Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells.
Adult hepatic progenitor (oval) cells are facultative stem cells in liver, which participate in a range of human liver diseases, including hepatocellular carcinoma (HCC). However, the molecular pathways regulating the expansion and differentiation of these cells are poorly understood. We show that active Wnt/beta-catenin signaling occurs preferentially within the oval cell population, and forced expression of constitutively active beta-catenin mutant promotes expansion of the oval cell population in the regenerated liver. More importantly, we identify a subpopulation of less differentiated progenitor-like cells in HCC cell lines and primary HCC tissues, which are defined by expression of the hepatic progenitor marker OV6 and endowed with endogenously active Wnt/beta-catenin signaling. These OV6(+) HCC cells possess a greater ability to form tumor in vivo and show a substantial resistance to standard chemotherapy compared with OV6(-) tumor cells. The fraction of tumor cells expressing OV6 is enriched after Wnt pathway activation, whereas inhibition of beta-catenin signaling leads to a decrease in the proportion of OV6(+) cells. In addition, the chemoresistance of OV6(+) HCC progenitor-like cells can be reversed by lentivirus-delivered stable expression of microRNA targeting beta-catenin. These results highlight the importance of the Wnt/beta-catenin pathway in activation and expansion of oval cells in normal rodent models and human HCCs. OV6(+) tumor cells may represent the cellular population that confers HCC chemoresistance, and therapies targeted to the Wnt/beta-catenin signaling may provide a specific method to disrupt this resistance mechanism to improve overall tumor control with chemotherapy.
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, PR China.
Wen
W
Yang
He-Xin
HX
Yan
Lei
L
Chen
Qiong
Q
Liu
Ya-Qin
YQ
He
Le-Xing
LX
Yu
Shu-Hui
SH
Zhang
Dan-Dan
DD
Huang
Liang
L
Tang
Xiao-Ni
XN
Kong
Chao
C
Chen
Shu-Qin
SQ
Liu
Meng-Chao
MC
Wu
Hong-Yang
HY
Wang
D000818:Animals; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D051153:Wnt Proteins; D051176:beta Catenin