Zinc finger protein X-linked promotes expansion of EpCAM+cancer stem-like cells in hepatocellular carcinoma.
Zinc finger protein X-linked (ZFX) is frequently upregulated in multiple human malignancies and also plays a critical role in the maintenance of self-renewal in embryonic stem cells. However, the role of ZFX in liver cancer stem cells (CSCs) remains obscure. We observed that the elevated expression of both ZFX and epithelial cell adhesion molecule (EpCAM) was associated with aggressive clinicopathological features and indicated poor prognosis in patients with hepatocellular carcinoma (HCC). ZFX was commonly enriched in liver EpCAM+CSCs. Knockdown of ZFX decreased the proportion of EpCAM+CSCs in HCC cells and suppressed their expression of stemness-related genes, self-renewal capacity, chemoresistance, metastatic potential, and tumorigenicity. Conversely, upregulation of ZFX in CSCs rescued these inhibitory effects and enhanced stem-like properties. Mechanistically, depletion of ZFX reduced nuclear translocation and transactivation of β-catenin, thereby inhibiting the self-renewal capacity of EpCAM+CSCs. Moreover, knockdown of β-catenin attenuated the self-renewal of EpCAM+HCC cells stably expressing ZFX, further indicating that β-catenin is required for ZFX-mediated expansion and maintenance of EpCAM+CSCs. Taken together, our findings indicate that ZFX activates and maintains EpCAM+liver CSCs by promoting nuclear translocation and transactivation of β-catenin. Furthermore, combination of ZFX and EpCAM may serve as a significant indicator for prognosis of patients with HCC.
The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.|Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China.
Chao
C
Wang
The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
Si-Yuan
SY
Fu
The Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
Ming-da
MD
Wang
The Second Military Medical University, Shanghai, China.
Wen-Bo
WB
Yu
The Second Military Medical University, Shanghai, China.
Qin-Shu
QS
Cui
The Second Military Medical University, Shanghai, China.
Hong-Ru
HR
Wang
Department of Urinary Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Hai
H
Huang
Liberty Mutual Group, Boston, MA, USA.
Wei
W
Dong
Department of Laboratory Diagnostic, Changhai Hospital, Second Military Medical University, Shanghai, China.
Wei-Wei
WW
Zhang
The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
Peng-Peng
PP
Li
The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
Chuan
C
Lin
The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
Ze-Ya
ZY
Pan
The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
Yuan
Y
Yang
The Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
Meng-Chao
MC
Wu
The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
Wei-Ping
WP
Zhou
D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D000066673:Cell Self Renewal / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D000071858:Epithelial Cell Adhesion Molecule / Q000235:genetics / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D016335:Zinc Fingers; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D000071858:Epithelial Cell Adhesion Molecule; D051741:Kruppel-Like Transcription Factors; D051176:beta Catenin; C062076:zinc finger protein, X-linked
EpCAM; Stemness; ZFX; cancer stem-like cells; hepatocellular carcinoma; β-catenin