title: 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.
authors.affiliation: Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Clinical Laboratory Department, Tianjin Medical University Cancer Institute and Hospital, Tianjin, P.R. China.
authors.forename: Shusheng
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University, Beijing, P.R. China.
authors.forename: Jinjing
authors.initials: J
authors.lastname: Tan
authors.affiliation: Oncology Department, Beijing Chaoyang Hospital, Capital Medical University, Beijing, P.R. China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, P.R. China.
authors.forename: Wen
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Oncology Department, Beijing Chaoyang Hospital, Capital Medical University, Beijing, P.R. China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Oncology Department, Beijing Chaoyang Hospital, Capital Medical University, Beijing, P.R. China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Xu
authors.affiliation: Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, P.R. China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, P.R. China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, P.R. China.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Huang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000473:pathology*; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000097:blood / Q000401:mortality / Q000473:pathology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D047468:Immunoprecipitation; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011268:Pregnancy-Specific beta 1-Glycoproteins / Q000032:analysis / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D010982:Platelet-Derived Growth Factor; D011268:Pregnancy-Specific beta 1-Glycoproteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C075278:platelet-derived growth factor A; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: PSG9; SMAD4; angiogenesis; colorectal cancer (CRC)