Transcriptomic profiling reveals hepatic stem-like gene signatures and interplay of miR-200c and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma

TY - JOUR

T1 - Transcriptomic profiling reveals hepatic stem-like gene signatures and interplay of miR-200c and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma

AU - Oishi, Naoki

AU - Kumar, Mia R

AU - Roessler, Stephanie

AU - Ji, Junfang

AU - Forgues, Marshonna

AU - Budhu, Anuradha

AU - Zhao, Xuelian

AU - Andersen, Jesper Bøje

AU - Ye, Qing-Hai

AU - Jia, Hu-Liang

AU - Qin, Lun-Xiu

AU - Yamashita, Taro

AU - Woo, Hyun Goo

AU - Kim, Yoon Jun

AU - Kaneko, Shuichi

AU - Tang, Zhao-You

AU - Thorgeirsson, Snorri S

AU - Wang, Xin Wei

N1 - Copyright © 2012 American Association for the Study of Liver Diseases.

PY - 2012/11

Y1 - 2012/11

N2 - Intrahepatic cholangiocellular carcinoma (ICC) is the second most common type of primary liver cancer. However, its tumor heterogeneity and molecular characteristics are largely unknown. In this study, we conducted transcriptomic profiling of 23 ICC and combined hepatocellular cholangiocarcinoma tumor specimens from Asian patients using Affymetrix messenger RNA (mRNA) and NanoString microRNA microarrays to search for unique gene signatures linked to tumor subtypes and patient prognosis. We validated the signatures in an additional 68 ICC cases derived from Caucasian patients. We found that both mRNA and microRNA expression profiles could independently classify Asian ICC cases into two main subgroups, one of which shared gene expression signatures with previously identified hepatocellular carcinoma (HCC) with stem cell gene expression traits. ICC-specific gene signatures could predict survival in Asian HCC cases and independently in Caucasian ICC cases. Integrative analyses of the ICC-specific mRNA and microRNA expression profiles revealed that a common signaling pathway linking miR-200c signaling to epithelial-mesenchymal transition (EMT) was preferentially activated in ICC with stem cell gene expression traits. Inactivation of miR-200c resulted in an induction of EMT, whereas activation of miR-200c led to a reduction of EMT including a reduced cell migration and invasion in ICC cells. We also found that miR-200c and neural cell adhesion molecule 1 (NCAM1) expression were negatively correlated and their expression levels were predictive of survival in ICC samples. NCAM1, a known hepatic stem/progenitor cell marker, was experimentally demonstrated to be a direct target of miR-200c. Conclusion: Our results indicate that ICC and HCC share common stem-like molecular characteristics and poor prognosis. We suggest that the specific components of EMT may be exploited as critical biomarkers and clinically relevant therapeutic targets for an aggressive form of stem cell-like ICC.

AB - Intrahepatic cholangiocellular carcinoma (ICC) is the second most common type of primary liver cancer. However, its tumor heterogeneity and molecular characteristics are largely unknown. In this study, we conducted transcriptomic profiling of 23 ICC and combined hepatocellular cholangiocarcinoma tumor specimens from Asian patients using Affymetrix messenger RNA (mRNA) and NanoString microRNA microarrays to search for unique gene signatures linked to tumor subtypes and patient prognosis. We validated the signatures in an additional 68 ICC cases derived from Caucasian patients. We found that both mRNA and microRNA expression profiles could independently classify Asian ICC cases into two main subgroups, one of which shared gene expression signatures with previously identified hepatocellular carcinoma (HCC) with stem cell gene expression traits. ICC-specific gene signatures could predict survival in Asian HCC cases and independently in Caucasian ICC cases. Integrative analyses of the ICC-specific mRNA and microRNA expression profiles revealed that a common signaling pathway linking miR-200c signaling to epithelial-mesenchymal transition (EMT) was preferentially activated in ICC with stem cell gene expression traits. Inactivation of miR-200c resulted in an induction of EMT, whereas activation of miR-200c led to a reduction of EMT including a reduced cell migration and invasion in ICC cells. We also found that miR-200c and neural cell adhesion molecule 1 (NCAM1) expression were negatively correlated and their expression levels were predictive of survival in ICC samples. NCAM1, a known hepatic stem/progenitor cell marker, was experimentally demonstrated to be a direct target of miR-200c. Conclusion: Our results indicate that ICC and HCC share common stem-like molecular characteristics and poor prognosis. We suggest that the specific components of EMT may be exploited as critical biomarkers and clinically relevant therapeutic targets for an aggressive form of stem cell-like ICC.

KW - Antigens, CD56

KW - Asian Continental Ancestry Group

KW - Bile Duct Neoplasms

KW - Bile Ducts, Intrahepatic

KW - Carcinoma, Hepatocellular

KW - Cell Line, Tumor

KW - Cholangiocarcinoma

KW - Epithelial-Mesenchymal Transition

KW - European Continental Ancestry Group

KW - Gene Expression Profiling

KW - Humans

KW - Kaplan-Meier Estimate

KW - Liver Neoplasms

KW - MicroRNAs

KW - Neoplastic Stem Cells

KW - RNA, Messenger

KW - Signal Transduction

U2 - 10.1002/hep.25890

DO - 10.1002/hep.25890

M3 - Journal article

C2 - 22707408

SN - 0270-9139

VL - 56

SP - 1792

EP - 1803

JO - Hepatology

JF - Hepatology

IS - 5

ER -