Extracellular Matrix Protein 1 Research Articles

MRI and Blood-based Biomarkers Are Associated With Surgery in Children and Adults With Ileal Crohn's Disease.

Despite advances in medical therapy, many children and adults with ileal Crohn's disease (CD) progress to fibrostenosis requiring surgery. We aimed to identify MRI and circulating biomarkers associated with the need for surgical management. This prospective, multicenter study included pediatric and adult CD cases undergoing ileal resection and CD controls receiving medical therapy. Noncontrast research MRI examinations measured bowel wall 3-dimensional magnetization transfer ratio normalized to skeletal muscle (normalized 3D MTR), modified Look-Locker inversion recovery (MOLLI) T1 relaxation, intravoxel incoherent motion (IVIM) diffusion-weighted imaging metrics, and the simplified magnetic resonance index of activity (sMaRIA). Circulating biomarkers were measured on the same day as the research MRI and included CD64, extracellular matrix protein 1 (ECM1), and granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies (Ab). Associations between MRI and circulating biomarkers and need for ileal resection were tested using univariate and multivariable LASSO regression. Our study sample included 50 patients with CD undergoing ileal resection and 83 patients with CD receiving medical therapy; mean participant age was 23.9 ± 13.1 years. Disease duration and treatment exposures did not vary between the groups. Univariate biomarker associations with ileal resection included log GM-CSF Ab (odds ratio [OR], 2.87; P = .0009), normalized 3D MTR (OR, 1.05; P = .002), log MOLLI T1 (OR, 0.01; P = .02), log IVIM perfusion fraction (f; OR, 0.38; P = .04), and IVIM apparent diffusion coefficient (ADC; OR, 0.3; P = .001). The multivariable model for surgery based upon correctedAkaike information criterion included age (OR, 1.03; P = .29), BMI (OR, 0.91; P = .09), log GM-CSF Ab (OR, 3.37; P = .01), normalized 3D MTR (OR, 1.07; P = .007), sMaRIA (OR, 1.14; P = .61), luminal narrowing (OR, 10.19; P = .003), log C-reactive protein (normalized; OR, 2.75; P = .10), and hematocrit (OR, 0.90; P = .13). After accounting for clinical and MRI measures of severity, normalized 3D MTR and GM-CSF Ab are associated with the need for surgery in ileal CD.

Laryngeal features in Lipoid proteinosis: a systematic review and meta-analysis of individual participant data.

Lipoid proteinosis (LP) or Urbach-Wiethe disease (OMIM 247100) is a rare syndrome characterised by early vocal folds infiltration and subsequent multi-organ involvement. LP is often unrecognised and its associated hoarseness is overlooked. The main objective of the study was to investigate hoarseness in LP and implement a diagnosis among otolaryngologists. PubMed/MEDLINE and OMIM databases were systematically searched. Authors concentrated the search on published articles starting from the discovery of the pathogenesis of LP by Hamada et al. in 2002. Only cases in which a diagnosis was reported both clinically and through biopsy and/or genetic molecular testing were included. Characteristics of the LP cases were extracted from each included study. Results were obtained through Generalized Estimating Equations. The search strategy yielded 217 articles, of which 74 (34.1%) met the selection criteria. A total of 154 cases were included. Hoarseness was described in all LP cases and clearly stated as the onset symptom in 68.8%. The onset was on average at 19months of age (CI: 3.00-20.00), while the mean age at diagnosis was 15years (CI: 10.00-30.00). Therefore, the diagnostic delay amounted to 13.42years (CI: 8.00-23.83). Hoarseness alone was responsible for an LP diagnosis in only 14.3% of cases. In 43.5% of cases, genetic analysis of the ECM1 gene was performed and exon 6 was the most frequently altered portion. Analysing the largest number of published cases, the study underlined that hoarseness is the key symptom for diagnosing LP since early childhood, though frequently overlooked.

Plasma Proteomics Elucidated a Protein Signature in COVID-19 Patients with Comorbidities and Early-Diagnosis Biomarkers.

Despite great scientific efforts, deep understanding of coronavirus-19 disease (COVID-19) immunopathology and clinical biomarkers remains a challenge. Pre-existing comorbidities increase the mortality rate and aggravate the exacerbated immune response against the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, which can result in more severe symptoms as well as long-COVID and post-COVID complications. In this study, we applied proteomics analysis of plasma samples from 28 patients with SARS-CoV-2, with and without pre-existing comorbidities, as well as their corresponding controls to determine the systemic protein changes caused by the SARS-CoV-2 infection. As a result, the protein signature shared amongst COVID-19 patients with comorbidities was revealed to be characterized by alterations in the coagulation and complement pathways, acute-phase response proteins, tissue damage and remodeling, as well as cholesterol metabolism. These altered proteins may play a relevant role in COVID-19 pathophysiology. Moreover, several novel potential biomarkers for early diagnosis of the SARS-CoV-2 infection were detected, such as increased levels of keratin K22E, extracellular matrix protein-1 (ECM1), and acute-phase response protein α-2-antiplasmin (A2AP). Importantly, elevated A2AP may contribute to persistent clotting complications associated with the long-COVID syndrome in patients with comorbidities. This study provides new insights into COVID-19 pathogenesis and proposes novel potential biomarkers for early diagnosis that could be facilitated for clinical application by further validation studies.

Use of data-independent acquisition mass spectrometry to identify an objective serum indicator of the need for osteoporotic therapeutic intervention

Osteoporosis is characterized by weakened bone microstructure and loss of bone mass. Current diagnostic criteria for osteoporosis are based on the T-score, which is a measure of bone mineral density. However, osteoporotic fragility fractures can occur regardless of the T-score, underscoring the need for additional criteria for the early detection of patients at fracture risk. To identify indicators of reduced bone strength, we performed serum proteomic analysis using data-independent acquisition mass spectrometry with serum samples from two patient groups, one with osteoporosis but no fractures and the other with osteopenia and fragility fractures. Collective evaluation of the results identified six serum proteins that changed to a similar extent in both patient groups compared with controls. Of these, extracellular matrix protein 1 (ECM1), which contributes to bone formation, showed the most significant increase in serum levels in both patient groups. An ELISA-based assay suggested that ECM1 could serve as a serum indicator of the need for therapeutic intervention; however, further prospective studies with a larger sample size are necessary to confirm these results. The present findings may contribute to the provision of early and appropriate therapeutic strategies for patients at risk of osteoporotic fractures. SignificanceThis study aimed to identify objective serum indicators of the need for therapeutic intervention in individuals at risk of osteoporotic fracture. Comprehensive proteome analyses of serum collected from patients with osteoporosis but no fractures, patients with osteopenia and fragility fractures, and controls were performed by data-independent acquisition mass spectrometry. Collective evaluation of the proteome analysis data and ELISA-based assays identified serum ECM1 as a potential objective marker of the risk of fragility fractures in patients with osteoporosis or osteopenia. The findings are an important step toward the development of appropriate bone health management methods to improve well-being and maintain quality of life.

Abstract 1843: Integrating machine learning with microfluidic technologies for proteomic profiling of extracellular vesicles in triple-negative breast cancer

Abstract Accurate diagnosis of breast cancer using circulating biomarkers present in plasma remains an important challenge. In particular, protein changes in tumor-derived extracellular vesicles (tdEVs) have emerged as potential biomarkers for breast cancer diagnosis because they accurately reflect dynamic changes in tumors. In this study, we compared the proteomes of extracellular vesicle (EV) isolated from the plasma of 100 breast cancer patients and 30 healthy individuals who visited Severance Hospital between Mar 2010 and Dec 2015. Microfluidic chip-based protocol that facilitates the removal of contaminants such as albumin and immunoglobulins was used for the extraction of enriched tdEVs with small amounts of plasma. Comparative analysis of the proteomes identified 26 significant biomarkers that could indicate differences between breast cancer patients and healthy individuals. Using the LsBoost-CNN-SVM hybrid machine learning algorithm, we especially identified key EV protein biomarkers for detecting triple-negative breast cancer (TNBC), a breast cancer subtype with a poor prognosis and a high recurrence rate, as well as lacking therapeutic and diagnostic targets. Remarkably, a signature consisting of three EV proteins, specifically extracellular matrix protein 1 (ECM1), mannose-binding lectin 2 (MBL2), and biotinidase (BTD), effectively distinguished TNBC patients from healthy individuals. In our proteomic analysis set (n=73), this signature exhibited impressive performance, achieving a sensitivity of 93.3% and specificity of 93% in the accurate discrimination of TNBC from the control group. The validation set (n=40) confirmed these findings, with 100% sensitivity and 80% specificity. This signature not only served as a diagnostic tool but also provided valuable insights into the risk of recurrence and patient prognosis. We found a novel diagnostic approach that holds the potential to revolutionize breast cancer diagnostics by enhancing the reliability of tumor-related information obtained from blood samples. Citation Format: Min Woo Kim, Jee Ye Kim, Young Kim, Suji Lee, Sol Moon, Ju-yong Hyon, Kyung-A Hyun, Yeji Yang, Seongmin Ha, Sunyoung Park, Hogyeong Gawk, Haeji Lee, Eun Hee Han, Jin Young Kim, Hyo-Il Jung, Young-Ho Chung, Seung Il Kim. Integrating machine learning with microfluidic technologies for proteomic profiling of extracellular vesicles in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1843.

Evaluation of endometrial receptivity in recurrent pregnancy loss and recurrent implantation failure.

The cause of implantation defects in patients with recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) has not been clearly established. We aimed to evaluate the immunohistochemical changes in HOXA-11, β1 integrin, focal adhesion kinase (FAK), cluster of differentiation 44 (CD44), and extracellular matrix protein 1 (ECM1) molecules during the receptive endometrial period in patients with RIF and RPL. This study was retrospectively conducted at a university hospital. After the exclusion of cases with pathology that may cause a change in the level of receptors in the endometrium, biopsies performed during the receptive period were selected, and the patients were categorized into RPL (n=15), RIF (n=16), control (n=16) groups. All preparations were immunohistochemically stained for HOXA-11, β1 integrin, FAK, CD44, and ECM1. HOXA-11 and β1 Integrin expression changes were similar between the RIF and control groups. However, FAK expression was significantly increased in the RIF group (p<0.01). Additionally, ECM1 and CD44 expressions were significantly decreased in the RIF group compared with the control group (p<0.01). There was no significant difference in the endometrial staining of HOXA-11, FAK, and ECM1 in patients with a history of RPL. However, β1 Integrin and CD44 levels were significantly decreased in the RPL group compared with the control group (p<0.05). Implantation is a complex process, and altered adhesion mechanisms involved in endometrial receptivity may be related to defective implantation in patients with RIF and RPL. Among the adhesion molecules, the expression of CD44, β1 integrin, FAK, and ECM1 molecules varies in inappropriate implantation compared with the normal population.

Elevated extracellular matrix protein 1 in circulating extracellular vesicles supports breast cancer progression under obesity conditions

The cargo content in small extracellular vesicles (sEVs) changes under pathological conditions. Our data shows that in obesity, extracellular matrix protein 1 (ECM1) protein levels are significantly increased in circulating sEVs, which is dependent on integrin-β2. Knockdown of integrin-β2 does not affect cellular ECM1 protein levels but significantly reduces ECM1 protein levels in the sEVs released by these cells. In breast cancer (BC), overexpressing ECM1 increases matrix metalloproteinase 3 (MMP3) and S100A/B protein levels. Interestingly, sEVs purified from high-fat diet-induced obesity mice (D-sEVs) deliver more ECM1 protein to BC cells compared to sEVs from control diet-fed mice. Consequently, BC cells secrete more ECM1 protein, which promotes cancer cell invasion and migration. D-sEVs treatment also significantly enhances ECM1-mediated BC metastasis and growth in mouse models, as evidenced by the elevated tumor levels of MMP3 and S100A/B. Our study reveals a mechanism and suggests sEV-based strategies for treating obesity-associated BC.

A Cross-Sectional Study of Protein Changes Associated with Dementia in Non-Obese Weight Matched Women with and without Polycystic Ovary Syndrome.

Dysregulated Alzheimer's disease (AD)-associated protein expression is reported in polycystic ovary syndrome (PCOS), paralleling the expression reported in type 2 diabetes (T2D). We hypothesized, however, that these proteins would not differ between women with non-obese and non-insulin resistant PCOS compared to matched control subjects. We measured plasma amyloid-related proteins levels (Amyloid-precursor protein (APP), alpha-synuclein (SNCA), amyloid P-component (APCS), Pappalysin (PAPPA), Microtubule-associated protein tau (MAPT), apolipoprotein E (apoE), apoE2, apoE3, apoE4, Serum amyloid A (SAA), Noggin (NOG) and apoA1) in weight and aged-matched non-obese PCOS (n = 24) and control (n = 24) women. Dementia-related proteins fibronectin (FN), FN1.3, FN1.4, Von Willebrand factor (VWF) and extracellular matrix protein 1 (ECM1) were also measured. Protein levels were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement. Only APCS differed between groups, being elevated in non-obese PCOS women (p = 0.03) relative to the non-obese control women. This differed markedly from the elevated APP, APCS, ApoE, FN, FN1.3, FN1.4 and VWF reported in obese women with PCOS. Non-obese, non-insulin resistant PCOS subjects have a lower AD-associated protein pattern risk profile versus obese insulin resistant PCOS women, and are not dissimilar to non-obese controls, indicating that lifestyle management to maintain optimal body weight could be beneficial to reduce the long-term AD-risk in women with PCOS.

Advances in treatment for Lipoid Proteinosis (Urbach-Wiethe disease): A systematic review.

Lipoid proteinosis, also known as Urbach-Wiethe disease, is a rare autosomal recessive genodermatosis, caused by mutations in the ECM1 gene. This results in the deposition of PAS-positive, hyaline-like material on the skin, mucosae, and internal organs. Here, we present a case report of a 48-year-old man with lipoid proteinosis who exhibited significant improvement after oral acitretin therapy. To address the lack of large case-control studies on lipoid proteinosis treatment, we performed a systematic review of the literature following the PRISMA 2020 criteria. The search was conducted in PubMed, Web of Science, Cochrane, and Scopus databases from inception until June 2023. To assess the methodological quality of case reports and case series, we used the critical appraisal tool JBI. We included 25 studies that met eligibility criteria. An overall sample of 44 patients with a histopathologically confirmed diagnosis was analyzed. Treatment ranged from systemic therapies (acitretin, etretinate, dimethyl sulfoxide, corticosteroids, D-penicillamine) to surgical or laser procedures. Regarding methodological quality, the main discrepancies arose in the reporting of participant characteristics and treatment interventions. Apparently, low-dose oral acitretin could have potential in managing lipoid proteinosis, exhibiting fewer side effects compared to other therapeutic agents. Further research is needed to establish more comprehensive and evidence-based treatment guidelines.

Salvianolic acid B attenuates liver fibrosis by targeting Ecm1 and inhibiting hepatocyte ferroptosis

Hepatocyte ferroptosis promotes the pathogenesis and progression of liver fibrosis. Salvianolic acid B (Sal B) exerts antifibrotic effects. However, the pharmacological mechanism and target has not yet been fully elucidated. In this study, liver fibrosis was induced by CCl4 in wild-type mice and hepatocyte-specific extracellular matrix protein 1 (Ecm1)-deficient mice, which were separately treated with Sal B, ferrostatin-1, sorafenib or cilengitide. Erastin- or CCl4-induced hepatocyte ferroptosis models with or without Ecm1 gene knockdown were evaluated in vitro. Subsequently, the interaction between Ecm1 and xCT and the binding kinetics of Sal B and Ecm1 were determined. We found that Sal B significantly attenuated liver fibrosis in CCl4-induced mice. Ecm1 deletion in hepatocytes abolished the antifibrotic effect of Sal B. Mechanistically, Sal B protected against hepatocyte ferroptosis by upregulating Ecm1. Further research revealed that Ecm1 as a direct target for treating liver fibrosis with Sal B. Interestingly, Ecm1 interacted with xCT to regulate hepatocyte ferroptosis. Hepatocyte ferroptosis in vitro was significantly attenuated by Sal B treatment, which was abrogated after knockdown of Ecm1 in LO2 cells. Therefore, Sal B alleviates liver fibrosis in mice by targeting up-regulation of Ecm1 and inhibiting hepatocyte ferroptosis. The interaction between Ecm1 and xCT regulates hepatocyte ferroptosis.

Downregulation of extracellular matrix protein 1 effectively ameliorates osteoarthritis progression in vivo

Osteoarthritis (OA) is the most common joint disease whose important pathological feature is degeneration of articular cartilage. Although extracellular matrix protein 1 (ECM1) serves as a central regulator of chondrocyte proliferation and hypertrophy, its role in OA remains largely unknown. This study aims to decipher the roles of ECM1 in OA development and therapy in animal models. In the present study, ECM1 expression was examined in clinical OA samples, experimental OA mice and OA cell models. Mice subjected to destabilised medial meniscus (DMM) surgery were intra-articularly injected with adeno-associated virus (AAV) expressing ECM1 (AAV-ECM1) or AAV containing shECM1 (AAV-shECM1). Histological analysis was performed to determine cartilage damage. mRNA sequencing was performed to explore the molecular mechanism. In addition, the downstream signaling was further confirmed by using specific inhibitors. Our data showed that ECM1 was upregulated in the cartilage of patients with OA, OA mice as well as OA cell models. Moreover, ECM1 over-expressing in knee joints by AAV-ECM1 accelerated OA progression, while knockdown of ECM1 by AAV-shECM1 alleviated OA development. Mechanistically, cartilage destruction increased ECM1 expression, which consequently exacerbated OA progression partly by decreasing PRG4 expression in the TGF-β/PKA/CREB-dependent manner. In conclusion, our study revealed the important role of ECM1 in OA progression. Targeted ECM1 inhibition is a potential strategy for OA therapy.

ECM1 promotes migration and invasion in endometriosis

Extracellular matrix protein 1 (ECM1) is a glycoprotein that may be a key player in tumorigenesis and tumor progression. However, knowledge regarding the role of ECM1 in endometriosis (EM) is still lacking. Microarray analyses were performed to compare the mRNA expression patterns between paired EU tissues and ectopic endometrial (EC) tissues (n = 4) from EM patients. ECM1 expression was significantly increased in the eutopic endometrial (EU) tissues than paired EC tissues of endometriotic patients and normal endometrial (NE) tissues of controls without EM. Blocking ECM1 with siRNA attenuated the migration and invasion of hEM15A cells and modified the distribution of the F-actin cytoskeleton. We conducted microarray analyses and bioinformatics analyses to investigate the differentially expressed genes (DEGs) and related pathways regulated by ECM1. A total of 161 DEGs between the siECM1 and the negative control (siNC) treatments were identified, consisting of 79 downregulated genes and 82 upregulated genes. Enriched DEGs were associated with 9 gene ontology (GO) terms. Moreover, a protein-protein interaction (PPI) network was constructed for the hub genes and modules. Radixin (RDX) was the second most downregulated gene in the siECM1 group compared with the siNC group. ECM1 knockdown significantly decreased the expression of RDX, RhoC, ROCK1, N-cadherin and β-catenin but not ROCK2. ECM1 showed high tissue-specific expression in EU tissues from EM patients, and may contribute to the migration, invasion and reorganization of the F-actin cytoskeleton in eutopic endometrial stromal cells via the RhoC/ROCK1 signaling pathway in EM.

Association of Extracelluar Matrix Protien 1 with Semen Parameters and Testosterone Concentration in Male Infertility

Background: Extracellular matrix protein 1 (ECM1) is a glycoprotein that interacts with extracellular proteins into semen predominantly by epididymis, supports considering the role of the epididymis in sperm maturation. Testosterone is a steroid hormone from the androgen group is primarily secreted in the testes. Objectives: The aim of this study is to assess the concentration of ECM1 and serum by (ELISA) kit with semen parameters in fertile and infertile men in Najaf City, Iraq. Material and Methods: A total of 90 participants (45 infertile and 45 fertile men) were mean age (40.02) control fertility male, while the mean age as infertile (40.22) years included in the current study. The patients were sub-grouped into: 45 infertile with semen abnormal oligozoospermia, azoospermia, asthenozoospermia and teratozoospermia patients, it used for measuring the concentration and parameters ECM1and serum testosterone by Elisa kit. Results: Statistical analysis showed highly significant differences between the two groups show (p &lt; 0.05). The level of ECM in the infertile group was lower in concentration than the control group with statistically significant differences (p &lt; 0.0001*). The difference between the totals was highly significant by a criterion (p &lt; 0.0001*) 45 in all group that studied a positive person correlation highly significant between serum testosterone (IU/mL) and seminal ECM1, (pg/mL) in all age groups of 45 male infertility at a (p &lt; 0.001*). Conclusion: The decrease in serum testosterone levels with the decrease in the level of seminal plasma ECM1 in infertile men provide evidence that levels can be used as reliable markers in the diagnostic criteria of male infertility. This study’s results suggest that concentration ECM1.

Exosome enriched leucine-rich alpha-2-glycoprotein-1 and extracellular matrix protein 1 proteins induce abnormal placental angiogenesis in pregnant mice

IntroductionGestational Diabetes Mellitus (GDM) is characterized by a high risk of fetal macrosomia and placenta hypervascularization. Exosomes has been known participating in various physiological and pathological processes, including pro-angiogenic function. However, the effects of umbilical cord blood derived exosomes from cases of GDM (GDM-exo) on placental vascular network formation remain unclear. MethodsIn the current study, we isolated and identified exosomes in umbilical cord blood from both normal (N-exo) and GDM pregnancies. Meanwhile, we investigated the effects of umbilical cord blood derived exosomes on placental angiogenesis both in vitro and in vivo. ResultsOur data indicated that in a mouse model, the placenta and fetus weight were significantly higher in the ones administrated with GDM-exo when compared with N-exo. Meanwhile, GDM-exo significantly enhanced placental endothelial cells functions in both HUVEC and HPMEC endothelial cell models. Importantly, we explored two up-regulated proteins in GDM-exo, namely leucine-rich alpha-2-glycoprotein-1 (LRG1) and extracellular matrix protein 1 (ECM1) by proteome analysis, which performed largely pro-angiogenic function and probably resulted in hypervascularization in GDM placenta. DiscussionThus, we proposed that abundant LRG1 and ECM1 enriched GDM-exo may take important roles in regulating pathological placental angiogenesis.

Extracellular Matrix Protein-1 as a Mediator of Inflammation-Induced Fibrosis After Myocardial Infarction

Irreversible fibrosis is a hallmark of myocardial infarction (MI) and heart failure. Extracellular matrix protein-1 (ECM-1) is up-regulated in these hearts, localized to fibrotic, inflammatory, and perivascular areas. ECM-1 originates predominantly from fibroblasts, macrophages, and pericytes/vascular cells in uninjured human and mouse hearts, and from M1 and M2 macrophages and myofibroblasts after MI. ECM-1 stimulates fibroblast-to-myofibroblast transition, up-regulates key fibrotic and inflammatory pathways, and inhibits cardiac fibroblast migration. ECM-1 binds HuCFb cell surface receptor LRP1, and LRP1 inhibition blocks ECM-1 from stimulating fibroblast-to-myofibroblast transition, confirming a novel ECM-1-LRP1 fibrotic signaling axis. ECM-1 may represent a novel mechanism facilitating inflammation-fibrosis crosstalk.

Citri Reticulatae Pericarpium-Reynoutria japonica Houtt. herb pair suppresses breast cancer liver metastasis by targeting ECM1-mediated cholesterol biosynthesis pathway

BackgroundLiver metastasis is a frequent event in breast cancer that causes low survival rate and poor prognosis. Citri Reticulatae Pericarpium-Reynoutria japonica Houtt. (CR), a traditional Chinese herb pair, is used for the treatment of breast cancer liver metastasis or cholesterol gallstone disease in clinics. PurposeThis study attempted to investigate the potential therapeutic target and mechanism of CR herb pair on breast cancer liver metastasis. MethodsThe anti-metastatic and cholesterol-lowering activities of CR extract were evaluated in triple-negative breast cancer (TNBC) cell lines and an experimental liver metastasis model. The role of extracellular matrix protein 1 (ECM1) in the cholesterol biosynthesis pathway was determined by the knockdown and overexpression of ECM1 gene of TNBC cells. Changes in the gene and protein expression levels of ECM1 and the cholesterol biosynthesis pathway after CR treatment were detected in vitro and in vivo by real-time PCR and Western blot. ResultsThe invasive and metastatic potentials and hypercholesterol levels of TNBC cells were positively associated with ECM1 expression. ECM1 knockdown reduced tumor cholesterol levels via downregulating cholesterol biosynthesis genes, including ACAT2, HMGCS1, HMGCR, MVK, and MVD, whereas ECM1 overexpression elicited the opposite effects. CR herb pair exerts the potential therapeutic effects on TNBC liver metastasis, which is partially mediated by disrupting ECM1-activated cholesterol biosynthesis process in TNBC cells. ConclusionThis study reveals that ECM1 is a novel target for the activation of cholesterol biosynthesis to promote TNBC liver metastasis occurrence. CR herb pair, an ECM1 inhibitor, maybe be considered to serve as an adjuvant therapeutic drug for liver metastasis in clinical practice.

Identification of biochemical biomarkers associated with premature cervical shortening in high-risk, asymptomatic pregnant women: a retrospective data analysis

Reliably predicting spontaneous preterm birth remains challenging, therefore it persists as a major contributor to perinatal morbidity and mortality. The use of biomarkers to predict premature cervical shortening, a recognised risk factor for spontaneous preterm birth, is yet to be fully explored in current literature. This study evaluates seven cervicovaginal biochemical biomarkers as possible predictors of premature cervical shortening. Asymptomatic, high-risk women (n = 131) presenting to a specialised preterm birth prevention clinic were analysed through a retrospective data analysis. Cervicovaginal biochemical biomarker concentrations were obtained, and the shortest cervical length measurement, up to 28 weeks’ gestation, was recorded. Associations between biomarker concentration and cervical length were then analysed. Of the seven biochemical biomarkers, Interleukin-1 Receptor Antagonist and Extracellular Matrix Protein-1 had statistically significant relationships with cervical shortening below 25 mm. Further investigation is required to validate these findings and any downstream clinical utility, with intentions to improve perinatal outcomes. IMPACT STATEMENT What is already known on this subject? Preterm birth is a major cause of perinatal morbidity and mortality. A woman’s risk of delivering preterm is currently stratified using historical risk factors, mid-gestation cervical length, and biochemical biomarkers such as foetal fibronectin. What do the results of this study add? In a cohort of high-risk, asymptomatic pregnant women, two cervicovaginal biochemical biomarkers, Interleukin-1 Receptor Antagonist and Extracellular Matrix Protein-1, displayed associations with premature cervical shortening. What are the implications of these findings for clinical practice and/or further research? Further investigation into the possible clinical utility of these biochemical biomarkers is warranted, with a view to improving preterm birth prediction and antenatal resource utilisation, thereby reducing the burden of preterm birth and its sequelae in a cost-effective manner.

Abstract 2813: Pyruvate kinase M2 confers radioresistance in head and neck cancer through reprograming the tumor-immune microenvironment via ECM1

Abstract Radiotherapy plays an essential role in cancer treatment, yet radioresistance remains a major barrier to therapeutic efficacy. A better understanding of the predominant pathways determining radiotherapy response could help develop mechanism-informed therapies to improve cancer management. PKM2, an enzyme that regulates the final rate-limiting step of glycolysis, has different functions in the occurrence, progression and metastasis of cancer. However, whether PKM2 plays a vital role in radioresistance is unclear, especially in head and neck squamous cell carcinoma (HNSCC). Here we report the upregulation of PKM2 in primary post-radiotherapy tumor tissues collected from radioresistant HNSCC patients. Using multidisciplinary approaches, we found elevated PKM2 in response to radiation, which confers radioresistance in HNSCC cells via extracellular matrix protein 1 (ECM1). Mechanistically, PKM2 activates STAT5 signaling pathway in HNSCC cells upon radiation, which enhances ECM1 expression. Moreover, ECM1 upregulation mediated by PKM2 prevents effector T cells from migrating to radioresistant head and neck tumors. While depletion of ECM1 overcomes PKM2-mediated radioresistance in orthotopic xenograft mice through altering the profile of chemo-attractants, which in turn remodels the tumor microenvironment to promote more cytotoxic T cells home to tumors. These novel and significant findings not only demonstrate a novel mechanism underpinning the interaction between tumor-derived PKM2 and immune cells in radioresistance but also provide a possible therapeutic strategy to overcome the failure of radiotherapy in HNSCC patients. Citation Format: Fanghui Chen, Yang Fan, Chris Tang, Qin Richard, Zheng Wei, Yong Teng. Pyruvate kinase M2 confers radioresistance in head and neck cancer through reprograming the tumor-immune microenvironment via ECM1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2813.

Urinary Eubacterium sp. CAG:581 Promotes Non-Muscle Invasive Bladder Cancer (NMIBC) Development through the ECM1/MMP9 Pathway.

Increasing evidence points to the urinary microbiota as a possible key susceptibility factor for early-stage bladder cancer (BCa) progression. However, the interpretation of its underlying mechanism is often insufficient, given that various environmental conditions have affected the composition of urinary microbiota. Herein, we sought to rule out confounding factors and clarify how urinary Eubacterium sp. CAG:581 promoted non-muscle invasive bladder cancer (NMIBC) development. Differentially abundant urinary microbiota of 51 NMIBC patients and 47 healthy controls (as Cohort 1) were first determined by metagenomics analysis. Then, we modeled the coculture of NMIBC organoids with candidate urinary Eubacterium sp. CAG:581 in anaerobic conditions and explored differentially expressed genes of these NMIBC tissues by RNA-Seq. Furthermore, we dissected the mechanisms involved into Eubacterium sp. CAG:581 by inducing extracellular matrix protein 1 (ECM1) and matrix metalloproteinase 9 (MMP9) upregulation. Finally, we used multivariate Cox modeling to investigate the clinical relevance of urinary Eubacterium sp. CAG:581 16S ribosomal RNA (16SrRNA) levels to the prognosis of 406 NMIBC patients (as Cohort 2). Eubacterium sp. CAG:581 infection accelerated the proliferation of NMIBC organoids (p < 0.01); ECM1 and MMP9 were the most upregulated genes induced by the increased colony forming units (CFU) gradient of Eubacterium sp. CAG:581 infection via phosphorylating ERK1/2 in NMIBC organoids of Cohort 1. Excluding the favorable impact of potential contributing factors, the ROC curve of Cohort 2 manifested its 3-year AUC value as 0.79 and the cut-off point of Eubacterium sp. CAG:581 16SrRNA as 10.3 (delta CT value). Our evidence suggests that urinary Eubacterium sp. CAG:581 promoted NMIBC progression through the ECM1/MMP9 pathway, which may serve as the promising noninvasive diagnostic biomarker for NMIBC.

Lichen Sclerosus: A Current Landscape of Autoimmune and Genetic Interplay.

Lichen sclerosus (LS) is an acquired chronic inflammatory dermatosis predominantly affecting the anogenital area with recalcitrant itching and soreness. Progressive or persistent LS may cause urinary and sexual disturbances and an increased risk of local skin malignancy with a prevalence of up to 11%. Investigations on lipoid proteinosis, an autosomal recessive genodermatosis caused by loss-of-function mutations in the extracellular matrix protein 1 (ECM1) gene, led to the discovery of a humoral autoimmune response to the identical molecule in LS, providing evidence for an autoimmune and genetic counterpart targeting ECM1. This paper provides an overview of the fundamental importance and current issue of better understanding the immunopathology attributed to ECM1 in LS. Furthermore, we highlight the pleiotropic action of ECM1 in homeostatic and structural maintenance of skin biology as well as in a variety of human disorders possibly associated with impaired or gained ECM1 function, including the inflammatory bowel disease ulcerative colitis, Th2 cell-dependent airway allergies, T-cell and B-cell activation, and the demyelinating central nervous system disease multiple sclerosis, to facilitate sharing the concept as a plausible therapeutic target of this attractive molecule.