Abstract
PSG9 is a member of the pregnancy-specific glycoprotein (PSG) family and has been shown to contribute to the progression of colorectal cancer (CRC) and cancer-related angiogenesis. Here, we aim to investigate abnormal PSG9 levels in patients with CRC and to emphasize the role of PSG9 in driving tumorigenesis. Serum from 140 patients with CRC and 125 healthy controls as well as 74 paired tumors and adjacent normal tissue were used to determine PSG9 levels. We discovered that PSG9 was significantly increased in serum (P<0.001) and in tumor tissues (P<0.001) from patients with CRC. Interestingly, the increased PSG9 levels correlated with poor survival (P=0.009) and microvessel density (MVD) (P=0.034). The overexpression of PSG9 strongly promoted the proliferation and migration of HCT-116 and HT-29 cells. However, PSG9 depletion inhibited the proliferation of SW-480 cells. Using a human umbilical vein endothelial cell tube-forming assay, we found that PSG9 promoted angiogenesis. The overexpression of PSG9 also increased the growth of tumor xenografts in nude mice. Co-immunoprecipitation experiments revealed that PSG9 was bound to SMAD4. The PSG9/SMAD4 complex recruited cytoplasmic SMAD2/3 to form a complex, which enhanced SMAD4 nuclear retention. The PSG9 and SMAD4 complex activated the expression of multiple angiogenesis-related genes (included IGFBP-3, PDGF-AA, GM-CSF, and VEGFA). Together, our findings illustrate the innovative mechanism by which PSG9 drives the progression of CRC and tumor angiogenesis. This occurs via nuclear translocation of PSG9/SMAD4, which activates angiogenic cytokines. Therefore, our study may provide evidence for novel treatment strategies by targeting PSG9 in antiangiogenic cancer therapy.
Highlights
PSG9 is a member of the pregnancy-specific glycoprotein (PSG) family
We explored whether PSG9 is a key component in the regulation of transforming growth factor (TGF)-β signalinginduced tumor angiogenesis via enhancement of nuclear retention of SMAD4, and we determined whether the expression of proangiogenic molecules is affected by the PSG9/SMAD4 interaction
We further tested the levels of circulating PSG9 proteins in serum samples and found abnormally high PSG9 levels in the serum of colorectal cancer (CRC) patients compared with serum from healthy controls (Figure 1A, Supplementary Table S1)
Summary
PSG9 is a member of the pregnancy-specific glycoprotein (PSG) family. Few studies have revealed the involvement of PSGs in tumor-related processes. Previous studies have recognized PSGs as secreted proteins that are the most abundant trophoblastic proteins in maternal blood during human pregnancy [4]. Human PSGs are heavily N-glycosylated proteins that consist of four immunoglobulin (Ig)-like domains, an amino-terminal Ig variable-like (N) domain and three Ig constant-like (C) domains [5]. PSG9 has a different protein structure from other PSG family members, www.impactjournals.com/oncotarget as it lacks an RGD (Arg-Gly-Asp)-motif [6]. Several studies have indicated that PSGs have a proangiogenic function because their expression induces endothelial tube formation [7]. The abnormally high levels of PSG9 detected in cases of familial adenomatous polyposis (FAP) and in adenomas may promote colorectal carcinogenesis [8]. The function and pathobiological importance of PSG9 remain to be determined
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