Correlation of syndecan gene amplification with metastatic potential and clinical outcomes in carcinomas.

Cell surface receptors play crucial roles in cellular responses to extracellular ligands, helping to modulate the functions of a cell based on information coming from outside the cell. Syndecan refers to a family of cell adhesion receptors that regulate both extracellular and cytosolic events. Alteration of syndecan expression disrupts regulatory mechanisms in a cell type-specific fashion, often leading to serious diseases, notably cancer. Given the multifaceted functions and distinct tissue distributions of syndecan, it will be important to unravel the gene-level intricacies of syndecan expression and thereby further understand its involvement in various carcinogenic processes. Although accumulating evidence indicates that the protein expression patterns of syndecan family members are significantly altered in cancer cells, the underlying gene-level mechanisms remain largely unknown. This review endeavors to explore syndecan gene expression levels across different cancer types by scrutinizing extensive cancer genome datasets using tools such as cBioPortal. Our analysis unveils that somatic mutations in SDC genes are rare occurrences, whereas copy number alterations are frequently observed across diverse cancers, particularly in SDC2 and SDC4. Notably, amplifications of SDC2 and SDC4 correlate with heightened metastatic potential and dismal prognosis. This underscores the recurrent nature of SDC2 and SDC4 amplifications during carcinogenesis and sheds light on their role in promoting cancer activity through augmented protein expression. The identification of these amplifications not only enriches our understanding of carcinogenic mechanisms but also hints at the potential therapeutic avenue of targeting SDC2 and SDC4 to curb cancer cell proliferation and metastasis.

Lower levels of plasma syndecan-4 are associated with loss of body weight and fat-free mass after bariatric surgery.

OBJECTIVE: Bariatric surgery induces a significant loss of both fat mass (FM) and fat-free mass (FFM). The proteoglycan receptor syndecan-4 (SDC4) plays a crucial role in adipose tissue and skeletal muscle functions. Thus, this study was performed (i) to assess plasma SDC4 levels after both Sleeve Gastrectomy (SG) and Roux-en-Y Gastric Bypass (RYGB) surgeries, and (ii) to explore potential associations with changes in body composition variables. RESULTS: Twenty-six patients (17 females) with severe obesity underwent SG (n = 13) or RYGB (n = 13) and were followed up to 1 year (1Y). Body weight, FM, FFM, and SCD4 were measured at baseline (BL), and at week 11 (W11) and 1Y after surgery. Independently of procedure, there was a significant body weight loss at W11, with an average FM and FFM reduction of 13.7 ± 0.6 kg and 5.3 ± 0.5 kg, respectively. Participants continued to lose weight afterwards, with a total weigth loss of 38.2 ± 1.5 kg at 1Y. No associations were found at BL between SDC4 levels and any anthropometric variable; however, SDC4 levels were lower than BL at both W11 and 1Y, independently of type of surgery. Additionally, changes in SDC4 between BL and 1Y were positively correlated with weight and FFM loss during the same period. TRIAL REGISTRATION: ClinicalTrials.gov NCT04051190 on 09/08/2019.

In silico evaluation of the gene expression profile of syndecan-4 in different breast tumor subtypes / Avaliação in silico do perfil de expressão gênica do sindecam-4 nos diferentes subtipos de tumores de mama

INTRODUCTION: Breast cancer is one of the main causes of death in women. Luminal tumors A and B show good response with hormonal treatments, tumors that overexpress HER-2 can be treated with monoclonal antibodies, whereas triple negative tumors have few treatments available because they present low or absent expression of hormone receptors and HER-2, in addition, they present worse tumor progression. Syndecans are heparan sulfate proteoglycans that have the function of interacting with growth factors, cytokines, and extracellular matrix, thus modulating important processes in tumor progression. OBJECTIVE: Analyze the expression of syndecan-4 in different subtypes of breast tumors. METHODS: Bioinformatics is a useful tool for the study of new biomarkers. In the present study, the TCGA database (514 patients) and Metabric (1,898 patients) were analyzed using the cBioportal software. Gene expression data were analyzed by RNA-Seq and Microarray from biopsies of breast tumors. RESULTS: An alteration in syndecan-4 gene expression was observed among the different subtypes of breast tumors. Patients with a triple-negative tumor had decreased expression for syndecan-4 in both databases. CONCLUSION: Syndecan-4 is a potential biomarker for breast tumor prognosis since decreased expression of syndecan-4 is related to triple-negative breast cancer.

INTRODUÇÃO: O câncer de mama corresponde a uma das principais causas de morte em mulheres. Os tumores luminais A e B apresentam boa resposta com tratamentos hormonais, os tumores que superexpressam HER-2 podem ser tratados com anticorpos monoclonais, já os tumores triplo-negativos apresentam poucos tratamentos disponíveis por apresentarem expressão baixa ou ausente dos receptores hormonais e HER-2, além de pior progressão tumoral. Os sindecans são proteoglicanos de heparam sulfato que tem função de interagir com fatores de crescimento, citocinas e matriz extracelular, modulando assim processos importantes na progressão tumoral. OBJETIVO: Analisar a expressão o sindecam-4 nos diferentes subtipos de tumores de mama. MÉTODOS: A bioinformática vem se mostrando útil para estudo de novos biomarcadores. No presente estudo, foi analisado o banco de dados TCGA (514 pacientes) e Metabric (1898 pacientes) utilizando o software cBioportal. Foram analisados os dados de expressão gênica por RNA-Seq e Microarray. RESULTADOS: Foi verificada alteração de expressão gênica do sindecam-4 entre os diferentes subtipos de tumores de mama. Pacientes com tumor triplo-negativo tiveram a expressão diminuída para sindecam-4 em ambos os bancos de dados. CONCLUSÃO: Foi verificado que sindecam-4 parece ser um potencial biomarcador em tumores de mama, a expressão diminuída de sindecam-4 parece estar relacionada a um pior prognóstico.

Adiponectin Reduces Glomerular Endothelial Glycocalyx Disruption and Restores Glomerular Barrier Function in a Mouse Model of Type 2 Diabetes.

Adiponectin has vascular anti-inflammatory and protective effects. Although adiponectin protects against the development of albuminuria, historically, the focus has been on podocyte protection within the glomerular filtration barrier (GFB). The first barrier to albumin in the GFB is the endothelial glycocalyx (eGlx), a surface gel-like barrier covering glomerular endothelial cells (GEnCs). In diabetes, eGlx dysfunction occurs before podocyte damage; hence, we hypothesized that adiponectin could protect from eGlx damage to prevent early vascular damage in diabetic kidney disease (DKD). Globular adiponectin (gAd) activated AMPK signaling in human GEnCs through AdipoR1. It significantly reduced eGlx shedding and the tumor necrosis factor-α (TNF-α)-mediated increase in syndecan-4 (SDC4) and MMP2 mRNA expression in GEnCs in vitro. It protected against increased TNF-α mRNA expression in glomeruli isolated from db/db mice and against expression of genes associated with glycocalyx shedding (namely, SDC4, MMP2, and MMP9). In addition, gAd protected against increased glomerular albumin permeability (Ps'alb) in glomeruli isolated from db/db mice when administered intraperitoneally and when applied directly to glomeruli (ex vivo). Ps'alb was inversely correlated with eGlx depth in vivo. In summary, adiponectin restored eGlx depth, which was correlated with improved glomerular barrier function, in diabetes.

Low dose cadmium inhibits syndecan-4 expression in glycocalyx of glomerular endothelial cells.

Cadmium (Cd) is one of the most polluting heavy metal in the environment. Cd exposure has been elucidated to cause dysfunction of the glomerular filtration barrier (GFB). However, the underlying mechanism remains unclear. C57BL/6J male mice were administered with 2.28 mg/kg cadmium chloride (CdCl2) dissolved in distilled water by oral gavage for 14 days. The expression of SDC4 in the kidney tissues was detected. Human renal glomerular endothelial cells (HRGECs) were exposed to varying concentrations of CdCl2 for 24 h. The mRNA levels of SDC4, along with matrix metalloproteinase (MMP)-2 and 9, were analyzed by quantitative PCR. Additionally, the protein expression levels of SDC4, MMP-2/9, and both total and phosphorylated forms of Smad2/3 (P-Smad2/3) were detected by western blot. The extravasation rate of fluorescein isothiocyanate-dextran through the Transwell was used to evaluate the permeability of HRGECs. SB431542 was used as an inhibitor of transforming growth factor (TGF)-ß signaling pathway to further investigate the role of TGF-ß. Cd reduced SDC4 expression in both mouse kidney tissues and HRGECs. In addition, Cd exposure increased permeability and upregulated P-Smad2/3 levels in HRGECs. SB431542 treatment inhibited the phosphorylation of Smad2/3, Cd-induced SDC4 downregulation, and hyperpermeability. MMP-2/9 levels increased by Cd exposure was also blocked by SB431542, demonstrating the involvement of TGF-ß/Smad pathway in low-dose Cd-induced SDC4 reduction in HRGECs. Given that SDC4 is an essential component of glycocalyx, protection or repair of endothelial glycocalyx is a potential strategy for preventing or treating kidney diseases associated with environmental Cd exposure.

Low expression of ZFP36L1 in osteosarcoma promotes lung metastasis by inhibiting the SDC4-TGF-ß signaling feedback loop.

ZFP36L1, which is a negative regulator of gene transcripts, has been proven to regulate the progression of several carcinomas. However, its role in sarcoma remains unknown. Here, by using data analyses and in vivo experiments, we found that ZFP36L1 inhibited the lung metastasis of osteosarcoma (OS). Knockdown of ZFP36L1 promoted OS cell migration by activating TGF-ß signaling and increasing SDC4 expression. Intriguingly, we observed a positive feedback loop between SDC4 and TGF-ß signaling. SDC4 protected TGFBR3 from matrix metalloproteinase (MMP)-mediated cleavage and therefore relieved the inhibition of TGF-ß signaling by soluble TGFBR3, while TGF-ß signaling positively regulated SDC4 transcription. We also proved that ZFP36L1 regulated SDC4 mRNA decay through adenylate-uridylate (AU)-rich elements (AREs) in its 3'UTR. Furthermore, treatment with SB431542 (a TGF-ß receptor kinase inhibitor) and MK2 inhibitor III (a MAPKAPK2 inhibitor that increases the ability of ZFP36L1 to degrade mRNA) dramatically inhibited OS lung metastasis, suggesting a promising therapeutic approach for the treatment of OS lung metastasis.

Different effects of crizotinib treatment in two non-small cell lung cancer patients with SDC4::ROS1 fusion variants.

The possibility of stratifying patients according to differences in ROS proto-oncogene 1 (ROS1) fusion partners has been discussed. This study aimed to clarify the clinicopathological differences between two SDC4::ROS1 positive NSCLC cases who had different responses to crizotinib. Cytology and pathology samples from two NSCLC cases with SDC4::ROS1 who were diagnosed and treated with crizotinib at Nihon University Itabashi Hospital were obtained. Case 1 has been well-controlled with crizotinib for over 5 years, but case 2 was worse and overall survival was 19 months. Sequencing analysis of ROS1 fusion genes was performed by reverse-transcription-PCR and Sanger's sequencing methods. In addition, thyroid transcription factor (TTF)-1, ROS-1, Ki67, and phosphorylated extracellular signal-regulated kinase (pERK)1/2 expression were investigated using immunohistochemistry. Sequencing analysis showed SDC4 exon2::ROS1 exon 32 (exon33 deleted) in case 1, and coexistence of SDC4 exon2::ROS1 exon 34 and SDC4 exon2::ROS1 exon35 in case 2. The Ki67 index was not different, but ROS1 and pERK1/2 expression levels tended to be higher in the tumor cells of case 2 than in case 1. Therapeutic response to crizotinib and patients' prognosis in ROS1 rearranged NSCLC may be related to the activation of ROS1 signaling, depending on ROS1 and pERK1/2 overexpression status, even if the ROS1 fusion partner is the same.

Systemically administered wound-homing peptide accelerates wound healing by modulating syndecan-4 function.

CAR (CARSKNKDC) is a wound-homing peptide that recognises angiogenic neovessels. Here we discover that systemically administered CAR peptide has inherent ability to promote wound healing: wounds close and re-epithelialise faster in CAR-treated male mice. CAR promotes keratinocyte migration in vitro. The heparan sulfate proteoglycan syndecan-4 regulates cell migration and is crucial for wound healing. We report that syndecan-4 expression is restricted to epidermis and blood vessels in mice skin wounds. Syndecan-4 regulates binding and internalisation of CAR peptide and CAR-mediated cytoskeletal remodelling. CAR induces syndecan-4-dependent activation of the small GTPase ARF6, via the guanine nucleotide exchange factor cytohesin-2, and promotes syndecan-4-, ARF6- and Cytohesin-2-mediated keratinocyte migration. Finally, we show that genetic ablation of syndecan-4 in male mice eliminates CAR-induced wound re-epithelialisation following systemic administration. We propose that CAR peptide activates syndecan-4 functions to selectively promote re-epithelialisation. Thus, CAR peptide provides a therapeutic approach to enhance wound healing in mice; systemic, yet target organ- and cell-specific.

Syndecan-4 proteoliposomes enhance revascularization in a rabbit hind limb ischemia model of peripheral ischemia.

Regenerative therapeutics for treating peripheral arterial disease are an appealing strategy for creating more durable solutions for limb ischemia. In this work, we performed preclinical testing of an injectable formulation of syndecan-4 proteoliposomes combined with growth factors as treatment for peripheral ischemia delivered in an alginate hydrogel. We tested this therapy in an advanced model of hindlimb ischemia in rabbits with diabetes and hyperlipidemia. Our studies demonstrate enhancement in vascularity and new blood vessel growth with treatment with syndecan-4 proteoliposomes in combination with FGF-2 or FGF-2/PDGF-BB. The effects of the treatments were particularly effective in enhancing vascularity in the lower limb with a 2-4 increase in blood vessels in the treatment group in comparison to the control group. In addition, we demonstrate that the syndecan-4 proteoliposomes have stability for at least 28 days when stored at 4°C to allow transport and use in the hospital environment. In addition, we performed toxicity studies in the mice and found no toxic effects even when injected at high concentration. Overall, our studies support that syndecan-4 proteoliposomes markedly enhance the therapeutic potential of growth factors in the context of disease and may be promising therapeutics for inducing vascular regeneration in peripheral ischemia. STATEMENT OF SIGNIFICANCE: Peripheral ischemia is a common condition in which there is a lack of blood flow to the lower limbs. This condition can lead to pain while walking and, in severe cases, critical limb ischemia and limb loss. In this study, we demonstrate the safety and efficacy of a novel injectable therapy for enhancing revascularization in peripheral ischemia using an advanced large animal model of peripheral vascular disease using rabbits with hyperlipidemia and diabetes.

Syndecan-4 is a maestro of gastric cancer cell invasion and communication that underscores poor survival.

Gastric cancer is a dominating cause of cancer-associated mortality with limited therapeutic options. Here, we show that syndecan-4 (SDC4), a transmembrane proteoglycan, is highly expressed in intestinal subtype gastric tumors and that this signature associates with patient poor survival. Further, we mechanistically demonstrate that SDC4 is a master regulator of gastric cancer cell motility and invasion. We also find that SDC4 decorated with heparan sulfate is efficiently sorted in extracellular vesicles (EVs). Interestingly, SDC4 in EVs regulates gastric cancer cell-derived EV organ distribution, uptake, and functional effects in recipient cells. Specifically, we show that SDC4 knockout disrupts the tropism of EVs for the common gastric cancer metastatic sites. Our findings set the basis for the molecular implications of SDC4 expression in gastric cancer cells and provide broader perspectives on the development of therapeutic strategies targeting the glycan-EV axis to limit tumor progression.

Differential effects of temperature and mTOR and Wnt-planar cell polarity pathways on syndecan-4 and CD44 expression in growth-selected turkey satellite cell populations.

Satellite cells (SCs) comprise a heterogeneous population of muscle stem cells. Thermal stress during the first week after hatch alters proliferation, myogenesis, and adipogenesis of SCs of turkey pectoralis major (p. major) muscle via mechanistic target of rapamycin (mTOR) and wingless-type mouse mammary tumor virus integration site family/planar cell polarity (Wnt/PCP) pathways. Pivotal genes in mTOR and Wnt/PCP pathways are mTOR and frizzled-7 (Fzd7), respectively. The objective of this study was to determine the differential effects of thermal stress on SDC4 and CD44 expression in turkey p. major muscle SCs and how the expression of SDC4 and CD44 is modulated by the mTOR and Wnt/PCP pathways. Satellite cells were isolated from the p. major muscle of 1-week-old faster-growing modern-commercial (NC) turkeys and slower-growing historic Randombred Control Line 2 (RBC2) turkeys, and were challenged with hot (43°C) and cold (33°C) thermal stress for 72 h of proliferation followed by 48 h of differentiation. The NC line SCs were found to contain a lower proportion of SDC4 positive and CD44 negative (SDC4+CD44-) cells and a greater proportion of SDC4 negative and CD44 positive (SDC4-CD44+) cells compared to the RBC2 line at the control temperature (38°C) at both 72 h of proliferation and 48 h of differentiation. In general, at 72 h of proliferation, the proportion of SDC4+CD44- cells decreased with heat stress (43°C) and increased with cold stress (33°C) relative to the control temperature (38°C) in both lines, whereas the proportion of SDC4-CD44+ cells increased with heat stress and decreased with cold stress. In general, the expression of SDC4 and CD44 in the NC SCs showed greater response to both hot and cold thermal stress compared to the RBC2 cells. Knockdown of mTOR or Fzd7 expression increased the proportion of SDC4+CD44- cells while the proportion of SDC4-CD44+ cells decreased during differentiation with line differences being specific to treatment temperatures. Thus, differential composition of p. major muscle SCs in growth-selected commercial turkey may be resulted, in part, from the alteration in SDC4 and CD44 expression. Results indicate differential temperature sensitivity and mTOR and Wnt/PCP pathway responses of growth-selected SC populations and this may have long-lasting effect on muscle development and growth.

Syndecan-4 Mediates the Cellular Entry of Adeno-Associated Virus 9.

Due to their low pathogenicity, immunogenicity, and long-term gene expression, adeno-associated virus (AAV) vectors emerged as safe and efficient gene delivery tools, over-coming setbacks experienced with other viral gene delivery systems in early gene therapy trials. Among AAVs, AAV9 can translocate through the blood-brain barrier (BBB), making it a promising gene delivery tool for transducing the central nervous system (CNS) via systemic administration. Recent reports on the shortcomings of AAV9-mediated gene delivery into the CNS require reviewing the molecular base of AAV9 cellular biology. A more detailed understanding of AAV9's cellular entry would eradicate current hurdles and enable more efficient AAV9-based gene therapy approaches. Syndecans, the transmembrane family of heparan-sulfate proteoglycans, facilitate the cellular uptake of various viruses and drug delivery systems. Utilizing human cell lines and syndecan-specific cellular assays, we assessed the involvement of syndecans in AAV9's cellular entry. The ubiquitously expressed isoform, syndecan-4 proved its superiority in facilitating AAV9 internalization among syndecans. Introducing syndecan-4 into poorly transducible cell lines enabled robust AAV9-dependent gene transduction, while its knockdown reduced AAV9's cellular entry. Attachment of AAV9 to syndecan-4 is mediated not just by the polyanionic heparan-sulfate chains but also by the cell-binding domain of the extracellular syndecan-4 core protein. Co-immunoprecipitation assays and affinity proteomics also confirmed the role of syndecan-4 in the cellular entry of AAV9. Overall, our findings highlight the universally expressed syndecan-4 as a significant contributor to the cellular internalization of AAV9 and provide a molecular-based, rational explanation for the low gene delivery potential of AAV9 into the CNS.

SDC4-rs1981429 and ATM-rs228590 may provide early biomarkers of breast cancer risk.

In Australia, 13% of women are diagnosed with breast cancer (BC) in their lifetime with approximately 20,000 women diagnosed with the disease in 2021. BC is characterised by complex histological and genomic influences with recent advances in cancer biology improving early diagnosis and personalised treatment interventions. The Phosphatidyl-inositol-3-kinase/Protein kinase B (PI3K/AKT) pathway is essential in apoptosis resistance, cell survival, activation of cellular responses to DNA damage and DNA repair. Heparan sulfate proteoglycans (HSPGs) are ubiquitous molecules found on the cell surface and in the extracellular matrix with essential functions in regulating cell survival, growth, adhesion and as mediators of cell differentiation and migration. HSPGs, particularly the syndecans (SDCs), have been linked to cancers, making them an exciting target for anticancer treatments. In the PI3K/AKT pathway, syndecan-4 (SDC4) has been shown to downregulate AKT Serine/Threonine Kinase (AKT1) gene expression, while the ATM Serine/Threonine Kinase (ATM) gene has been found to inhibit this pathway upstream of AKT. We investigated single-nucleotide polymorphisms (SNPs) in HSPG and related genes SDC4, AKT1 and ATM and their influence on the prevalence of BC. SNPs were genotyped in the Australian Caucasian Genomics Research Centre Breast Cancer (GRC-BC) population and in the Griffith University-Cancer Council Queensland Breast Cancer Biobank (GU-CCQ BB) population. We identified that SDC4-rs1981429 and ATM-rs228590 may influence the development and progression of BC, having the potential to become biomarkers in early BC diagnosis and personalised treatment.

Syndecan-4 and stromal cell-derived factor-1 alpha functionalized endovascular scaffold facilitates adhesion, spreading and differentiation of endothelial colony forming cells and functions under flow and shear stress conditions.

Acellular vascular scaffolds with capture molecules have shown great promise in recruiting circulating endothelial colony forming cells (ECFCs) to promote in vivo endothelialization. A microenvironment conducive to cell spreading and differentiation following initial cell capture are key to the eventual formation of a functional endothelium. In this study, syndecan-4 and stromal cell-derived factor-1 alpha were used to functionalize an elastomeric biomaterial composed of poly(glycerol sebacate), Silk Fibroin and Type I Collagen, termed PFC, to enhance ECFC-material interaction. Functionalized PFC (fPFC) showed significantly greater ECFCs capture capability under physiological flow. Individual cell spreading area on fPFC (1474 ± 63 µm2 ) was significantly greater than on PFC (1187 ± 54 µm2 ) as early as 2 h, indicating enhanced cell-material interaction. Moreover, fPFC significantly upregulated the expression of endothelial cell specific markers such as platelet endothelial cell adhesion molecule (24-fold) and Von Willebrand Factor (11-fold) compared with tissue culture plastic after 7 days, demonstrating differentiation of ECFCs into endothelial cells. fPFC fabricated as small diameter conduits and tested using a pulsatile blood flow bioreactor were stable and maintained function. The findings suggest that the new surface functionalization strategy proposed here results in an endovascular material with enhanced endothelialization.

Syndecan-4 regulates the HER2-positive breast cancer cell proliferation cells via CK19/AKT signalling.

Despite the use of the highly specific anti-HER2 receptor (trastuzumab) therapy, HER2-positive breast cancers account for 20-30% of all breast cancer carcinomas, with HER2 status a challenge to treatment interventions. The heparan sulfate proteoglycans (HSPGs) are prominently expressed in the extracellular matrix (ECM), mediate breast cancer proliferation, development, and metastasis with most studies to date conducted in animal models. This study examined HSPGs in HER2-positive human breast cancer cell lines and their contribution to cancer cell proliferation. The study examined the cells following enhancement (via the addition of heparin) and knockdown (KD; using short interfering RNA, siRNA) of HSPG core proteins. The interaction of HSPG core proteins and AKT signalling molecules was examined to identify any influence of this signalling pathway on cancer cell proliferation. Our findings illustrated the HSPG syndecan-4 (SDC4) core protein significantly regulates cell proliferation with increased BC cell proliferation following heparin addition to cultures and decreased cell number following SDC4 KD. In addition, along with SDC4, significant changes in CK19/AKT signalling were identified as mediators of BC HER2-positive BC cell proliferation. This study provides evidence for a cell growth regulatory axis involving HSPGs/CK19 and AKT that represents a potential molecular target to prevent proliferation of HER2-positive breast cancer cells.

SDC4-rs1981429, ATM-rs228590 and biomarkers of breast cancer risk.

This is a correspondence on published article on SDC4-rs1981429, ATM-rs228590 and biomarkers of breast cancer risk. Confounding factors are discussed.

High expression of syndecan-4 is related to clinicopathological features and poor prognosis of pancreatic adenocarcinoma.

OBJECTIVE: Pancreatic adenocarcinoma (PAAD) is a leading cause of cancer-related mortality in adults. Syndecan-4 (SDC4) is involved in cancer pathogenesis. Therefore, this study aimed to explore the expression and clinical significance of SDC4 in PAAD. METHODS: Differentially expressed genes (DEGs) between PAAD and normal pancreas were screened from the GTEx and TCGA databases, and the correlationship between the DEGs and prognosis were analyzed. The prognostic value of the screened SDC4, SERPINE1, and SLC2A1 was evaluated using the Kaplan-Meier curve and SDC4 was subsequently selected as the better candidate. Also, SDC4 expression was analyzed in PAAD tissues, the other risk factors affecting postoperative survival were analyzed using Cox regression analysis, and SDC4-mediated pathways enrichment was identified by GSVA and GSEA. SDC4 expression in PAAD tissues and adjacent normal tissues of selected PAAD patients was detected by RT-qPCR and immunohistochemistry. The correlation between SDC4 and clinical features was evaluated by the χ2 test. RESULTS: SDC4 was highly expressed in PAAD tissues. Elevated SDC4 was correlated with reduced overall survival. SDC4 enrichment pathways included spliceosome function, proteasome activity, pentose phosphate pathway, base excision repair, mismatch repair, DNA replication, oxidative phosphorylation, mitotic spindle formation, epithelial-mesenchymal transition, and G2M checkpoints. SDC4 was elevated in PAAD tissues of PAAD patients compared with adjacent normal tissues. High SDC4 expression was related to metastatic differentiation, TNM stage, lymphatic metastasis, and lower 3-year survival rate. SDC4 was an independent risk factor affecting postoperative survival. CONCLUSION: SDC4 was highly expressed in PAAD and was related to clinicopathological features and poor prognosis, which might be an important index for PAAD early diagnosis and prognosis.

Role of syndecan-4 in breast cancer pathophysiology.

Expression of the cell surface heparan sulfate proteoglycan syndecan-4 is dysregulated in breast cancer, the most frequent malignancy in women. High expression of syndecan-4 correlates with a worse survival in the subgroup of estrogen receptor negative and estrogen/progesterone-receptor negative patients. Aberrant expression of syndecan-4 in breast cancer involves both transcriptional and posttranscriptional mechanisms, including estrogen- and growth factor-dependent regulation, mutations in GAPVD1, NUP153, PDE4DIP, and RREB1, as well as targeting by microRNAs. At the functional level, syndecan-4 plays an important role in various stages of breast cancer progression by interacting with ligands as diverse as plasma proteins, extracellular matrix proteins, growth factors, and surface receptors, as well as members of the integrin family. Mechanisms including integrin recycling, ectodomain shedding, and crosstalk with other syndecans expand the repertoire of syndecan-4 function. Through these interactions, syndecan-4 regulates cellular processes such as adhesion, migration, and invasion. Additional possible functions of syndecan-4 in cells of the microenvironment contribute to the complexity of its pathophysiology. Notably, syndecan-4 expression is modulated by drugs used in breast cancer treatment, such as trastuzumab and zoledronate. Overall, these findings mark syndecan-4 as a novel pathogenesis factor and promising target for therapeutic interventions in breast cancer.

LINC00707 Promotes Cell Proliferation in Cervical Cancer via the miR-374c-5p/SDC4 Axis.

Cervical cancer (CC) is the second main reason of cancer-related deaths in women around the world. Long intergenic nonprotein coding RNA 707, which is known as LINC00707, has been elucidated to facilitate the progression of multifarious tumors, but how it may exert functions in CC has not been elucidated yet. By using quantitative real-time RT-PCR (RT-qPCR), we identified the expression pattern LINC00707 may possess in CC. Loss-of-function assays including Cell Counting Kit-8 (CCK-8), colony formation, and transferase-mediated dUTP nick-end labeling (TUNEL) assays were taken to verify the effects of LINC00707 inhibition on CC cell proliferation and apoptosis. The downstream RNAs were selected through bioinformatics prediction, and their interaction with LINC00707 was verified through mechanism assays including the luciferase reporter assay, RNA pull-down assay, and RNA immunoprecipitation (RIP) assay. According to results, LINC00707 was upregulated in CC cells, and LINC00707 insufficiency inhibited cell proliferation while facilitating cell apoptosis. MicroRNA (miRNA) miR-374c-5p interacted with LINC00707, and syndecan-4 (SDC4) was verified to be the downstream target gene. Data of rescue assays proved that LINC00707 could promote CC cell malignancy via the miR-374c-5p/SDC4 axis, which revealed a potential treatment option for CC.

Serum syndecan-4 correlates with blood pressure and cardiovascular parameters but not proinflammatory markers in healthy older women.

Aging is accompanied by a low-grade proinflammatory status that plays a role in age-related vascular alterations. Syndecan-4 (SDC4) is a key component of the endothelial glycocalyx, and its extracellular domain can be shed by matrix metalloproteinase-9 (MMP-9). In vitro studies demonstrated that MMP-9-mediated shedding of SDC4 is induced by tumor necrosis factor-α (TNF- α) in human endothelial cells. However, the relationship between circulating shed SDC4, systemic inflammation, and age-related vascular alterations remains unknown. Here, we used linear regression models to examine the associations of serum SDC4 levels with cardiovascular hemodynamic phenotypes, serum MMP-9, and serum TNF-α and inteleukin-6 in healthy older women (n = 74). Serum SDC4 was not associated with proinflammatory cytokines or arterial elasticity. Nevertheless, we found significant correlations of SDC4 with MMP-9, heart rate, left ventricular ejection time, systemic vascular resistance, and blood pressure. Our preliminary evidence suggests that systemic inflammation might not induce SDC4 shedding in healthy aging.