Previous research into lung cancer, the leading cause of cancer death in the United States, has focused on protein-coding genes to identify oncogenes and tumor suppressors. However, scientists at The Genome Institute at Washington University School of Medicine are exploring long intragenic non-coding RNAs (lncRNAs), which have been shown to play a critical role in tumorigenesis. Led by Christopher Maher, PhD, the team recently reported novel lncRNAs detected in 567 adenocarcinoma and squamous cell carcinoma lung tumors. The work was published online on August 13 in Genome Biology.
The GENCODE consortium amassed 9,277 human lncRNAs, but it is possible that lncRNAs may outnumber protein-coding genes. lncRNAs are more difficult to identify since they are only expressed in specific tissues and often at much lower expression levels than protein-coding genes. These lncRNAs may serve as clinical markers and be essential in cancer biology, typically facilitating epigenetic gene repression through chromatin-modifying complexes.
However, the role of lncRNAs in tumorigenesis in lung cancer remains poorly defined. MALAT1 has been associated with high metastatic potential and poor prognosis in non-small cell lung cancer. Intronic non-coding RNAs, including lncRNA-LET, AK126698, and lncRNA-1 (SCAL1), have been implicated in lung cancer development. The substantial quantity of known and undiscovered lncRNAs may yield novel biomarkers and therapeutic targets.
Maher’s team used publicly available transcriptome sequencing data from 370 lung adenocarcinoma and 197 lung squamous cell carcinoma tumors to identify over 3,000 novel lncRNAs. By comparing both adenocarcinoma and squamous cell tumors to matched controls, they discovered 111 differentially expressed lncRNAs, which they termed lung-cancer associated lncRNAs (LCALs). The team used publicly available exon array-based data coupled with qRT-PCR and RACE to validate a subset of LCALs. To confirm that LCALs were lung-cancer specific, a meta-analysis was performed across an additional 324 tumor and normal pairs sequenced as part of The Cancer Genome Atlas (TCGA). Additional exome sequencing data from TCGA was incorporated to identify LCALs that were associated with commonly mutated genes. The most differentially expressed lncRNA, LCAL1, was functionally validated and determined to regulate cellular proliferation in vitro.
"To date, lung cancer research has primarily focused on the deregulation of protein-coding genes to identify oncogenes and tumor suppressors as potential diagnostic and therapeutic targets, thus potentially missing the important role of long non-coding genes in lung cancer disease etiology,” says Dr. Maher. “Our study highlights the lncRNA landscape that may contribute to lung cancer by revealing a set of 111 lung cancer associated lncRNAs. The significance of these is further supported by our in vitro analysis of the most up-regulated lncRNA in lung cancer, LCAL1, demonstrating its role in regulating cellular proliferation in multiple histologies."