Cartilage Oligomeric Matrix Protein Expression Research Articles

Intracellular cartilage oligomeric matrix protein augments breast cancer resistance to chemotherapy

Chemotherapy persists as the primary intervention for breast cancer, with chemoresistance posing the principal obstacle to successful treatment. Herein, we show that cartilage oligomeric matrix protein (COMP) expression leads to increased cancer cell survival and attenuated apoptosis under treatment with several chemotherapeutic drugs, anti-HER2 targeted treatment, and endocrine therapy in several breast cancer cell lines tested. The COMP-induced chemoresistance was independent of the breast cancer subtype. Extracellularly delivered recombinant COMP failed to rescue cells from apoptosis while endoplasmic reticulum (ER)-restricted COMP-KDEL conferred resistance to apoptosis, consistent with the localization of COMP in the ER, where it interacted with calpain. Calpain activation was reduced in COMP-expressing cells and maintained at a lower level of activation during treatment with epirubicin. Moreover, the downstream caspases of calpain, caspases -9, -7, and -3, exhibited significantly reduced activation in COMP-expressing cells under chemotherapy treatment. Chemotherapy, when combined with calpain activators, rendered the cells expressing COMP more chemosensitive. Also, the anti-apoptotic proteins phospho-Bcl2 and survivin were increased in COMP-expressing cells upon chemotherapy. Cells expressing a mutant COMP lacking thrombospondin repeats exhibited reduced chemoresistance compared to cells expressing full-length COMP. Evaluation of calcium levels in the ER, cytosol, and mitochondria revealed that COMP expression modulates intracellular calcium homeostasis. Furthermore, patients undergoing chemotherapy or endocrine therapy demonstrated significantly reduced overall survival time when tumors expressed high levels of COMP. This study identifies a novel role of COMP in chemoresistance and calpain inactivation in breast cancer, a discovery with potential implications for anti-cancer therapy.

Osteoarthritis as a Systemic Disease Promoted Prostate Cancer In Vivo and In Vitro.

Osteoarthritis (OA) is increasing worldwide, and previous work found that OA increases systemic cartilage oligomeric matrix protein (COMP), which has also been implicated in prostate cancer (PCa). As such, we sought to investigate whether OA augments PCa progression. Cellular proliferation and migration of RM1 murine PCa cells treated with interleukin (IL)-1α, COMP, IL-1α + COMP, or conditioned media from cartilage explants treated with IL-1α (representing OA media) and with inhibitors of COMP were assessed. A validated murine model was used for tumor growth and marker expression analysis. Both proliferation and migration were greater in PCa cells treated with OA media compared to controls (p < 0.001), which was not seen with direct application of the stimulants. Migration and proliferation were not negatively affected when OA media was mixed with downstream and COMP inhibitors compared to controls (p > 0.05 for all). Mice with OA developed tumors 100% of the time, whereas mice without OA only 83.4% (p = 0.478). Tumor weight correlated with OA severity (Pearson correlation = 0.813, p = 0.002). Moreover, tumors from mice with OA demonstrated increased Ki-67 expression compared to controls (mean 24.56% vs. 6.91%, p = 0.004) but no difference in CD31, PSMA, or COMP expression (p > 0.05). OA appears to promote prostate cancer in vitro and in vivo.

Cartilage Oligomeric Matrix Protein in Osteoarthritis and Obesity-Do New Considerations Emerge?

The diagnosis of osteoarthritis (OA) is based on radiological changes that are delayed, along with clinical symptoms. Early and very early diagnosis at the stage of molecular pathology may eventually offer an opportunity for early therapeutic intervention that may retard and prevent future damage. Cartilage oligomeric matrix protein (COMP) is a non-collagenous extracellular matrix protein that promotes the secretion and aggregation of collagen and contributes to the stability of the extracellular matrix. There are contradictory literature data and currently, the parameter is used only for scientific purposes and its significance is not well-determined. The serum level of COMP in patients with metabolic type OA of the knee has not been evaluated. The aim of the study was to analyze serum COMP levels in metabolic knee OA and controls with different BMI. Our results showed that the mean COMP values were significantly higher in the control group (1518.69 ± 232.76 ng/mL) compared to the knee OA patients (1294.58 ± 360.77 ng/mL) (p = 0.0012). This may be related to the smaller cartilage volume in OA patients. Additionally, COMP levels negatively correlated with disease duration (p = 0.04). The COMP level in knee OA with BMI below 30 kg/m2 (n = 61, 1304.50 ± 350.60 ng/mL) was higher compared to cases with BMI ≥ 30 kg/m2 (n = 76, 1286.63 ± 370.86 ng/mL), but the difference was not significant (p = 0.68). Whether this finding is related to specific features in the evolution of the metabolic type of knee OA remains to be determined. Interestingly, comparison of COMP levels in the controls with different BMI revealed significantly higher values in overweight and obese individuals (1618.36 ± 203.76 ng/mL in controls with BMI ≥ 25 kg/m2, n = 18, 1406.61 ± 216.41 ng/mL, n = 16; p = 0.0092). Whether this finding is associated with increased expression of COMP in the adipose tissue or with more intensive cartilage metabolism in relation to higher biomechanical overload in obese patients, considering the earlier development of metabolic type knee OA as an isolated finding, remains to be determined.

Diagnostic value of serum COMP and ADAMTS7 for intervertebral disc degeneration

ObjectiveIntervertebral disc degeneration (IVDD) is a major cause of morbidity and disability. Our study aimed to investigate the potential of cartilage oligomeric matrix protein (COMP) and ADAMTS7 (A disintegrin and metalloproteinases with thrombospondin motifs 7) as biomarkers for IVDD together with their functional relationship.MethodsIVD tissues and peripheral blood samples were collected from IVDD rabbit models over 1–4 weeks. Tissues and blood samples were also collected from clinical patients those were stratified into four equal groups according to Pfirrmann IVDD grading (I–V) with baseline data collected for each participant. COMP and ADAMTS7 expression were analyzed and biomarker characteristics were assessed using linear regression and receiver operating curve (ROC) analyses.ResultsCOMP and ADAMTS7 expression increased in tissues and serum during IVDD progression. Serum COMP (sCOMP) and serum ADAMTS7 (sADAMTS7) levels increased in a time-dependent manner following IVD damage in the rabbit model while significant positive correlations were detected between sCOMP and sADAMTS7 and Pfirrmann grade in human subjects. ROC analysis showed that combining sCOMP and sADAMTS7 assay results produced an improved diagnostic measure for IVDD compared to individual sCOMP or sADAMTS7 tests. In vitro assays conducted on human cell isolates revealed that COMP prevented extracellular matrix degradation and antagonized ADAMTS7 expression although this protective role was uncoupled under microenvironmental conditions mimicking IVDD.ConclusionsIncreases in circulating COMP and ADAMTS7 correlate with IVDD progression and may play regulatory roles. Assays for sCOMP and/or sADAMTS7 levels can discriminate between healthy subjects and IVDD patients, warranting further clinical assessment.

Abstract 2889: Cartilage oligomeric matrix protein as a potential biomarker and therapeutic target of radiation resistance in NSCLC

Abstract Despite recent advances in lung cancer treatment, the survival rate of non-small cell lung cancer (NSCLC) is ~57% largely due to treatment resistance. Cartilage Oligomeric Matrix Protein (COMP) has previously been implicated in promoting metastasis and is associated with poor survival outcomes in breast, prostate and colorectal cancers. Patients with prostate cancer and osteoarthritis (a condition characterized by elevated circulating COMP) had both increased tumor COMP expression and rate of metastasis. Additionally, elevated COMP expression, among others, was observed in a study that investigated the gene expression of invasive NSCLC cell lines, though association with COMP was not further studied. Therefore, COMP could potentially increase the metastatic potential for NSCLC and thus serve as a therapeutic target to reduce tumor aggressiveness. We performed proliferation and migration assays on NSCLC cell lines, A549 and NCI-H1975, treated with 2 µg/mL COMP to identify COMP’s role in NSCLC progression. Plated cells in monolayer were treated with either COMP (2µg/mL) or PBS (control), and then within each group received either: 1] one of two different inhibitors of COMP signaling (either the αᵥ integrin antagonist cilengitide (1µM), or the Src inhibitor PP2 (1µM)), or 2] no additional treatment. Replicates from each group then received 2Gy Cs137 γ-radiation, or no irradiation. Proliferation and migration were monitored via the IncuCyte ZOOM live-cell imaging system over a 48hr interval. Radiation alone reduced both proliferation (-22%, p&amp;lt;0.0001) and migration (-40%, p&amp;lt;0.01) of A549 cells. However, exogenous COMP treatment attenuated the effects of radiation, maintaining both A549 proliferation (19% vs irradiated control, p&amp;lt;0.05) and migration (91% vs irradiated control, p&amp;lt;0.0001). While the overall pattern for NCI-H1975 cells with/without COMP treatment was similar, the magnitude of the responses was reduced vs A549 cells and non-significant. In contrast, radiation resistance with COMP treatment was abrogated by exogenous treatment of both COMP inhibitors. Cilengitide treatment resulted in lower proliferation rates of the COMP treated, irradiated A549 (-16%, p&amp;lt;0.05) and NCI-H1975 cell lines (-58%, p&amp;lt;0.0001) vs COMP treatment alone, while PP2 reduced proliferation and migration rates for both irradiated and non-irradiated COMP treated cell lines (p&amp;lt;0.0001). PP2 treatment alone did not reduce migration rates of either irradiated control cell lines. In conclusion, COMP serves to radioprotect NSCLC in an undetermined manner, and could serve as both a prognostic biomarker for and therapeutic target against radiation resistance in patients with NSCLC. Support: Milton Raben Foundation Citation Format: Kaitlyn E. Reno, Sun H. Park, Michael K. Farris, Ryan T. Hughes, Joseph E. Moore, Chirayu M. Patel, Jeffrey S. Willey. Cartilage oligomeric matrix protein as a potential biomarker and therapeutic target of radiation resistance in NSCLC [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 2889.

COMP promotes pancreatic fibrosis by activating pancreatic stellate cells through CD36-ERK/AKT signaling pathways

BackgroundPancreatic fibrosis is one of the most important pathological features of chronic pancreatitis (CP) and pancreatic stellate cells (PSCs) are the key cells of fibrosis. As an extracellular matrix (ECM) glycoprotein, cartilage oligomeric matrix protein (COMP) is critical for collagen assembly and ECM stability and recent studies showed that COMP exert promoting fibrosis effect in the skin, lungs and liver. However, the role of COMP in activation of PSCs and pancreatic fibrosis remain unclear. We aimed to investigate the role and specific mechanisms of COMP in regulating the profibrotic phenotype of PSCs and pancreatic fibrosis. MethodsELISA method was used to determine serum COMP in patients with CP. Mice model of CP was established by repeated intraperitoneal injection of cerulein and pancreatic fibrosis was evaluated by Hematoxylin-Eosin staining (H&E) and Sirius red staining. Immunohistochemical staining was used to detect the expression changes of COMP and fibrosis marker such as α-SMA and Fibronectin in pancreatic tissue of mice. Cell Counting Kit-8, Wound Healing and Transwell assessed the proliferation and migration of human pancreatic stellate cells (HPSCs). Western blotting, qRT-PCR and immunofluorescence staining were performed to detect the expression of fibrosis marker, AKT and MAPK family proteins in HPSCs. RNA-seq omics analysis as well as small interfering RNA of COMP, recombinant human COMP (rCOMP), MEK inhibitors and PI3K inhibitors were used to study the effect and mechanism of COMP on activation of HPSCs. ResultsELISA showed that the expression of COMP significantly increased in the serum of CP patients. H&E and Sirius red staining analysis showed that there was a large amount of collagen deposition in the mice in the CP model group and high expression of COMP, α-SMA, Fibronectin and Vimentin were observed in fibrotic tissues. TGF-β1 stimulates the activation of HPSCs and increases the expression of COMP. Knockdown of COMP inhibited proliferation and migration of HPSCs. Further, RNA-seq omics analysis and validation experiments in vitro showed that rCOMP could significantly promote the proliferation and activation of HPSCs, which may be due to promoting the phosphorylation of ERK and AKT through membrane protein receptor CD36. rCOMP simultaneously increased the expression of α-SMA, Fibronectin and Collagen I in HPSCs. ConclusionIn conclusion, this study showed that COMP was up-regulated in CP fibrotic tissues and COMP induced the activation, proliferation and migration of PSCs through the CD36-ERK/AKT signaling pathway. COMP may be a potential therapeutic candidate for the treatment of CP. Interfering with the expression of COMP or the communication between COMP and CD36 on PSCs may be the next direction for therapeutic research.

Superoxide-Mediated Upregulation of MMP9 Participates in BMPR2 Destabilization and Pulmonary Hypertension Development.

we previously reported in studies on organoid-cultured bovine pulmonary arteries that pulmonary hypertension (PH) conditions of exposure to hypoxia or endothelin-1 caused a loss of a cartilage oligomeric matrix protein (COMP) stabilization of bone morphogenetic protein receptor-2 (BMPR2) function, a known key process contributing to pulmonary hypertension development. Based on subsequent findings, these conditions were associated with an extracellular superoxide-mediated increase in matrix metalloproteinase 9 (MMP-9) expression. We investigated if this contributed to PH development using mice deficient in MMP9. wild-type (WT) mice exposed to Sugen/Hypoxia (SuHx) to induce PH had increased levels of MMP9 in their lungs. Hemodynamic measures from MMP9 knockout mice (MMP9 KO) indicated they had attenuated PH parameters compared to WT mice based on an ECHO assessment of pulmonary artery pressure, right ventricular systolic pressure, and Fulton index hypertrophy measurements. In vitro vascular reactivity studies showed impaired endothelium-dependent and endothelium-independent NO-associated vasodilatory responses in the pulmonary arteries of SuHx mice and decreased lung levels of COMP and BMPR2 expression. These changes were attenuated in MMP9 KO mice potentially through preserving COMP-dependent stabilization of BMPR2. this study supports a new function of superoxide in increasing MMP9 and the associated impairment of BMPR2 in promoting PH development which could be a target for future therapies. superoxide, through promoting increases in MMP9, mediates BMPR2 depletion and its consequent control of vascular function in response to PH mediators and the SuHx mouse model of PH.

Cartilage oligomeric matrix protein overexpression is an independent poor prognostic indicator in patients with intrahepatic cholangiocarcinoma

Cartilage oligomeric matrix protein (COMP) interacts with various extracellular matrix proteins in tissues. Elevated COMP levels recently linked to worse overall survival in multiple cancer types. COMP's significance in intrahepatic cholangiocarcinoma (iCCA) remains uncertain. Here we report a retrospective study to explore COMP's impact on iCCA outcomes. We collected 182 patients' iCCA tumor tissues. COMP overexpression was associated with adverse factors like R1 resection (p = 0.008), advanced T stage (p < 0.001), large duct type (p = 0.004), and poorly differentiated histology (p = 0.002). COMP overexpression correlates with poorer DFS (HR, 3.651; p = 0.001), OS (HR, 1.827; p = 0.023), LRFS (HR, 4.077; p < 0.001), and MFS (HR, 3.718; p < 0.001). High COMP expression ties to worse overall survival (p = 0.0001), DSS (p < 0.0001), LRFS (p < 0.0001), and MFS (p < 0.0001). In conclusion, COMP overexpression links to poor prognosis and pathological features in iCCA, indicating its potential as a biomarker.

COMP Improves Ang-II-Induced Atrial Fibrillation via TGF-β Signaling Pathway.

Cartilage oligomeric matrix protein (COMP) regulates transforming growth factor-β (TGF-β) signaling pathway, which has been proved to be associated with skin fibrosis and pulmonary fibrosis. Atrial fibrosis is a major factor of atrial fibrillation (AF). Nevertheless, the interaction between COMP and TGF-β as well as their role in AF remains undefined. The purpose of this study is to clarify the role of COMP in AF and explore its potential mechanism. The hub gene of AF was identified from two datasets using bioinformatics. Furthermore, it was verified by the downregulation of COMP in angiotensin-II (Ang-II)-induced AF in mice. Moreover, the effect on AF was examined using CCK8 assay, ELISA, and western blot. The involvement of TGF-β pathway was further discussed. The expression of COMP was the most significant among all these hub genes. Our experimental results revealed that the protein levels of TGF-β1, phosphorylated Smad2 (P-Smad2), and phosphorylated Smad3 (P-Smad3) were decreased after silencing COMP, which indicated that COMP knockdown could inhibit the activation of TGF-β pathway in AF cells. However, the phenomenon was reversed when the activator SRI was added. COMP acts as a major factor and can improve Ang-II-induced AF via TGF-β signaling pathway. Thus, our research enriches the understanding of the interaction between COMP and TGF-β in AF, and provides reference for the pathogenesis and diagnosis of AF.

The clinical and genetic features in patients coexisting primary breast and thyroid cancers.

We attempted to examine the clinical characteristics in patients with breast cancer (BC) and thyroid cancer (TC); explore the potential mechanisms of tumorigenesis and progression. Using the Surveillance, Epidemiology, and End Result Program-9 (SEER-9) database, a retrospective study (1975-2017) was conducted on patients with BC and TC. We identified the common differentially expressed genes involved in BC and TC using the Gene Expression Omnibus database (GEO). Immunohistochemical staining (IHC) was performed to verify the expression of the hit gene in patients with co-occurrence of BC and TC. Using The Cancer Genome Atlas (TCGA) database, the relationship between gene expression and clinicopathological characters was determined. Gene set enrichment analysis (GSEA) was used to identify the pathways enriched in BC and TC. BC patients had a higher predisposition to develop TC (standardized incidence ratio, SIR: 1.29) and vice-versa (SIR: 1.12). Most of these patients were differentiated thyroid carcinoma (DTC) and hormone receptor (HR) - positive BC. The mRNA expression of COMP (Cartilage oligomeric matrix protein) was significantly overexpressed in BC and TC by analyzing the GEO database. The protein expression of COMP was increased in both BC and TC tissues obtained from the same patients validated by IHC. COMP was correlated with worse OS in BC (stage II-IV) and TC; it was the independent factor for prognosis of BC. GSEA indicated that the estrogen response and epithelial-mesenchymal transition (EMT) pathways were significantly enriched in both TC- and BC- COMP overexpressed groups. The co-occurrence risk of BC and TC in the same individual is higher than in the general population. Overexpression of COMP could promote oncogenesis and progression in patients with BC and TC through estrogen signaling and EMT pathways.

Expression of Cartilage Oligomeric Matrix Protein in colorectal cancer is an adverse prognostic factor and correlates negatively with infiltrating immune cells and PD-L1 expression.

Cartilage Oligomeric Matrix Protein (COMP) is an oncogenic protein that has been associated with a decrease in infiltrating T-cells in periampullary adenocarcinoma. This study aimed to investigate whether this is also the case for colorectal cancer (CRC) and to evaluate the relationship between COMP expression and clinopathological features. Immunohistochemistry was used to determine the expression levels of COMP in tumor cells and stroma in primary tumors from a cohort of 537 CRC patients. The expression of immune cell markers, including CD3+, CD8+, FoxP3+, CD68+, CD56+, CD163+, and PD-L1, was evaluated previously. Tumor fibrosis was assessed by Sirius Red staining and evaluation of collagen fiber organization. COMP expression correlated positively with TNM-stage and grade of differentiation. Patients with CRC expressing high levels of COMP had significantly shorter OS than those with low COMP expression (p<0.0001), and fewer infiltrating T-cells were detected in tumors with high COMP expression. Additionally, a negative correlation was identified between the expression of COMP and PD-L1 on both tumor cells and immune cells. Cox regression analysis showed that tumors expressing high levels of COMP had significantly shorter OS, independent of all evaluated immune cell markers. Tumor fibrosis was correlated with high expression of COMP in the stroma (p<0.0001), and tumors with high levels of COMP expression and denser fibrosis displayed more sparse immune cell infiltration. The results suggest that COMP expression in CRC may exert an immune regulatory effect by increasing dense fibrosis and decreasing immune cell infiltration. These findings support the notion that COMP is an important factor in the development and progression of CRC.

Cartilage oligomeric matrix protein acts as a molecular biomarker in multiple cancer types.

The main function of cartilage oligomeric matrix protein (COMP) is to maintain the synthesis and stability of the extracellular matrix by interacting with collagen. At present, there are relatively few studies on the role of this protein in tumors. This study aimed to explore the relationship between COMP and pan-cancer, and analyzed its diagnostic and prognostic value. The Cancer Genome Atlas database, the Genotype-Tissue Expression database and the Cancer Cell Line Encyclopedia database was used for gene expression analysis. The receiver operating characteristic curve was used to assess the diagnostic value of COMP in pan-cancer. Kaplan-Meier plots were used to assess the relationship between COMP expression and prognosis of cancers. R software v4.1.1 was used for statistical analysis, and the ggplot2 package was used for visualization. COMP was significantly overexpressed in 15 human cancers and showed significantly difference in 12 molecular subtypes and 16 immune subtypes. In addition, the expression of COMP is associated with tumor immune evasion. The ROC curve showed that the expression of COMP could predict the occurrence of 16 kinds of tumors with relative accuracy, including adrenocortical carcinoma (ACC) (AUC=0.737), breast invasive carcinoma (BRCA) (AUC=0.896), colon adenocarcinoma (COAD) (AUC=0.760), colon adenocarcinoma/rectum adenocarcinoma esophageal carcinoma (COADREAD) (AUC=0.775), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC) (AUC=0.875), kidney renal papillary cell carcinoma (KIRP) (AUC=0.773), kidney chromophobe (KICH) (AUC=0.809), ovarian serous cystadenocarcinoma (OV) (AUC=0.906), prostate adenocarcinoma (PRAD) (AUC=0.721), pancreatic adenocarcinoma (PAAD) (AUC=0.944), rectum adenocarcinoma (READ) (AUC=0.792), skin cutaneous melanoma (SKCM) (AUC=0.746), stomach adenocarcinoma (STAD) (AUC=0.711), testicular germ cell tumors (TGCT) (AUC=0.823), thymoma (THYM) (AUC=0.777) and uterine carcinosarcoma (UCS) (AUC=0.769). Furthermore, COMP expression was correlated with overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI) in ACC (OS, HR=4.95, DSS, HR=5.55, PFI, HR=2.79), BLCA (OS, HR=1.59, DSS, HR=1.72, PFI, HR=1.36), KIRC (OS, HR=1.36, DSS, HR=1.94, PFI, HR=1.57) and COADREAD (OS, HR=1.46, DSS, HR=1.98, PFI, HR=1.43). We selected previously unreported bladder urothelial carcinoma (BLCA) for further study and found that COMP could be an independent risk factor for OS, DSS and PFI. Moreover, we found differentially expressed genes of COMP in BLCA and obtained top 10 hub genes, including LGR4, LGR5, RSPO2, RSPO1, RSPO3, RNF43, ZNRF3, FYN, LYN and SYK. Finally, we verified the function of COMP at the cellular level by using J82 and T24 cells and found that knockdown of COMP could significantly inhibit migration and invasion. This finding supports that COMP could be a potential biomarker for pan-cancer diagnosis and prognosis encompassing tumor microenvironment, disease stage and prognosis. This finding supports that COMP could be a potential biomarker for pan-cancer diagnosis and prognosis encompassing tumor microenvironment, disease stage and prognosis.

Expression of cartilage oligomeric matrix protein in periampullary adenocarcinoma is associated with pancreatobiliary-type morphology, higher levels of fibrosis and immune cell exclusion

ABSTRACT Cartilage oligomeric matrix protein (COMP) is an emerging regulator of tumor progression. The aim of this study was to evaluate the expression of COMP in periampullary adenocarcinoma with respect to prognostic value for survival and relapse, levels of fibrosis and infiltrating immune cells. COMP expression was evaluated using immunohistochemistry in primary tumors and subsets of paired lymph node metastases in tissue microarrays including 175 patients with periampullary adenocarcinoma. Collagen content was assessed with Sirius Red-Fast Green staining. High COMP levels were detected in cancer cells and in stroma, in 46% and 57% of the patients, respectively. High COMP expression was strongly associated with more aggressive pancreatobiliary-type (PB-type) compared to intestinal-type tumors (p < .0001). Importantly, high expression of COMP correlated with the exclusion of cytotoxic T-cells from the cancer cell compartment of the tumors, particularly in PB-type tumors. Higher levels of fibrosis measured by the density of collagen fibers correlated with high COMP levels in both cancer cells and stroma. This in turn could lead to exclusion of cytotoxic T-cells from accessing the cancer cells, a recognized immunotherapy resistance mechanism. Targeting COMP could therefore be considered as a novel therapeutic strategy in PB-type periampullary adenocarcinoma.

Upregulation of Cartilage Oligomeric Matrix Protein Predicts Poor Prognosis in Urothelial Carcinoma.

PurposeCartilage oligomeric matrix protein (COMP) is known as a large pentameric glycoprotein, which interacts with various extracellular matrix proteins in tissues. COMP has been reported to play a role in multiple connective tissue disorders. Recently, elevated COMP levels have been found to be associated with increased tumor size, metastases, faster recurrence of cancer, and overall poorer survival in several cancers. However, the clinical importance of COMP in urothelial carcinoma remains unclear. We investigated the association between COMP expression and clinical outcomes in urothelial carcinoma.Patients and MethodsIn this retrospective study, we collected urothelial carcinoma (UC) tissue from 340 upper urinary tract UC (UTUC) patients and 295 urinary bladder UC (UBUC) patients. Pearson’s chi-square test, Kaplan–Meier analysis, and the multivariate Cox proportional hazards model was used to examine the relationship between COMP expression and patient characteristics, pathological findings, and patient survival, such as metastasis-free survival (MFS) and disease-specific survival (DSS).ResultsA total of 295 UBUC patients and 340 UTUC patients were recruited. The COMP mRNA level was significantly higher among invasive tumors (pT2–pT4) than in noninvasive tumors (pTa-T1) in UBUC groups (P < 0.01). COMP overexpression was associated with advanced T stage, nodal metastases, vascular invasion, perineural invasion, high histological grade, and high mitotic rate in both UBUC and UTUC cohorts. COMP overexpression was predictive of shorter DSS (hazard ratio [HR] in UBUC, 3.986, P < 0.001; in UTUC, 2.283, P = 0.027] and MFS (HR in UBUC, 6.813, P < 0.001; in UTUC, 4.070, P < 0.001). Kaplan–Meier analysis demonstrated high COMP expression associated with poor DSS and MFS in UTUC and UBUC groups (all P < 0.0001).ConclusionCOMP overexpression was linked to poor clinical prognosis and poor pathological features in UC. These results suggest COMP as a biomarker for UC.

THE EFFECT OF FORCED RUNNING EXERCISE ON THE KNEE JOINT ARTICULAR CARTILAGE OF CARTILAGE OLIGOMERIC MATRIX PROTEIN DEFICIENT MICE

Purpose: Mechanical loading is a key factor for proper assembly and maintenance of the cartilage extracellular matrix (ECM) in which proteins like cartilage oligomeric matrix protein (COMP) provide matrix stability by connecting collagen II with extrafibrillar structures. Previous studies have shown that the expression of COMP is mechanosensitive and involved in mechanotransduction in articular cartilage. Surprisingly, COMP deficient (COMP-/-) mice did not show any anatomical, histological and ultrastructural differences compared to wildtype littermates at any stage of skeletal development.

Expression of cartilage oligomeric matrix protein (COMP) associates with capsular invasion in salivary gland pleomorphic adenoma.

Accumulating evidence shows that pleomorphic adenoma (PA) exhibits a unique capsular invasion and with a crucial role in recurrence. This study was designed to explore RNA expression profiles in salivary gland PA in an attempt to further analyse genes associate with capsule invasion. We evaluated the expression profiles of 4salivary gland PA patients by RNA-sequencing. The principal functions of the differentially expressed mRNAs (DEGs) were explored using GO and KEGG analysis. Then, RT-qPCR and correlation analyses were performed to verify the candidate DEGs in 59 PA patients, and immunohistochemical examinations were conducted to validate candidate DEGs. Finally, the COMP-related genes were screened using correlation and biological pathway enrichment analysis, and further validated by RT-qPCR. A total of 974 DEGs were significantly upregulated, and 1464 were downregulated (fold change ≥2.0; p<0.05). Based on GO and KEGG analyses, extracellular matrix organization and the PI3K-Akt signalling pathway might play pivotal roles in the tumorigenesis of PA. 40 DEGs were screened and validated by RT-qPCR, 11 upregulated and 5 downregulated DEGs were consistent with the sequencing results. Cartilage oligomeric matrix protein (COMP) was identified to have a significant correlation with the capsular invasion of PA and expression of COMP in patients with invasive capsular PA was significantly stronger than PA. Finally, further results could reveal that 5highest scoring genes were screened as hub genes for COMP. These findings suggested that COMP may be a prognostic target for PA and might contribute to its capsular invasion.

High Levels of Expression of Cartilage Oligomeric Matrix Protein in Lymph Node Metastases in Breast Cancer Are Associated with Reduced Survival.

Simple SummaryCartilage oligomeric matrix protein (COMP) is an emerging independent prognostic marker for breast cancer patients. COMP expression by cancer cells affects their metabolism, metastases, and the abundance of cancer stem cell populations. This study assessed the levels of COMP in the sera of metastatic breast cancer patients. Further, matched tumor tissues from the primary tumor and metastases were stained for COMP expression with immunohistochemistry. The levels of serum COMP were highest in the blood of metastatic ER-positive and HER2-positive patients. The expression of COMP in primary tumors correlated with COMP expression in the metastatic loci. Lymph node metastases (LNM) with COMP expression were associated with reduced survival. The expression of COMP in LNM at the time of primary diagnosis could indicate later development of visceral and lung metastases.Cartilage oligomeric matrix protein (COMP) is a regulator of the extracellular matrix and is expressed primarily in the cartilage. Recently, COMP expression was also documented in breast cancer patients both in sera and tumor biopsies, in both of which it could serve as an independent prognostic marker. This study aimed to assess COMP as a potential biomarker in the group of metastatic breast cancer patients. Levels of COMP were measured by ELISA in serum samples of 141 metastatic breast cancer patients. Biopsies from primary tumors, synchronous lymph node metastases, and distant metastases were stained for COMP expression. The levels of serum COMP were higher in patients with ER- and HER2-positive tumors when compared to triple-negative tumors and correlated with the presence of bone and lung metastases, circulating tumor cell count, and clusters. Most of the primary tumors expressing COMP (70%) retained the expression also in the lymph node metastases, which correlated with visceral metastases and reduced survival. In conclusion, COMP appears as a valuable biomarker in metastatic breast cancer patients indicating a more severe stage of the disease. Serum COMP levels were associated with specific types of metastases in patients with metastatic breast cancer emphasizing that further studies are warranted to elucidate its potential role as a monitoring marker.

Prioritization and functional analysis of GWAS risk loci for Barrett's esophagus and esophageal adenocarcinoma.

Genome-wide association studies (GWAS) have identified ~20 genetic susceptibility loci for esophageal adenocarcinoma (EAC), and its precursor, Barrett's esophagus (BE). Despite such advances, functional/causal variants and gene targets at these loci remain undefined, hindering clinical translation. A key challenge is that most causal variants map to non-coding regulatory regions such as enhancers, and typically, numerous potential candidate variants at GWAS loci require testing. We developed a systematic informatics pipeline for prioritizing candidate functional variants via integrative functional potential scores (FPS) consolidated from multi-omics annotations, and used this pipeline to identify two high-scoring variants for experimental interrogation: chr9q22.32/rs11789015 and chr19p13.11/rs10423674. Minimal candidate enhancer regions spanning these variants were evaluated using luciferase reporter assays in two EAC cell lines. One of the two variants tested (rs10423674) exhibited allele-specific enhancer activity. CRISPR-mediated deletion of the putative enhancer region in EAC cell lines correlated with reduced expression of two genes-CREB-regulated transcription coactivator 1 (CRTC1) and Cartilage oligomeric matrix protein (COMP); expression of five other genes remained unchanged (CRLF1, KLHL26, TMEM59L, UBA52, RFXANK). Expression quantitative trait locus mapping indicated that rs10423674 genotype correlated with CRTC1 and COMP expression in normal esophagus. This study represents the first experimental effort to bridge GWAS associations to biology in BE/EAC and supports the utility of FPS to guide variant prioritization. Our findings reveal a functional variant and candidate risk enhancer at chr19p13.11 and implicate CRTC1 and COMP as putative gene targets, suggesting that altered expression of these genes may underlie the BE/EAC risk association.

Cartilage oligomeric matrix protein affects the biological behavior of papillary thyroid carcinoma cells by activating the PI3K/AKT/Bcl-2 pathway.

Objective: To explore the effect of cartilage oligomeric matrix protein (COMP) on papillary thyroid carcinoma (PTC).Methods: COMP expression levels in PTC tissues and matched adjacent normal tissues were measured using tissue microarrays. Human PTC cells were cultured and transduced with lentiviral short hairpin RNA against COMP (COMP-shRNA), a negative control (NC) shRNA, or mock transfected (Control). We used the Cell Counting Kit-8, performed colony formation assays, wound healing assays, Transwell invasion assays, flow cytometry, and measured the expression of apoptosis-related proteins at the mRNA and protein levels to explore the effects of COMP on the biological behavior of PTC cells and to discover the specific signaling pathway involved in these processes.Results: COMP expression was significantly higher in PTC tissues than in adjacent normal tissues. At the cellular level, COMP promoted cell migration, increased the invasiveness of PTC cells, and inhibited apoptosis. However, differences in cell proliferation were only observed within 72 hours. At the same time, colony formation assays showed that silencing COMP inhibited the proliferation of PTC cells. We also found that COMP regulated the behavior of PTC cells by activating the PI3K/AKT/Bcl-2 pathway.Conclusions: COMP is upregulated in PTC, which enhances cancer cell invasion and inhibits apoptosis, contributing to the development and progression of PTC. Thus, COMP may serve as a new biomarker for PTC.

Expression of cartilage oligomeric matrix protein in the synovial chondromatosis of the temporomandibular joint

OBJECTIVE To detect the expression of cartilage oligomeric matrix protein (COMP) in the synovial chondromatosis of the temporomandibular joint (TMJSC), and to discuss the possible interactions between COMP, transforming growth factor (TGF)-β3, TGF-β1 and bone morphogenetic protein-2 (BMP-2) in the development of this neoplastic disease. METHODS Patients in Peking University School and Hospital of Stomatology from January 2011 to February 2020 were selected, who had complete medical records, TMJSC was verified histologically after operation. The expressions of COMP, TGF-β3, TGF-β1 and BMP-2 in the TMJSC of the temporomandibular joint were detected by immunohistochemistry and quantitative real-time PCR (RT-PCR) at the protein level and mRNA level respectively, compared with the normal synovial tissue of temporomandibular joint. The histological morphology, protein expression and distribution of TMJSC tissues were observed microscopically, and the positive staining proteins were counted and scored. SPSS 22.0 statistical software was used to analyze the expression differences between the related proteins in TMJSC tissue and the normal synovial tissue of temporomandibular joint and to compare their differences. P < 0.05 indicated that the difference was statistically significant. RESULTS Immunohistochemical results showed that the positive expression of COMP in TMJSC tissues was mostly found in synovial tissues and chondrocytes adjacent to synovial tissues, and the difference was statistically significant, compared with the normal temporomandibular joint synovial tissues. The positive expression of COMP was significantly different between recurrent TMJSC and non-recurrent ones. The positive expressions of TGF-β3, TGF-β1 and BMP-2 were higher than the normal synovial tissue, and were also mostly found in the synovial cells and adjacent chondrocytes, which was further confirmed by Western blot. According to the RT-PCR results, the expressions of COMP, TGF-β3, TGF-β1 and BMP-2 in TMJSC were higher than those in the normal synovial tissue. CONCLUSION The expression of COMP in TMJSC of temporomandibular joint increased significantly, compared with the normal synovial tissue. There may be interactions between COMP and cytokines related to the proliferation and differentiation, like TGF-β3, TGF-β1 and BMP-2, which may play a potential role in the pathogenesis of TMJSC.