Therapeutics targeting CD90-integrin-AMPK-CD133 signal axis in liver cancer

Abstract

CD90 is used as a marker for cancer stem cell in liver cancer. We aimed to study the mechanism by which CD90 promoted liver cancer progression and identify the new therapeutic targets on CD90 signal pathway. Ectopic expression of CD90 in liver cancer cell lines enhanced anchorage-independent growth and tumor progression. Furthermore, CD90 promoted sphere formation in vitro and upregulated the expression of the cancer stem cell marker CD133. The CD133 expression was higher in CD45-CD90+ cells in liver cancer specimen. The natural carcinogenic molecules TGF-β-1, HGF, and hepatitis B surface antigen increased the expression of CD90 and CD133. Inhibition of CD90 by either shRNA or antibody attenuated the induction of CD133 and anchorage-independent growth. Lentiviral delivery of CD133 shRNA abolished the tumorigenicity induced by CD90. Ectopic expression of CD90 induced mTOR phosphorylation and AMPK dephosphorylation. Mutation of integrin binding-RLD domain in CD90 attenuated the induction of CD133 and anchorage-independent growth. Similar results were observed after silencing β3 integrin. Signaling analyses revealed that AMPK/mTOR and β3 integrin were required for the induction of CD133 and tumor formation by CD90. Importantly, the energy restriction mimetic agent OSU-CG5 reduced the CD90 population in fresh liver tumor sample and repressed the tumor growth. In contrast, sorafenib did not decrease the CD90+ population. In conclusion, the signal axis of CD90-integrin-mTOR/AMPK-CD133 is critical for promoting liver carcinogenesis. Molecules inhibiting the signal axis, including OSU-CG5 and other inhibitors, may serve as potential novel cancer therapeutic targets in liver cancer.

Identification of CD90 as Putative Cancer Stem Cell Marker and Therapeutic Target in Insulinomas

“…On the other hand, another study, while still mainly descriptive, demonstrated that transfection of a liver cancer cell line with a CD90 expression vector paralleled a decrease in E-cadherin expression and thereby increased migration and invasion of the liver cancer cells, implying a causal effect of CD90 expression and increased tumorigenicity [33]. Most recent and elegant evidence on the signaling network of CD90 comes from Chen et al, who demonstrated that the signal axis of CD90-integrin-mTOR/ AMPK-CD133 is critical for promoting liver carcinogenesis [34]. Future studies should focus on knockdown of CD90 in Table 2.…”

Multiple roles of CD90 in cancer

“…However, in cancers where high CD90 expression was observed, CD90 might activate MAPK pathway as seen in T cells [122,123] to promote proliferation. A recent study by Chen et al demonstrated that in liver cancer cell lines (HepG2 and Hep3B), CD90 ectopic expression upregulated mTOR phosporylation and diminished AMPK phosphorylation levels resulting in upregulation of stem cell marker CD133 [7]. They further demonstrated that signal transduction in this case was through RLD (RCC1 Like Domain) of CD90 through binding with ανβ5 integrin which was attenuated by mutation of the RLD domain [7].…”

“…Similarly, CD90 + CD133 + cells isolated from HCC cell line HepG2 and Hep3B expressed very high levels of self-renewal gene Oct4 and drug resistance gene ABCG2, indicating that they might be cancer stem cells involved in disease relapse [75]. A recent study by Chen et al reported that downregulation of CD90 by shRNA reduced CD133 expression through mTOR-AMPK pathway, inhibited anchorage independent growth and in vivo tumor formation of HepG2 and Hep3B cell lines [7] whereas CD90 overexpression resulted in upregulation of CD133 and CD24 through mTOR pathway [7] (Fig. 1b).…”

“…CD90 is a GPI-anchored cell surface protein which is involved in cell-cell and cell-matrix interaction and has been implicated in several cancers. In many cancers, CD90 expression identifies the cancer stem cells [7][8][9][10][11][12][13] and overexpression in the tumor microenvironment promotes cancer proliferation and dissemination [3,14,15]. In others, CD90 expression causes inhibition of tumor invasion and anchorage independent growth [16][17][18].…”

Surface markers of liver cancer stem cells and innovative targeted-therapy strategies for HCC (Review)

“…CD90 has been shown to upregulate the expression of the molecular marker CD133, and this abnormal expression can promote tumor progression. The CD90/integrin/mechanistic target of rapamycin kinase (mTOR)/AMP-activated protein kinase (AMPK)/CD133 signaling pathway serves an important role in tumor formation, and inhibition of this pathway by the energy-limited simulant, OSU-CG5, reduced the proportion of CD90 + cells in fresh HCC specimens and inhibited tumor growth (83).…”