SRPX2 is a novel chondroitin sulfate proteoglycan that is overexpressed in gastrointestinal cancer.

Department of Genome Biology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan.
PLoS ONE (Impact Factor: 3.53). 01/2012; 7(1):e27922. DOI: 10.1371/journal.pone.0027922
Source: PubMed

ABSTRACT SRPX2 (Sushi repeat-containing protein, X-linked 2) has recently emerged as a multifunctional protein that is involved in seizure disorders, angiogenesis and cellular adhesion. Here, we analyzed this protein biochemically. SRPX2 protein was secreted with a highly posttranslational modification. Chondroitinase ABC treatment completely decreased the molecular mass of purified SRPX2 protein to its predicted size, whereas heparitinase, keratanase and hyaluroinidase did not. Secreted SRPX2 protein was also detected using an anti-chondroitin sulfate antibody. These results indicate that SRPX2 is a novel chondroitin sulfate proteoglycan (CSPG). Furthermore, a binding assay revealed that hepatocyte growth factor dose-dependently binds to SRPX2 protein, and a ligand-glycosaminoglycans interaction was speculated to be likely in proteoglycans. Regarding its molecular architecture, SRPX2 has sushi repeat modules similar to four other CSPGs/lecticans; however, the molecular architecture of SRPX2 seems to be quite different from that of the lecticans. Taken together, we found that SRPX2 is a novel CSPG that is overexpressed in gastrointestinal cancer cells. Our findings provide key glycobiological insight into SRPX2 in cancer cells and demonstrate that SRPX2 is a new member of the cancer-related proteoglycan family.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gene silencing by DNA hypermethylation of CpG islands is a well characterized phenomenon in cancer. The effect of hypomethylation in particular of non-CpG island genes is much less well described. By genome-wide screening we identified 105 genes in microsatellite stable (MSS) colorectal adenocarcinomas with an inverse correlation (Spearman's rho ≤ -0.40) between methylation and expression. Of these, 35 (33%) were hypomethylated non-CpG island genes and two of them, APOLD1 (Spearman's rho -0.82) and SRPX2 (Spearman's rho -0.80) were selected for further analyses. Hypomethylation of both genes were localized events not shared by adjacent genes. A set of 662 FFPE DNA samples not only confirmed that APOLD1 and SRPX2 are hypomethylated in CRC, but also revealed hypomethylation to be significantly (p<0.01) associated with tumors being localized in the left side, CIMP negative, MSS, BRAF wt, undifferentiated, and of adenocarcinoma histosubtype. Demethylation experiments supported SRPX2 being epigenetically regulated via DNA methylation, whereas other mechanisms in addition to DNA methylation seem to be involved in the regulation of APOLD1. We further identified miR-149 as a potential novel post-transcriptional regulator of SRPX2. In carcinoma tissue miR-149 was down-regulated and inversely correlated to SRPX2 (rho -0.77). Furthermore, ectopic expression of miR-149 significantly reduced SRPX2 transcript levels. Our study highlights that in colorectal tumors, hypomethylation of non-CpG island associated promoters deregulate gene expression nearly as frequent as do CpG-island hypermethylation. The hypomethylation of SRPX2 is focal and not part of a large block. Furthermore, it often translates to an increased expression level, which may be modulated by miR-149. © 2012 Wiley Periodicals, Inc.
    International Journal of Cancer 11/2012; · 6.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Altered development of the human cerebral cortex can cause severe malformations with often intractable focal epileptic seizures and may participate in common pathologies, notably epilepsy. This raises important conceptual and therapeutic issues. Two missense mutations in the sushi repeat-containing protein SRPX2 had been previously identified in epileptic disorders with or without structural developmental alteration of the speech cortex. In the present study, we aimed to decipher the precise developmental role of SRPX2, to have a better knowledge on the consequences of its mutations, and to start addressing therapeutic issues through the design of an appropriate animal model. Using an in utero Srpx2 silencing approach, we show that SRPX2 influences neuronal migration in the developing rat cerebral cortex. Wild-type, but not the mutant human SRPX2 proteins, rescued the neuronal migration phenotype caused by Srpx2 silencing in utero, and increased alpha-tubulin acetylation. Following in utero Srpx2 silencing, spontaneous epileptiform activity was recorded post-natally. The neuronal migration defects and the post-natal epileptic consequences were prevented early in embryos by maternal administration of tubulin deacetylase inhibitor tubacin. Hence epileptiform manifestations of developmental origin could be prevented in utero, using a transient and drug-based therapeutic protocol.
    Brain 07/2013; · 10.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The presence of iduronic acid in chondroitin/dermatan sulfate changes the properties of the polysaccharides, as it generates a more flexible chain with increased binding potentials. Iduronic acid in chondroitin/dermatan sulfate influences multiple cellular properties such as migration, proliferation, differentiation, angiogenesis and regulation of cytokine/growth factor activities. During pathological conditions such as wound healing, inflammation and cancer iduronic acid has diverse regulatory functions. Iduronic acid is formed by the two epimerases DS-epimerase 1 and DS-epimerase 2 which have different tissue distribution and properties. The role of IdoA in chondroitin/dermatan sulfate is underlined by the vast changes of connective tissue features in patients with a new type of Ehler-Danlos syndrome, adducted thumb-clubfoot syndrome. Future direction of research is to understand the roles of the two epimerases and their interplay with sulfotransferases involved in CS/DS biosynthesis. Further, a better definition of chondroitin/dermatan sulfate functions using different knock-out models is needed. In this review, we focus on the two enzymes responsible for iduronic acid formation and the role of iduronic acid in health and disease. © 2013 The Authors Journal compilation © 2013 FEBS.
    FEBS Journal 02/2013; · 4.25 Impact Factor

Full-text (2 Sources)

Available from
Sep 25, 2014