Aberrant MUC1-TRIM46-KRTCAP2 Chimeric RNAs in High-Grade Serous Ovarian Carcinoma

Cancers

Kalpana Kannan²  Gona Karimi Kordestani²  Anika Galagoda²  Cristian Coarfa¹  Laising Yen² 

[1] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA;Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA;

关键词: chimeric RNA;    high-grade serous ovarian cancer;    MUC1;    TCGA;    RNA-seq;   

DOI  :  10.3390/cancers7040878

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.