Pregnancy-specific glycoprotein 9 (PSG9), a driver for colorectal cancer, enhances angiogenesis via activation of SMAD4

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.

SNHG15 affects the growth of glioma microvascular endothelial cells by negatively regulating miR-153

“…VEGFA is a member of the PDGF/VEGF growth factor family which encodes a heparin-binding protein that plays predominant roles in angiogenesis by inducing proliferation and migration of vascular endothelial cells. It is upregulated in many known tumors and its expression is correlated with tumor stage and progression (28)(29)(30). Cdc42 is a small GTPase of the Rho-subfamily which regulates cytoskeletal dynamics, cell shape, and numerous other cellular processes including polarity, migration, cell cycle progression and cell fate determination.…”

<p>Analysis of risk factors for colon cancer progression</p>

“…Further study found this annotation came from pregnancy specific glycoprotein (PSG) 1, 4, 5, 6, 7, 9, 11. Among them, PSG9 was found to be upregulated in the early stage of colorectal cancer (CRC), and drives the progression of CRC and tumor angiogenesis 10,11. In pancreatic adenocarcinoma, cytoplasmic localized PSG1 is associated with shortened median survival 12 .…”

Multispectral imaging reveals hyper active TGF-β signaling in colorectal cancer

“…For instance, we previously identified PSG9 that directly binding to SMAD4 and promoted its nuclear translocation, subsequently activation genes expression associated with angiogenesis. 25 Usually, SMAD1/5/9 and SMAD2/3 existed as complexes and conducted canonical and mixed TGF-b/BMP signaling respectively in cytoplasm. 26 In addition, phosphorylated SMAD1/5/9 and SMAD2/3 complexes were distributed in nucleus.…”