BMB Rep. 2015; 48(3): 127-128  
Self-renewal and circulating capacities of metastatic hepatocarcinoma cells required for collaboration between TM4SF5 and CD44
Doohyung Lee & Jung Weon Lee*
Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Korea
Correspondence to: E-mail:
Received: March 9, 2015; Published online: March 31, 2015.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

Tumor metastasis involves circulating and tumor-initiating capacities of metastatic cancer cells. Hepatic TM4SF5 promotes EMT for malignant growth and migration. Hepatocellular carcinoma (HCC) biomarkers remain unexplored for metastatic potential throughout metastasis. Here, novel TM4SF5/CD44 interaction- mediated self-renewal and circulating tumor cell (CTC) capacities were mechanistically explored. TM4SF5-dependent sphere growth was correlated with CD133+, CD24-, ALDH activity, and a physical association between CD44 and TM4SF5. The TM4SF5/CD44 interaction activated c-Src/STAT3/ Twist1/ B mi1 signaling for spheroid formation, while disturbing the interaction, expression, or activity of any component in this signaling pathway inhibited spheroid formation. In serial xenografts of less than 5,000 cells/injection, TM4SF5-positive tumors exhibited locally-increased CD44 expression, suggesting tumor cell differentiation. TM4SF5-positive cells were identified circulating in blood 4 to 6 weeks after orthotopic liver-injection. Anti-TM4SF reagents blocked their metastasis to distal intestinal organs. Altogether, our results provide evidence that TM4SF5 promotes self-renewal and CTC properties supported by CD133+/TM4SF5+/CD44+(TM4SF5-bound)/ALDH+/ CD24- markers during HCC metastasis.
Keywords: Biomarkers, Circulating tumor cells, Epithelial-mesenchymal transition, Hepatic cancer, Self-renewal

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