Journal
CANCERS
Volume 7, Issue 4, Pages 2083-2093Publisher
MDPI
DOI: 10.3390/cancers7040878
Keywords
chimeric RNA; high-grade serous ovarian cancer; MUC1; TCGA; RNA-seq
Categories
Funding
- DOD [W81XWH-10-10327]
- Duncan Cancer Center
- Ovarian Cancer Research Foundation OCRF [PPD/BCM/01.12]
- NIH [R01EB013584, HD007495, DK56338, CA125123]
- PCF Young Investigator award
- Alkek Foundation for Molecular Discovery
- Integrated Microscopy Core at Baylor College of Medicine
- Dan L. Duncan Cancer Center
- John S. Dunn Gulf Coast Consortium for Chemical Genomics
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High-grade serous ovarian cancer (HGSC) is among the most lethal forms of cancer in women. By analyzing the mRNA-seq reads from The Cancer Genome Atlas (TCGA), we uncovered a novel cancer-enriched chimeric RNA as the result of splicing between MUC1, a highly glycosylated transmembrane mucin, TRIM46, a tripartite motif containing protein, and KRTCAP2, a keratinocyte associated protein. Experimental analyses by RT-PCR (reverse transcription PCR) and Sanger sequencing using an in-house cohort of 59 HGSC patient tumors revealed a total of six MUC1-TRIM46-KRTCAP2 isoforms joined by different annotated splice sites between these genes. These chimeric isoforms are not detected in non-cancerous ovaries, yet are present in three out of every four HGSC patient tumors, a significant frequency given the exceedingly heterogeneous nature of this disease. Transfection of the cDNA of MUC1-TRIM46-KRTCAP2 isoforms in mammalian cells led to the translation of mutant MUC1 fusion proteins that are unglycosylated and cytoplasmically localized as opposed to the cell membrane, a feature resembling the tumor-associated MUC1. Because the parental MUC1 is overexpressed in 90% of HGSC tumors and has been proposed as a clinical biomarker and therapeutic target, the chimeric MUC1-TRIM46-KRTCAP2 isoforms identified in this report could represent significantly better MUC1 variants for the same clinical utilities.
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