Abstract
Circulating tumor cells (CTCs) play a major role in the metastasis and recurrence of hepatocellular carcinoma (HCC). Here, we found that major vault protein (MVP) is expressed on the surface of HCC cells and further induced under stressful environments. MVP knockdown reduces cell proliferation and induces apoptosis in HCC cells. Treatment of HCC cells with anti-MVP antibody (α-MVP) recognizing cell-surface MVP (csMVP) inhibits cell proliferation, migration, and invasion. csMVP-positive HCC cells have a higher clonogenic survival than csMVP-negative HCC cells, and treatment of HCC cells with α-MVP inhibits clonogenic survival, suggesting that csMVP contributes to HCC cell survival, migration, and invasion. The function of csMVP is mediated through mTOR, FAK, ERK and Akt signaling pathways. csMVP-positive CTCs are detected in HCC patients (89.7%) but not in healthy donors, and the number of csMVP-positive CTCs is further increased in patients with metastatic cancers. csMVP is exclusively detectable in CTCs with mesenchymal phenotype or intermediate phenotype with neither epithelial nor mesenchymal markers, suggesting that csMVP-associated survival and metastatic potential harbor CTCs with nonepithelial phenotypes. The results suggest that csMVP promotes cancer progression and serves as a surface marker for mesenchymal and intermediate CTCs in patients with HCC and metastatic cancers.
Highlights
Circulating tumor cells (CTCs) play a major role in the metastasis and recurrence of hepatocellular carcinoma (HCC)
While searching for novel oncofetal antigens on human embryonic stem cells, we accidentally found that major vault protein (MVP) is detected on the cell surface of hESCs with rabbit polyclonal antibodies against the C-terminal region of MVP (α-MVP) (Fig. 1a)
Multi-color immunocytochemistry showed that both cell-surface MVP (csMVP) and epidermal growth factor receptor (EGFR) are colocalized at the cell surface (Fig. 1b)
Summary
Circulating tumor cells (CTCs) play a major role in the metastasis and recurrence of hepatocellular carcinoma (HCC). The results suggest that csMVP promotes cancer progression and serves as a surface marker for mesenchymal and intermediate CTCs in patients with HCC and metastatic cancers. CTC analysis in patients with HCC may provide meaningful information on how tumor cells survive, remain dormant, and initiate recurrence during cancer metastasis and recurrence. CTCs should remain alive in the bloodstream and other tissues until establishing metastasis or recurrence after shedding into the bloodstream by the primary tumor They should escape anoikis and evade host immune defenses. The function of csMVP was mediated through mTOR, FAK, ERK and Akt signaling pathways, which are associated with cancer cell survival and metastasis. The findings are the first report showing that csMVP is a novel surface marker for mesenchymal and intermediate CTCs in patients with HCC and metastatic cancers. We discuss and propose the biological significance of csMVP-positive CTCs in HCC and metastatic cancers
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