Abstract
Background: Recent studies have revealed that the adiponectin-associated protein belonging to the C1qTNF family mediates various biological processes. However, the pathobiological property of C1qTNF6 in carcinogenesis remains unclear. Here, we investigated the expression status of C1qTNF6 in human hepatocellular carcinomas and subsequently attempted to determine the role of C1qTNF6 in tumor neovascularization. Methods: Immunohistochemical staining was performed to evaluate the expression of C1qTNF6 in hepatocellular carcinoma tissue specimens. Various eukaryotic recombinant C1qTNF6 proteins were prepared to ask whether C1qTNF6 could activate Akt pathway in human liver sinusoidal microvascular endothelial cells. Xenograft assay was carried out to know the effect of C1qTNF6 on tumor neovascularization. Results: C1qTNF6 was not immunohistochemically detected in any non-cancerous liver tissues but was detected in 21 of 30 hepatocellular carcinoma tissue specimens. C1qTNF6 was not uniformly distributed but rather focally localized in hepatocellular carcinoma cells. Interestingly, it was also localized on the tumor endothelial cells, which were in close proximity of C1qTNF6-expressing hepatocellular carcinoma cells. Eukaryotic recombinant C1qTNF6 increased the level of active phosphorylated Akt molecules in cultured vascular endothelial cells via its C-terminal C1q domain. In the xenograft assay, enforced expression of C1qTNF6 markedly reduced the central hypovascular necrosis areas of the transplanted HepG2 hepatocellular carcinoma cells. Conclusion: These results indicate that C1qTNF6 is overexpressed and possibly contributes to tumor angiogenesis by activating the Akt pathway in many hepatocellular carcinomas.
Highlights
Tumor neovascularization is critical for the growth of malignant tumors [1, 2]
While examining the expression of C1qTNF6 in various human tumors, we found that many Hepatocellular carcinoma (HCC) cells expressed C1qTNF6
Immunohistochemical staining showed that C1qTNF6 was expressed in 21 of the 30 HCC tissue specimens tested
Summary
Tumor neovascularization is critical for the growth of malignant tumors [1, 2]. Hepatocellular carcinoma (HCC), in particular, is a hypervascular neoplasm that requires a rich blood supply for its growth; various approaches involving the interruption of blood supply have been used for the treatment of patients with HCC [3,4,5]. Several secretory molecules, including adiponectin [7,8,9,10,11,12,13,14], have a similar molecular structure and constitute a highly conserved protein family, the C1qTNF-related protein superfamily [15, 16]. T. Takeuchi et al / Expression of a secretory protein C1qTNF6, a C1qTNF family member known as cartducin) participates in chondrogenesis as well as promotes proliferation and migration of vascular endothelial cells [12, 13]. We report that C1qTNF6 was overexpressed in many HCCs, promoted the phosphorylation of Akt molecules in sinusoidal microvascular endothelial cells, and accelerated neovascularization in transplanted HCC cells. Bodies were preadsorbed with full-length recombinant C1qTNF6, the preparation of which is described below
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