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


CONCLUSIONS
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.
National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Naoki
N
Oishi
Mia R
MR
Kumar
Stephanie
S
Roessler
Junfang
J
Ji
Marshonna
M
Forgues
Anuradha
A
Budhu
Xuelian
X
Zhao
Jesper B
JB
Andersen
Qing-Hai
QH
Ye
Hu-Liang
HL
Jia
Lun-Xiu
LX
Qin
Taro
T
Yamashita
Hyun Goo
HG
Woo
Yoon Jun
YJ
Kim
Shuichi
S
Kaneko
Zhao-You
ZY
Tang
Snorri S
SS
Thorgeirsson
Xin Wei
XW
Wang
D044466:Asian People / Q000235:genetics; D001650:Bile Duct Neoplasms / Q000235:genetics*; D001653:Bile Ducts, Intrahepatic; D019002:CD56 Antigen / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D014411:Neoplastic Stem Cells; D012333:RNA, Messenger / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D044465:White People / Q000235:genetics
D019002:CD56 Antigen; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C522918:NCAM1 protein, human; D012333:RNA, Messenger