Human bile contains MicroRNA-laden extracellular vesicles that can be used for cholangiocarcinoma diagnosis

Ling Li, David Masica, Masaharu Ishida, Ciprian Tomuleasa, Sho Umegaki, Anthony N. Kalloo, Christos Georgiades, Vikesh K. Singh, Mouen Khashab, Stuart Amateau, Zhiping Li, Patrick Okolo, Anne Marie Lennon, Payal Saxena, Jean Francois Geschwind, Todd Schlachter, Kelvin Hong, Timothy M. Pawlik, Marcia Canto, Joanna LawReem Sharaiha, Clifford R. Weiss, Paul Thuluvath, Michael Goggins, Eun Ji Shin, Haoran Peng, Vivek Kumbhari, Susan Hutfless, Liya Zhou, Esteban Mezey, Stephen J. Meltzer, Rachel Karchin, Florin M. Selaru

Research output: Contribution to journalArticlepeer-review

120 Citations (Scopus)

Abstract

Cholangiocarcinoma (CCA) presents significant diagnostic challenges, resulting in late patient diagnosis and poor survival rates. Primary sclerosing cholangitis (PSC) patients pose a particularly difficult clinical dilemma because they harbor chronic biliary strictures that are difficult to distinguish from CCA. MicroRNAs (miRs) have recently emerged as a valuable class of diagnostic markers; however, thus far, neither extracellular vesicles (EVs) nor miRs within EVs have been investigated in human bile. We aimed to comprehensively characterize human biliary EVs, including their miR content. We have established the presence of extracellular vesicles in human bile. In addition, we have demonstrated that human biliary EVs contain abundant miR species, which are stable and therefore amenable to the development of disease marker panels. Furthermore, we have characterized the protein content, size, numbers, and size distribution of human biliary EVs. Utilizing multivariate organization of combinatorial alterations (MOCA), we defined a novel biliary vesicle miR-based panel for CCA diagnosis that demonstrated a sensitivity of 67% and specificity of 96%. Importantly, our control group contained 13 PSC patients, 16 with biliary obstruction of varying etiologies (including benign biliary stricture, papillary stenosis, choledocholithiasis, extrinsic compression from pancreatic cysts, and cholangitis), and 3 with bile leak syndromes. Clinically, these types of patients present with a biliary obstructive clinical picture that could be confused with CCA. Conclusion: These findings establish the importance of using extracellular vesicles, rather than whole bile, for developing miR-based disease markers in bile. Finally, we report on the development of a novel bile-based CCA diagnostic panel that is stable, reproducible, and has potential clinical utility.

Original languageEnglish
Pages (from-to)896-907
Number of pages12
JournalHepatology
Volume60
Issue number3
DOIs
Publication statusPublished - 2014 Sep
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology

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