Oncotarget

Research Papers:

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

Lei Yang _, Shusheng Hu, Jinjing Tan, Xiaojing Zhang, Wen Yuan, Qian Wang, Lingling Xu, Jian Liu, Zheng Liu, Yanjun Jia and Xiaoxi Huang

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Oncotarget. 2016; 7:61562-61574. https://doi.org/10.18632/oncotarget.11146

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Abstract

Lei Yang1,*, Shusheng Hu2,*, Jinjing Tan3, Xiaojing Zhang4, Wen Yuan1, Qian Wang4, Lingling Xu4, Jian Liu1, Zheng Liu1, Yanjun Jia1, Xiaoxi Huang1

1Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, P.R. China

2Clinical Laboratory Department, Tianjin Medical University Cancer Institute and Hospital, Tianjin, P.R. China

3Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University, Beijing, P.R. China

4Oncology Department, Beijing Chaoyang Hospital, Capital Medical University, Beijing, P.R. China

*These authors have contributed equally to this article

Correspondence to:

Lei Yang, email: [email protected]

Keywords: colorectal cancer (CRC), angiogenesis, PSG9, SMAD4

Received: March 23, 2016     Accepted: July 27, 2016     Published: August 09, 2016

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.


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