Novel splicing variants of recepteur d'origine nantais (RON) tyrosine kinase involving exons 15–19 in lung cancer. (February 2016)

• Record Type: Journal Article
• Authors: Krishnaswamy, Soundararajan; Mohammed, Abdul Khader; Amer, Osama E.; Tripathi, Gyanendra; Alokail, Majed S.; Al-Daghri, Nasser M.
• Is Part Of: Lung cancer. Volume 92(2016)
• Page Start: 41
• Page End: 46
• Publication Date: 2016-02
• Subjects: MST1R macrophage stimulating 1 receptor -- RTK receptor tyrosine kinase -- MSP macrophage stimulating protein -- SCLC small cell lung cancer -- NSCLC non-small cell lung cancer -- EGFR epidermal growth factor receptor; RON -- MST1R -- Receptor tyrosine kinase -- Alternative splicing -- RON isoforms; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2015.12.002
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: RON is aberrantly expressed in cancer and is a potential target RTK for therapy. We identified four novel alternatively spliced transcript variants in lung cancer. Some cell lines contained up to four uniquely spliced transcript sequence variants. Skipping of exon(s) occurred in the region coding for the kinase domain of RON. Sequence details of these variants may aid in isoform specific target validation. Abstract: Background: Altered expressions of receptor tyrosine kinases drive the growth and metastasis of several cancers. RON is a single pass transmembrane receptor tyrosine kinase (RTK) shown to be aberrantly expressed in various cancer types. However, target validation and successful therapeutic targeting of RON in cancers is hampered by the co-existence of unknown number/types of isoforms, which are structurally similar but functionally diverse. Objective: The objective of this study was to identify differential splicing in the C-terminal region of RON transcripts to better understand RON signaling in cancers. mRNA transcript sequence between exons 14 and 20 of RON was PCR amplified and sequenced using cDNA from 10 SCLC and 13 NSCLC cell lines. Specific exon deletions were identified by aligning sequencing chromatograms with reference RON cDNA sequence. Results: We identified the presence of four unique transcript sequence variants of RON formed through skipping of exons 15–19, 16–19, 16–17 and 16. The transcript variants, except the one lacking exons 15–19, were found in more than one cell line. Several cell lines contained two to four of these uniquely spliced transcript variants. dbEST (Expressed Sequence Tags database) or other DNA sequence databases did not contain RON cDNA sequences corresponding to any of the above exon deletions indicating that all these transcript sequence alterations are novel. Conclusions: Results of our study indicate common occurrence of different types of alternatively spliced transcripts of RON in lung cancer with potential to be translated into proteins lacking active kinase domain. Our findings suggest that tumors produce several dominant negative isoforms which probably inhibit ligand dependent RON signaling, and hence, raise important questions regarding the appropriateness of blocking wild type RON signaling for therapy. Further, presence of transcript variants and their isoform products may interfere with quantitative and functional analysis during target validation.