Sushi Repeat-containing Protein X-linked 2 Research Articles

Abstract TP319: Time Course of Novel Hypothalamic Protein Sushi Repeat-Containing Protein X- Linked 2 Expression in a Rat Model of Subarachnoid Hemorrhage

Background: Hypothalamic injury after subarachnoid hemorrhage (SAH) is known to be associated with short- and long-term prognosis. Recently, a novel hypothalamic protein, Sushi repeat-containing protein X-linked 2 (SRPX2), was reported as a potential biomarker for hypothalamic damage after traumatic brain injury. However, there are no reports on SRPX2 in SAH, and its role is unknown. In this study, we investigated the expression of SRPX2 in the hypothalamus after SAH using a rat model of SAH. Methods: We made endovascular perforation model of SAH using 300g - 450g SD rats, and they were divided into two groups: Sham operated and SAH group. The endpoints were 3, 6, 12, 24, and 72 hours after SAH, and 7 days and 4 weeks after SAH, and physiological findings and neurological symptoms were measured. In addition, changes in SRPX-2 in the hypothalamic injury and related factors were examined immunohistochemically. Results: The SAH group showed significant neurological deterioration, and a significant decrease in body temperature after 3 h of SAH. Expression of SRPX2 in the hypothalamus was also significantly decreased at 3 h after SAH. However, it was not associated with changes in FJC- and TUNEL-positive cells suggestive of cell death or DHE expression suggestive of oxidative stress. On the other hand, OXT showed a significant decrease after 3 hours of SAH as measured by ELISA in serum from the jugular vein. Conclusions: This is the first study to investigate the expression of SRPX2 in the hypothalamus after SAH time course. Although our results suggest that SRPX2 may not be directly associated with hypothalamic injury after SAH, the fact that SRPX2 expression was decreased during the hyperacute phase and OXT and body temperature were also decreased at the same time suggests that SRPX2 may be indirectly associated with hypothalamic injury after SAH through regulation of endocrine and autonomic function in the hypothalamic-pituitary axis. Further studies are warranted to investigate the possibility that SRPX2 may be indirectly related to hypothalamic disturbances after SAH through endocrine and autonomic regulation of the hypothalamic-pituitary axis.

SRPX2 Promotes Tumor Proliferation and Migration via the FAK Pathway in Papillary Thyroid Carcinoma.

Thyroid cancer is the most common form of endocrine cancer around the world, and among which papillary thyroid carcinoma (PTC) is the most ubiquitous pathological sub-kind. Sushi repeat-containing protein X-linked 2 (SRPX2) was reported to be an independent prognostic factor and significantly overexpressed in advanced PTC patients. However, the biological functions of SRPX2 remain ambiguous in PTC. Here, we explored SRPX2 expression profiles and functions in PTC, finding that SRPX2 expression was remarkably upregulated in PTC tissues and cell lines. Further colony formation, CCK-8, as well as transwell assay, suggested that SRPX2 silencing remarkably dampened PTC growth and migration. Mouse xenograft models were established to find that SRPX2 silence remarkably suppressed PTC proliferation and migration in vivo. Following mechanism studies revealed that SRPX2 realized its functions in the PTC process partially through activating the Focal adhesion kinase (FAK) phosphorylation. In conclusion, this study investigated the functions and mechanisms of the SRPX2/FAK pathway in PTC progression. SRPX2 could act as a prospective biologic signature and therapeutic target molecule for PTC.

Sushi-Repeat-Containing Protein X-Linked 2: A Potential Therapeutic Target for Inflammation and Cancer Therapy.

Accumulating evidence has showed that sushi-repeat-containing protein X-linked 2 (SRPX2) is an abnormal expression in a variety of cancers and involved in cancer carcinogenesis, chemosensitivity, and prognosis, which mainly promote cancer cell metastasis, invasion, and migration by regulating the uPAR/integrins/FAK signaling pathway, epithelial-mesenchymal transition (EMT), angiogenesis, and glycosylation. Inflammation has been regarded as a key role in regulating cancer initiation, progression, EMT, and therapeutics. Furthermore, SRPX2 exhibited excellent antifibrosis effect via the TGFβR1/SMAD3/SRPX2/AP1/SMAD7 signaling pathway. Therefore, this review provides compelling evidence that SRPX2 might be a therapeutic target for inflammation and cancer-related inflammation for future cancer therapeutics.

Local administration of liposomal-based Srpx2 gene therapy reverses pulmonary fibrosis by blockading fibroblast-to-myofibroblast transition.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fatal interstitial lung disease characterized by abnormal transition and proliferation of fibroblasts. The uncontrolled transition of fibroblasts, commonly known as myofibroblasts, are the principal source of the enormous extracellular matrix (ECM) depositing in lung parenchyma, leading to gradual failure of gas exchange and mortality of the patients. However, up to now, rare effective therapeutic strategies have been developed to blockade fibroblast-to-myofibroblast transition (FMT) in IPF.Method: We illustrated that the lungs originated from IPF patients and mice with pulmonary fibrosis are characterized by the overexpression of sushi-repeat-containing protein, X-linked 2 (SRPX2). Further functionality studies identified the pivotal role of SRPX2 in FMT. Mechanistically, SRPX2 was involved in a TGFβR1/SMAD3/SRPX2/AP1/SMAD7 positive feedback loop. Specifically, SRPX2 was upregulated by TGF-β1 in a TGFβR1/SMAD3-dependent manner, after which SRPX2 in turn repressed the expression of AP1, subsequently minimized SMAD7 expression, through which it reduced the formation of inhibitory complex with TGFβR1 and enhanced SMAD signaling pathway to promote FMT and exacerbate pulmonary fibrosis. Notably, intratracheal administration of siRNA-loaded liposomes could effectively suppress the expression of Srpx2 in the lung and remarkably protect mice against BLM-induced pulmonary fibrosis, concomitant with a significant reduction of FMT.Results: Accordingly, these data indicate that Srpx2 plays an essential role in the pathogenesis of pulmonary fibrosis and suggests the strategy aiming at silencing Srpx2 could be a promising therapeutic approach against pulmonary fibrosis in clinical settings.

SRPX2 promotes cell proliferation and invasion via activating FAK/SRC/ERK pathway in non-small cell lung cancer.

Recent studies showed that sushi repeat containing protein X linked 2 (SRPX2) could participate in the development of various malignant tumors. However, its role in non-small cell lung cancer (NSCLC) was unknown. The aim of the study was to prospectively investigate the role of SRPX2 in NSCLC cell proliferation, migration and invasion and reveal the underlying mechanism. Quantitative real-time polymerase chain reaction (qRT-PCR), western blot and immunohistochemistry - IHC) were used to measure detect the mRNA and protein levels, respectively, in NSCLC tissues and cell lines. Cell Counting Kit-8 (CCK-8), colony formation, wound healing and transwell assays were utilized to assess cell proliferation, migration and invasion. In vivo subcutaneous xenograft tumor model was established to detect the tumorigenic function of SRPX2, and IHC assay was performed to measure protein expression. SRPX2 expression was upregulated in NSCLC tissues and cell lines, and positively correlated with tumor size, lymph node metastasis, distant metastasis and clinical stage. High SRPX2 expression also predicted poor prognosis. In vitro experiments indicated that overexpression of SRPX2 promoted the proliferation, migration, and invasion of SPC-A1 cells while knockdown of SRPX2 caused the opposite effects in A549 cells. Specifically, SRPX2 activated FAK/SRC/ERK pathway and its downstream effectors and promoted epithelial-mesenchymal transition (EMT). Taken together, our findings revealed a functional role of SRPX2 in NSCLC cell proliferation, migration and invasion. The underlying mechanism was, at least partially, the activation of FAK/SRC/ERK pathway. This study provides the molecular basis for targeting SRPX2 in potential clinical application for NSCLC.

Sushi Repeat Containing Protein X-linked 2 Is a Downstream Signal of LEM Domain Containing 1 and Acts as a Tumor-Promoting Factor in Oral Squamous Cell Carcinoma.

Because oral squamous cell carcinomas (OSCCs) have a high potential for locoregional invasion and nodal metastasis, early detection and treatment are essential. A LAP2, emerin, MAN1 (LEM) domain containing 1 (LEMD1) is associated with local progression, clinical stage, nodal metastasis, poor prognosis, angiogenesis, and lymphangiogenesis in OSCC. Although LEMD is a cancer-testis antigen, the cancer-related signals related to LEMD1 remain unknown. In this study, we used a microarray analysis of OSCC cells to identify sushi repeat containing protein X-linked 2 (SRPX2) as a LEMD1-related downstream signal. LEMD1 expression was correlated with lymph node metastasis of OSCC according to the immunohistochemistry analysis. Furthermore, patients expressing SRPX2 had a significantly worse prognosis than those without SRPX2 expression. The concentration of SRPX2 in OSCC was positively correlated with the concentrations of LEMD1, urokinase plasminogen activator receptor (uPAR), and hepatocyte growth factor (HGF). In OSCC cells, SRPX2 secretion levels were elevated by interactions with uPAR and HGF. We also found that SRPX2 promotes endothelial cell proliferation and adhesion between endothelial cells and OSCC cells. These results suggest that SRPX2 might be a useful tumor marker for OSCC.

SRPX2 Promotes Cell Proliferation and Invasion in Osteosarcoma Through Regulating Hippo Signaling Pathway.

Background/PurposeOsteosarcoma (OS), a primary bone malignancy, is characterized by a high rate of metastasis. It has been found that Sushi repeat containing protein X-linked 2 (SRPX2) is involved in tumor cell proliferation, adhesion, invasion and migration. The current work aimed to explore the effect of SRPX2 on OS cell invasion and proliferation.MethodsImmunohistochemistry (IHC), Western blotting and reverse transcription-polymerase chain reaction (RT-PCR) were used to detect the expression of the associated protein in OS tissues and cell lines. Cell counting kit-8 (CCK8), transwell and colony formation assays were used to determine cell viability, invasion, and proliferation, respectively. The in vivo tumorigenic ability of SRPX2 gene was determined using nude mouse tumorigenesis test.ResultsSRPX2 knockdown suppressed the viability, while SRPX2 overexpression increased the invasion and colony formation ability of the cells in vitro. In vivo experiments demonstrated that SRPX2 knockdown inhibited tumor growth and invasion as evidenced by decreased Ki67 and N-cadherin levels, and increased E-cadherin level. Downregulation of SRPX2 increased YAP phosphorylation resulting in reduced nuclear translocation to activate Hippo signaling pathway. The promotion of cell viability, colony-forming ability, and invasion, and the inhibition of CTGF, Cyr61, and Birc5 levels promoted by SRPX2 overexpression were reversed by YAP inhibition.ConclusionSRPX2 increased cell proliferation and invasion in osteosarcoma by activating Hippo signaling pathway.

Genotype and Injury Effect on the Expression of a Novel Hypothalamic Protein Sushi Repeat-Containing Protein X-Linked 2 (SRPX2)

Sushi repeat-containing protein X-linked 2 (SRPX2) is a novel hypothalamic protein and a ligand of the urokinase-type plasminogen activator receptor (uPAR), which is essential for proteolysis of extracellular matrix and tissue remodeling after an insult to the brain. However, little is known about regulation of SRPX2. Our objective was to investigate if SRPX2 expression is altered by (i) the deficiency of uPAR or uPA (urokinase-type plasminogen activator), and (ii) traumatic brain injury (TBI). SRPX2 expression was assessed in wild type (Wt), Plaur−/− (uPAR-deficient), and Plau−/− (uPA-deficient) mice, with and without controlled cortical impact injury (CCI). The number of SRPX2+ neurons in hypothalamus was comparable to that in Wt littermates in Plaur−/− (2985 ± 138 vs. 2890 ± 92, p > 0.05) and Plau−/− mice (2180 ± 232 vs. 2027 ± 77, p > 0.05). The number of hypothalamic SRPX2+ neurons in the Wt-CCI group was comparable to that in controls (3645 ± 288 vs. 3385 ± 192, p > 0.05). Hypothalamic, hippocampal and thalamic Srpx2 gene expression was unaltered after TBI. However, at 4 days post-TBI Srpx2 gene expression was upregulated in the perilesional cortex of Plau−/−-CCI mice up to 123% of that in the sham group (p < 0.05). Unsupervised hierarchical clustering using SRPX2 expression did not identify genotype or injury-specific clusters. Our data demonstrate that SRPX2 expression in the hypothalamus is resistant to genetic deficiencies in the urokinase-system or to the hypothalamus-affecting TBI. The contribution of elevated Srpx2 gene expression in perilesional cortex to post-TBI recovery process, however, requires further exploration.

Knockdown of SRPX2 inhibits the proliferation, migration, and invasion of prostate cancer cells through the PI3K/Akt/mTOR signaling pathway.

Sushi repeat-containing protein X-linked 2 (SRPX2), a novel chondroitin sulfate proteoglycan, is reported to play a critical role in tumorigenesis. However, the expression and functional role of SRPX2 in prostate cancer have not been defined. Thus, the aim of this study was to investigate the expression and functional role of SRPX2 in human prostate cancer. Our results showed that the expression of SRPX2 was obviously increased in human prostate cancer tissues and cell lines. In addition, knockdown of SRPX2 inhibited the proliferation, migration, and invasion of prostate cancer cells, as well as prevented the epithelial-mesenchymal transition process in prostate cancer cells. Mechanically, knockdown of SRPX2 efficiently inhibited the activation of PI3K/Akt/mTOR pathway in prostate cancer cells. Taken together, these data demonstrated that knockdown of SRPX2 inhibits the proliferation and metastasis in human prostate cancer cells, partly through the PI3K/Akt/mTOR signaling pathway. Thus, SRPX2 may be a novel therapeutic target for the treatment of prostate cancer.

SRPX2 knockdown inhibits cell proliferation and metastasis and promotes chemosensitivity in esophageal squamous cell carcinoma

Sushi repeat-containing protein X-linked 2 (SRPX2), a chondroitin sulfate proteoglycan, functions as a critical regulator in several types of malignancy. However, its expression and biological functions in esophageal squamous cell carcinoma (ESCC) remain unclear. Thus, the objective of this paper was to investigate the expression pattern and biological functions of SRPX2 in ESCC. Our results demonstrated that SRPX2 is highly expressed in human ESCC tissues and cell lines. Knockdown of SRPX2 significantly suppressed the proliferation, migration and invasion of ESCC cells, as well as prevented the epithelial-to-mesenchymal transition (EMT) process in ESCC cells. Furthermore, knockdown of SRPX2 increased the sensitivity of ESCC cells towards cisplatin. Exploration of the underlying mechanisms of its action showed that knockdown of SRPX2 sharply down-regulated the expression levels of β-catenin, cyclin D1 and c-myc in ESCC cells. In conclusion, these findings indicated that knockdown of SRPX2 inhibits cell proliferation and metastasis, and promotes chemosensitivity in ESCC cells through the inactivation of Wnt/β-catenin signaling pathway. Thus, SRPX2 may be a promising target molecular for the treatment of ESCC.

High SRPX2 protein expression predicts unfavorable clinical outcome in patients with prostate cancer.

BackgroundSushi repeat-containing protein X-linked 2 (SRPX2) is overexpressed in a variety of different tumor tissues and correlated with poor prognosis in patients. Little research focuses on the role of SRPX2 expression in prostate cancer (PCa), and the clinicopathological significance of the protein expression in this tumor is relatively unknown. However, our previous transcriptome data from those cancer stem-like cells indicated the role of SRPX2 in PCa.Materials and methodsIn this study, RT-PCR and Western blotting were firstly used to examine the SRPX2 expression in three PCa cell lines including LNCaP, DU145, and PC3, and then SRPX2 protein expression was immunohistochemically investigated and statistically analyzed in a series of 106 paraffin-embedded PCa tissue specimens.ResultsSignificantly lower levels of SRPX2 expression were verified in the LNCaP cells, compared with the expression in the aggressive DU145 and PC3 cells, in both mRNA and protein levels. Immunohistochemically, there were variable SRPX2 protein expressions in the clinical samples. Moreover, high levels of SRPX2 expression in the PCa tissues were significantly associated with Gleason score (P=0.008), lymph node metastasis (P=0.009), and distant metastasis (P=0.021). Furthermore, higher levels of SRPX2 expression in the PCa tissues were significantly associated with shorter overall survival (OS) (P<0.001).ConclusionOur results demonstrate that SRPX2 is highly expressed in aggressive PCa cells in vitro, and its protein expression in PCa is significantly associated with malignant clinical features and shorter OS, strongly indicating its prognostic value in prostate cancers.

Sushi repeat-containing protein X-linked 2: A novel phylogenetically conserved hypothalamo-pituitary protein.

Sushi repeat-containing protein X-linked 2 (SRPX2) is a novel protein associated with language development, synaptic plasticity, tissue remodeling, and angiogenesis. We investigated the expression and spatial localization of SRPX2 in normal mouse, rat, monkey, and human brain using in situ hybridization and immunohistochemistry. Antibody specificity was determined using in vitro siRNA based silencing of SRPX2. Cell type-specific expression was verified by double-labeling with oxytocin or vasopressin. Western blot was used to detect SRPX2 protein in rat and human plasma and cerebrospinal fluid. Unexpectedly, SRPX2 mRNA expression levels were strikingly higher in the hypothalamus as compared to the cortex. All SRPX2 immunoreactive (ir) neurons were localized in the hypothalamic paraventricular, periventricular, and supraoptic nuclei in mouse, rat, monkey, and human brain. SRPX2 colocalized with vasopressin or oxytocin in paraventricular and supraoptic neurons. Hypothalamic SRPX2-ir positive neurons gave origin to dense projections traveling ventrally and caudally toward the hypophysis. Intense axonal varicosities and terminal arborizations were identified in the rat and human neurohypophysis. SRPX2-ir cells were also found in the adenohypophysis. Light SRPX2-ir projections were observed in the dorsal and ventral raphe, locus coeruleus, and the nucleus of the solitary tract in mouse, rat and monkey. SRPX2 protein was also detected in plasma and CSF. Our data revealed intense phylogenetically conserved expression of SRPX2 protein in distinct hypothalamic nuclei and the hypophysis, suggesting its active role in the hypothalamo-pituitary axis. The presence of SRPX2 protein in the plasma and CSF suggests that some of its functions depend on secretion into body fluids.

SRPX2, an independent prognostic marker, promotes cell migration and invasion in hepatocellular carcinoma

Sushi repeat-containing protein X-linked 2 (SRPX2), a novel chondroitin sulfate proteoglycan, is overexpressed in human cancer. Recent studies have reported that SRPX2 overexpression is observed in gastrointestinal cancer, and promotes migration and invasion of cancer cells. While, the clinical significance and biological function of SRPX2 remain rarely known in hepatocellular carcinoma (HCC). Here, we found that the levels of SRPX2 in HCC tissues were notably overexpressed compared to non-cancerous specimens. Accordingly, the levels of SRPX2 were obviously up-regulated in HCC cells compared with LO2 cells. The positive expression of SRPX2 was prominently correlated with venous infiltration and advanced TNM tumor stage. Furthermore, SRPX2 expression acted as an independent prognostic marker for HCC patients. SRPX2 knockdown prominently inhibited the invasion and migration of HCCLM3 cells, while SRPX2 restoration enhanced these cellular biological behaviors of Hep3B cells in vitro. Moreover, SRPX2 knockdown suppressed pulmonary metastasis of HCCLM3 cells in nude mice. Mechanically, SRPX2 knockdown reduced the levels of phosphorylated focal adhesion kinase (p-FAK), p-AKT, matrix metallopeptidase 2 (MMP2) and MMP9 in HCCLM3 cells. In turn, SRPX2 overexpression promoted the activation of FAK/AKT pathway and increased MMP2/9 expression in Hep3B cells. Thus, SRPX2 contributes to migration and invasion of HCC cells probably by targeting FAK/AKT pathway-mediated MMP2/9 expression. SRPX2 potentially acts as an independent prognostic predictor and a drug-target for HCC patients.

Sushi repeat-containing protein X-linked 2 promotes angiogenesis through the urokinase-type plasminogen activator receptor dependent integrin αvβ3/focal adhesion kinase pathways.

Sushi repeat-containing protein X-linked 2 (SRPX2) is a newly identified chondroitin sulfate proteoglycan that is markedly elevated in multiple solid tumors. It is also suggested that SRPX2 is associated with angiogenesis. A conditioned medium of SRPX2 overexpressing colorectal cancer (CRC) cells and SRPX2 recombinant protein was used to evaluate the effect of secretory SRPX2 on the angiogenesis ability of human umbilical vein endothelial cells (HUVECs) and the involved molecular mechanisms. It was revealed that the activity of SRPX2 is dependent on the urokinase-type plasminogen activator receptor and cooperation of the integrin αvβ3 co-receptor. Subsequent studies showed that both PI3K/Akt and Ras/MAPK pathways and phosphorylation of focal adhesion kinase is involved in the intracellular signaling pathway of SRPX2/uPAR. This study suggests that SRPX2 promotes angiogenesis of HUVECs through the cooperation of the uPAR and integrin/FAK pathway.

Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma

Telomere maintenance is a hallmark of cancer and likely to be targeted in future treatments. In glioblastoma established methods of identifying telomerase and alternative lengthening of telomeres leave a significant proportion of tumors with no defined telomere maintenance mechanism. This study investigated the composition of these tumors using RNA-Seq. Glioblastomas with an indeterminate telomere maintenance mechanism had an increased immune signature compared with alternative lengthening of telomeres and telomerase-positive tumors. Immunohistochemistry for CD163 confirmed that the majority (80%) of tumors with an indeterminate telomere maintenance mechanism had a high presence of tumor-associated macrophages. The RNA-Seq and immunostaining data separated tumors with no defined telomere maintenance mechanism into three subgroups: alternative lengthening of telomeres like tumors with a high presence of tumor-associated macrophages and telomerase like tumors with a high presence of tumor-associated macrophages. The third subgroup had no increase in tumor-associated macrophages and may represent a distinct category. The presence of tumor-associated macrophages conferred a worse prognosis with reduced patient survival times (alternative lengthening of telomeres with and without macrophages P=0.0004, and telomerase with and without macrophages P=0.013). The immune signatures obtained from RNA-Seq were significantly different between telomere maintenance mechanisms. Alternative lengthening of telomeres like tumors with macrophages had increased expression of interferon-induced proteins with tetratricopeptide repeats (IFIT1–3). Telomerase-positive tumors with macrophages had increased expression of macrophage receptor with collagenous structure (MARCO), CXCL12 and sushi-repeat containing protein x-linked 2 (SRPX2). Telomerase-positive tumors with macrophages were also associated with a reduced frequency of total/near total resections (44% vs >76% for all other subtypes, P=0.014). In summary, different immune signatures are found among telomere maintenance mechanism-based subgroups in glioblastoma. The reduced extent of surgical resection of telomerase-positive tumors with macrophages suggests that some tumor-associated macrophages are more unfavorable.

SRPX2 Enhances the Epithelial-Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Cells.

Glioblastoma (GBM) is the most common and most aggressive central nervous system tumor in adults. Due to GBM cell invasiveness and resistance to chemotherapy, current medical interventions are not satisfactory, and the prognosis for GBM is poor. It is necessary to investigate the underlying mechanism of GBM metastasis and drug resistance so that more effective treatments can be developed for GBM patients. sushi repeat-containing protein, X-linked 2 (SRPX2) is a prognostic biomarker in many different cancer cell lines and is associated with poor prognosis in cancer patients. SRPX2 overexpression promotes interactions between tumor and endothelial cells, leading to tumor progression and metastasis. We hypothesize that SRPX2 also contributes to GBM chemotherapy resistance and metastasis. Our results revealed that GBM tumor samples from 42 patients expressed higher levels of SRPX2 than the control normal brain tissue samples. High-SRPX2 expression levels are correlated with poor prognosis in those patients, as well as resistance to temozolomide in cultured GBM cells. Up-regulating SRPX2 expression in cultured GBM cell lines facilitated invasiveness and migration of GBM cells, while down-regulating SRPX2 through RNA interference was inhibitory. These results suggest that SRPX2 plays an important role in GBM metastasis. Epithelial to mesenchymal transition (EMT) is one of the processes that facilitate GBM metastasis and resistance to chemotherapy. EMT marker expression was decreased in SRPX2 down-regulated GBM cells, and MAPK signaling pathway marker expression was also decreased when SRPX2 is knocked down in GBM-cultured cells. Blocking the MAPK signaling pathway inhibited GBM metastasis but did not inhibit cell invasion and migration in SRPX2 down-regulated cells. Our results indicate that SRPX2 facilitates GBM metastasis by enhancing the EMT process via the MAPK signaling pathway.

Increased Sushi repeat-containing protein X-linked 2 is associated with progression of colorectal cancer.

Sushi repeat-containing protein X-linked 2 (SRPX2) is a novel chondroitin sulfate proteoglycan overexpressed in gastrointestinal cancer. Its role in tumor biology remains unknown. The aim of this study was to investigate the expression of SRPX2 in colorectal cancer and its potential association with cancer progression. The expression of SRPX2 and its clinicopathological significance was evaluated using immunohistochemistry in a tissue microarray including 88 colon cancer and pairing normal tissues. The impact of SRPX2 on behavior of colorectal cancer cells and possible mechanism was explored using gene transfection and silencing. Strong staining of SRPX2 was noted in 71 (80.7 %) of 88 colon cancer specimen and 30 (34.1 %) of 88 adjacent normal tissues (P < 0.001). The expression of SRPX2 was significantly correlated with histological differentiation grade (P = 0.003), infiltration depth (P = 0.003), and clinical stage (P = 0.006). The expression of SRPX2 was significantly higher in HCT116 than in HT29 and SW480 cells. Suppression of endogenous SRPX2 expression by small interfering ribonucleic acid (siRNA) in HCT116 cells resulted in significant reduction in the ability of cell proliferation, adhesion, migration, and invasion. Up-regulation of endogenous SRPX2 in SW480 cells significantly promoted the migration and invasion of SW480 cells. In addition, inhibition of SRPX2 by siRNA led to notable down-regulation of β-catenin, matrix metalloproteinase (MMP)-2, and MMP-9. These findings indicate that overexpressed SRPX2 exerts an oncogenic role in colorectal cancer. SRPX2 may promote the invasion of colorectal cancer through MMP-2 and MMP-9 modulated by Wnt/β-catenin pathway.

Impact of overexpression of Sushi repeat‐containing protein X‐linked 2 gene on outcomes of gastric cancer

Sushi repeat-containing protein X-linked 2 (SRPX2) was first described as a downstream target gene for E2A-HLA, which causes pro-B acute leukemia. SRPX2 is considered to promote cellular migration and adhesion in cancers. Our objective was to evaluate the relative expression of the SRPX2 gene and to determine whether such expression correlates with outcomes in patients with gastric cancer. Surgical specimens of cancer tissue and adjacent normal mucosa obtained from 227 patients with previously untreated gastric cancer were examined. SRPX2 mRNA expression levels of cancer tissue and adjacent normal mucosa were measured by quantitative real-time polymerase chain reaction. We evaluated the clinicopathological significance of the relative expression of SRPX2 in patients with gastric cancer. SRPX2 expression was higher in cancer tissue than in adjacent normal mucosa (P < 0.001). On analysis of the relations between gene expression and clinicopathological factors, SRPX2 expression correlated with tumor size and distant metastasis. Overall survival was significantly lower in patients whose tumors had high SRPX2 expression than in those who had low SRPX2 expression (P = 0.003). Multivariate analysis showed that high SRPX2 expression was an independent predictor of survival (HR = 2.028, 95% CI = 1.265-3.251). SRPX2 expression was significantly higher in gastric cancer tissue than in adjacent normal mucosa, and overexpression of the SRPX2 gene is considered a useful independent predictor of outcomes in patients with gastric cancer.

The Human Language–Associated Gene SRPX2 Regulates Synapse Formation and Vocalization in Mice

Synapse formation in the developing brain depends on the coordinated activity of synaptogenic proteins, some of which have been implicated in a number of neurodevelopmental disorders. Here, we show that the sushi repeat-containing protein X-linked 2 (SRPX2) gene encodes a protein that promotes synaptogenesis in the cerebral cortex. In humans, SRPX2 is an epilepsy- and language-associated gene that is a target of the foxhead box protein P2 (FoxP2) transcription factor. We also show that FoxP2 modulates synapse formation through regulating SRPX2 levels and that SRPX2 reduction impairs development of ultrasonic vocalization in mice. Our results suggest FoxP2 modulates the development of neural circuits through regulating synaptogenesis and that SRPX2 is a synaptogenic factor that plays a role in the pathogenesis of language disorders.

Clinical utility of measuring expression levels of KAP1, TIMP1 and STC2 in peripheral blood of patients with gastric cancer

BackgroundWe examined preoperative kinesin II-associated protein (KAP1), TIMP metallopeptidase inhibitor 1 (TIMP1) and stanniocalcin 2 (STC2) expression levels in patients with gastric cancers to assess their clinical application for diagnosing and monitoring diseases.MethodsReal-time reverse transcription-polymerase chain reaction was used to detect the expression levels of KAP1, TIMP1, STC2, talin 2 (TLN2), sushi-repeat-containing protein, X-linked 2 (SRPX2) and secreted protein, acidic, cysteine-rich (SPARC) in the patients’ peripheral blood karyocytes. The data were analyzed with receiver operating characteristics (ROC) curves.ResultsA total of 112 patients with gastric cancer, 42 patients with recurrence and 107 healthy volunteers were recruited. There were significant correlations between KAP1, TIMP1 and STC2 levels, and TNM tumor stages and distant metastases. The area under the ROC curves (AUC) of KAP1 was 0.803 ± 0.040 (P = 0.0001), the AUC of TIMP1 was 0.767 ± 0.043 (P = 0.0001) and the AUC of STC2 was 0.769 ± 0.045 (P = 0.0001), thus differentiating preoperative gastric cancer patients from healthy volunteers by ROC curve analysis. The AUC of STC2 was 0.739 ± 0.070 (P = 0.004) and the AUC of KAP1 was 0.418 ± 0.088 (P = 0.319), thus differentiating recurrence of gastric cancer from healthy volunteers by ROC curve analysis. High TIMP1 and STC2 expression levels were suspected to be poor prognostic factors of disease recurrence in patients with gastric cancer.ConclusionsKAP1, TIMP1 and STC2 expression levels may be potential biomarkers for the screening, diagnosis, prognosis and surveillance of gastric cancer.