26]
Summary
Lung cancer is one of the most common human cancers and a leading cause of cancer death worldwide [1,2] It includes two principal histological subtypes, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), and the latter accounts for 80–85% of all cases. Alterations in alternative splicing have been demonstrated to be associated with various diseases, including cancer. Splicing changes that affected transcripts of VEGFA, MACF1, APP, and NUMB were demonstrated in patients with lung adenocarcinoma [9]. Modulation of caspase 9 alternative splicing was demonstrated to affect the sensitivity of NSCLC cells to some chemotherapeutic agents [12]
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