YKL-40 Expression Research Articles

Conserved YKL-40 changes in mice and humans after postoperative delirium

Delirium is a common postoperative neurologic complication among older adults. Despite its prevalence (14%–50%) and likely association with inflammation, the exact mechanisms that underpin postoperative delirium are unclear. This project aimed to characterize systemic and central nervous system (CNS) inflammatory changes following surgery in mice and humans. Matched plasma and cerebrospinal fluid (CSF) samples from the “Investigating Neuroinflammation Underlying Postoperative Brain Connectivity Changes, Postoperative Cognitive Dysfunction, Delirium in Older Adults” (INTUIT; NCT03273335) study were compared to murine endpoints. Delirium-like behavior was evaluated in aged mice using the 5-Choice Serial Reaction Time Test (5-CSRTT). Using a well established orthopedic surgical model in the FosTRAP reporter mouse we detected neuronal changes in the prefrontal cortex, an area implicated in attention, but notably not in the hippocampus. In aged mice, plasma interleukin-6 (IL-6), chitinase-3-like protein 1 (YKL-40), and neurofilament light chain (NfL) levels increased after orthopedic surgery, but hippocampal YKL-40 expression was decreased. Given the growing evidence for a YKL-40 role in delirium and other neurodegenerative conditions, we assayed human plasma and CSF samples. Plasma YKL-40 levels were similarly increased after surgery, with a trend toward a greater postoperative plasma YKL-40 increase in patients with delirium. However, YKL-40 levels in CSF decreased following surgery, which paralleled the findings in the mouse brain. Finally, we confirmed changes in the blood-brain barrier (BBB) as early as 9 h after surgery in mice, which warrants more detailed and acute evaluations of BBB integrity following surgery in humans. Together, these results provide a nuanced understanding of neuroimmune interactions underlying postoperative delirium in mice and humans, and highlight translational biomarkers to test potential cellular targets and mechanisms.

YKL-39 is an independent prognostic factor in gastric adenocarcinoma and is associated with tumor-associated macrophage infiltration and angiogenesis

BackgroundGastric cancer has a high incidence and mortality rate. Angiogenesis is necessary for tumor infiltration and metastasis and affects patient prognosis. YKL-39 has monocyte chemotactic activity and pro-angiogenic activity in some tumors. In this study, we investigated the relationship between YKL-39 and tumor-associated macrophages and microangiogenesis in gastric cancer to determine its potential as a prognostic biomarker.Materials and methodsA total of 119 patients with gastric cancer who had undergone gastrectomy at the 940th Hospital of the Joint Security Force between 2014 and 2018 were included in this study. We assayed the protein expression of YKL-39, CD68, and CD34 by immunohistochemistry in tissues of 119 patients with gastric cancer, as well as the intracellular expression of YKL-39 and CD68 by immunofluorescence. Data were analyzed with SPSS Statistics 25.0 to explore the impact of expression of YKL-39, CD68, and CD34 in gastric cancer patients and the relationship among them.ResultsOur results show that YKL-39 was expressed in both the nucleus and cytoplasm of gastric cancer cells and tumor mesenchyme. YKL-39 protein expression was associated with the depth of tumor infiltration, lymph node metastasis, and TNM stage; CD68 protein expression was associated with lymph node metastasis and TNM stage; CD34 protein expression was not associated with clinicopathological characteristics. Expression of YKL-39 was positively correlated with CD68 and CD34 (p < 0.001), and high expression of YKL-39 was associated with poor prognosis (p < 0.05).ConclusionIn gastric cancer, YKL-39 expression is positively correlated with the degree of tumor-associated macrophage infiltration and angiogenesis, and is a potential prognostic marker for gastric cancer.

Upregulation of YKL-40 Promotes Metastatic Phenotype and Correlates with Poor Prognosis and Therapy Response in Patients with Colorectal Cancer.

YKL-40 is a heparin- and chitin-binding glycoprotein that belongs to the family of glycosyl hydrolases but lacks enzymatic properties. It affects different (patho)physiological processes, including cancer. In different tumors, YKL-40 gene overexpression has been linked to higher cell proliferation, angiogenesis, and vasculogenic mimicry, migration, and invasion. Because, in colorectal cancer (CRC), the serological YKL-40 level may serve as a risk predictor and prognostic biomarker, we investigated the underlying mechanisms by which it may contribute to tumor progression and the clinical significance of its tissue expression in metastatic CRC. We demonstrated that high-YKL-40-expressing HCT116 and Caco2 cells showed increased motility, invasion, and proliferation. YKL-40 upregulation was associated with EMT signaling activation. In the AOM/DSS mouse model, as well as in tumors and sera from CRC patients, elevated YKL-40 levels correlated with high-grade tumors. In retrospective analyses of six independent cohorts of CRC patients, elevated YKL-40 expression correlated with shorter survival in patients with advanced CRC. Strikingly, high YKL-40 tissue levels showed a predictive value for a better response to cetuximab, even in patients with stage IV CRC and mutant KRAS, and worse sensitivity to oxaliplatin. Taken together, our findings establish that tissue YKL-40 overexpression enhances CRC metastatic potential, highlighting this gene as a novel prognostic candidate, a predictive biomarker for therapy response, and an attractive target for future therapy in CRC.

Cornus officinalis prior and post-processing: Regulatory effects on intestinal flora of diabetic nephropathy rats.

Background: Diabetic nephropathy (DN) is one of the most common and serious chronic complications in the clinic. Cornus officinalis has the effects of replenishing qi and nourishing yin, tonifying liver and kidney, and it is one of the main traditional Chinese medicines used clinically to treat diabetes and its complications. However, the effect and mechanism of Cornus officinalis before and after processing on intestinal flora of diabetic nephropathy need to be further elucidated. Methods: SD rats were randomly divided into a blank group (10 rats) and DN groups (70 rats). After 4 weeks of high-sugar and high-fat diet, the DN rat model was established by intraperitoneal injection of streptozotocin. After successful modeling, the rats were randomly divided into DN model group, irbesartan group (1.35 mg·kg−1), Cornus officinalis group (281.25 mg·kg−1), wine Cornus officinalis group (281.25 mg·kg−1), wine honey Cornus officinalis group (281.25 mg·kg−1), auxiliary wine group (10 ml·kg−1), auxiliary wine honey group (10 ml·kg−1). During the observation of the rats’ general state, after 6 weeks of continuous administration, the fasting blood glucose of rats in each group was detected, and the kidney index was calculated. The serum creatinine levels, urea nitrogen and 24 h urinary microalbumin were detected by enzyme-linked immunosorbent assay. The expression levels of YKL-40, Wnt4, β-catenin and TGF-β 1 mRNA in renal tissue were detected by fluorescence quantitative PCR. Hematoxylin-eosin staining was used to observe the changes in renal pathological injury in each group; GC-MS detected the changes of short chain fatty acid content. Feces were collected for 16 s high-throughput sequencing to analyze the effects of Cornus officinalis on the diversity of intestinal flora in DN before and after processing. Results: Compared with the blank group, the serum creatinine, urea nitrogen, 24 h urinary microalbumin, kidney index and fasting blood glucose in the DN model group were significantly increased (p < 0.05). The renal tissue morphology was disordered and a large number of inflammatory cells were infiltrated. The expression of YKL-40, Wnt4, β-catenin and TGF-β 1 mRNA was significantly increased (p < 0.05). Compared with the DN model group, the serum creatinine, urea. Nitrogen, 24 h urine microalbumin, kidney index and fasting blood glucose of rats in each administration group were significantly decreased (p < 0.05), and the general condition and pathological renal damage of DN rats were improved. The effect of wine honey Cornus officinalis was the best, and the expression of YKL-40, Wnt4, β-catenin and TGF-β 1 mRNA was significantly decreased (p < 0.05). In each administration group, the improvement of the above indicators in the wine honey Cornus officinalis group was significantly better than that in the raw Cornus officinalis group and wine Cornus officinalis group (p < 0.05), There was no significant difference compared with the irbesartan group (p > 0.05). Each administration group had a significant callback effect on the content of short-chain fatty acids in rat feces, with increased intestinal beneficial bacteria and decreased pathogenic bacteria. Compared with the blank group, the abundance of Firmicutes in the DN model group increased, the abundance of Bacteroidetes decreased, and the ratio showed an upward trend in the DN model group decreased. Each administration group could improve the relative abundance of the above intestinal flora in the model group to varying degrees. Conclusion: The processing of Cornus officinalis may improve the renal injury of DN rats by blocking the activation of Wnt/β-catenin signaling pathway, regulating the structural composition of intestinal microorganisms, and ultimately playing a role in renal protection.

Develop companion radiopharmaceutical YKL40 antibodies as potential theranostic agents for epithelial ovarian cancer

Epithelial ovarian cancer (EOC) is usually diagnosed at an advanced stage and has poor prognosis. Theranostic agents are the current trend in drug development, but are lacking in EOC. YKL40 is predominantly expressed and involved in tumorigenesis in EOC. In this study, we developed a companion theranostic agent targeting YKL40. We measured YKL40 expression levels in ascites using ELISA and correlated them with the clinical outcomes of patients with EOC. We developed radionuclide labeled In-111/Lu-177-DTPA-YKL40 neutralizing antibodies and investigated their radiochemical purity, SPECT/CT imaging, bio-distribution, and therapeutic responses in ovarian cancer xenograft mice. We demonstrated that YKL40 expression levels in ascites were significantly higher in EOC patients with serous histological type, high tumor grade, advanced stage, tumor recurrence, chemoresistance, and tumor-related death. The radiochemical purity of In-111/Lu-177-DTPA-YKL40 neutralizing antibodies reached more than 90% after 24 h of labeling. SPECT/CT imaging showed significant accumulation of In-111-DTPA-YKL40 and Lu-177-DTPA-YKL40 antibodies at the tumor site of ovarian cancer xenograft mice 24 h after administration. Lu-177-DTPA-YKL40 antibodies significantly inhibited tumor growth in ovarian cancer xenograft mice. Our study indicated that In-111/Lu-177-DTPA-YKL40 neutralizing antibodies could be potential companion theranostic agents for patients with EOC.

Prognostic value of YKL-40 in colorectal carcinoma patients: A meta-analysis.

BACKGROUNDIn recent years, the predictive role of YKL-40 for long-term survival in colorectal cancer patients has been gradually investigated. However, whether it is a reliable and valuable prognostic indicator for patients with colorectal carcinoma has not been verified. AIMTo identify the prognostic value of serum/plasma concentration of YKL-40 or expression status of YKL-40 in tumor cells in colorectal carcinoma patients. METHODSSeveral electronic databases including the PubMed, EMBASE, Web of Science, CNKI, VIP and WanFang were searched for relevant studies. The hazard ratios (HR) and 95% confidence intervals (CI) were combined and the primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS), respectively. All statistical analysis were conducted by STATA 15.0 software. RESULTSA total of nine studies involving 2545 patients were included. The pooled results indicated that YKL-40 was significantly associated with poor OS (HR = 1.80, 95%CI: 1.32-2.45, P < 0.001) and PFS (HR = 1.62, 95%CI: 1.22-2.16, P = 0.001). Subgroup analysis stratified by the treatment, tumor type and source of YKL-40 showed similar results.CONCLUSIONElevated serum/plasma concentration of YKL-40 or positive expression in tumor cells was related with worse prognosis of colorectal carcinoma patients. YKL-40 might serve as a novel and reliable indicator for the evaluation of prognosis in colorectal cancer.

Adenosine A2A Receptor Suppressed Astrocyte-Mediated Inflammation Through the Inhibition of STAT3/YKL-40 Axis in Mice With Chronic Cerebral Hypoperfusion-induced White Matter Lesions.

White matter lesions are an important pathological manifestation of cerebral small vessel disease, with inflammation playing a pivotal role in their development. The adenosine A2a receptor (ADORA2A) is known to inhibit the inflammation mediated by microglia, but its effect on astrocytes is unknown. Additionally, although the level of YKL-40 (expressed mainly in astrocytes) has been shown to be elevated in the model of white matter lesions induced by chronic cerebral hypoperfusion, the specific regulatory mechanism involved is not clear. In this study, we established in vivo and in vitro chronic cerebral hypoperfusion models to explore whether the ADORA2A regulated astrocyte-mediated inflammation through STAT3/YKL-40 axis and using immunohistochemical, western blotting, ELISA, PCR, and other techniques to verify the effect of astrocytes ADORA2A on the white matter injury. The in vivo experiments showed that activation of the ADORA2A decreased the expression of both STAT3 and YKL-40 in the astrocytes and alleviated the white matter injury, whereas its inhibition had the opposite effects. Similarly, ADORA2A inhibition significantly increased the expression of STAT3 and YKL-40 in astrocytes in vitro, with more proinflammatory cytokines being released by astrocytes. STAT3 inhibition enhanced the inhibitory effect of ADORA2A on YKL-40 synthesis, whereas its activation reversed the phenomenon. These results suggest that the activation of ADORA2A in astrocytes can inhibit the inflammation mediated by the STAT3/YKL-40 axis and thereby reduce white matter injury in cerebral small vessel disease.

YKL-40 tissue expression in lichen planus

YKL-40 tissue expression in lichen planus

YKL-40 Aggravates Early-Stage Atherosclerosis by Inhibiting Macrophage Apoptosis in an Aven-dependent Way.

Objective: programmed cell removal in atherosclerotic plaques plays a crucial role in retarding lesion progression. Macrophage apoptosis has a critical role in PrCR, especially in early-stage lesions. YKL-40 has been shown to be elevated as lesions develop and is closely related to macrophages. This study aimed to determine the effect of YKL-40 on regulating macrophage apoptosis and early-stage atherosclerosis progression. Research design and Methods: The correlations among the expression level of YKL-40, the area of early-stage plaque, and the macrophage apoptosis rate in plaques have been shown in human carotid atherosclerotic plaques through pathological and molecular biological detection. These results were successively confirmed in vivo (Ldlr −/- mice treated by YKL-40 recombinant protein/neutralizing antibody) and in vitro (macrophages that Ykl40 up-/down-expressed) experiments. The downstream targets were predicted by iTRAQ analysis. Results: In early-stage human carotid plaques and murine plaques, the YKL-40 expression level had a significant positive correlation with the area of the lesion and a significant negative correlation with the macrophage apoptosis rate. In vivo, the plaque area of aortic roots was significantly larger in the recomb-YKL-40 group than that in IgG group (p = 0.0247) and was significantly smaller in the anti-YKL-40 group than in the IgG group (p = 0.0067); the macrophage apoptosis rate of the plaque in aortic roots was significantly lower in the recomb-YKL-40 group than that in IgG group (p = 0.0018) and was higher in anti-YKL-40 group than that in VC group. In vitro, the activation level of caspase-9 was significantly lower in RAW264.7 with Ykl40 overexpressed than that in controls (p = 0.0054), while the expression level of Aven was significantly higher than that in controls (p = 0.0031). The apoptosis rate of RAW264.7 treated by recomb-YKL40 was significantly higher in the Aven down-regulated group than that in the control group (p < 0.001). The apoptosis inhibitor Aven was confirmed as the target molecule of YKL-40. Mechanistically, YKL-40 could inhibit macrophage apoptosis by upregulating Aven to suppress the activation of caspase-9. Conclusion: YKL-40 inhibits macrophage apoptosis by upregulating the apoptosis inhibitor Aven to suppress the activation of caspase-9, which may impede normal PrCR and promote substantial accumulation in early-stage plaques, thereby leading to the progression of atherosclerosis.

Reciprocal induction of hepatitis C virus replication and stimulation of hepatic profibrogenic cytokine release and cellular viability by YKL-40.

BackgroundPrevious studies have suggested the YKL-40/chitinase 3-like protein 1 protein is upregulated in chronic hepatitis C virus (HCV) infection with fibrosis. We sought to determine whether HCV regulates YKL-40 expression and to elucidate the mechanisms by which YKL-40 mediates the liver fibrosis caused by HCV infection.MethodsWe used purified protein, small molecule inhibitors and short-interfering RNAs to over-express or knock down certain kinases to explore the mechanisms underlying the regulation by HCV of YKL-40 expression in the Japanese fulminant hepatitis 1 (JFH1) model.ResultsHCV induced YKL-40 production in hepatic parenchymal cells. Further, HCV-mediated upregulation of YKL-40 through cooperative induction of tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS)-mitogen-activated protein kinase MAPKs, which are nuclear factor-κB (NF-κB)-dependent pathways. YKL-40 protein also mildly increased HCV replication, triggering hepatic profibrogenic cytokine release and cellular viability as feedback. Additionally, hepatic parenchymal cells were the sole source of YKL-40 production in the infectious JFH1 model, whereas YKL-40 was under-detected in hepatic stellate cells (HSCs) in the presence or absence of the JFH1 supernatant, which was not investigated so far.ConclusionsHCV induced and maintained secretion of YKL-40 through sustained activation of NF-κB via cooperative induction of the TNF-α and ROS-MAPKs pathways. HCV interacted with YKL-40 to enhance the progression of hepatic fibrosis. These findings support a potential role for blockade of YKL-40 as an antifibrotic strategy.

LPS-induced inflammatory response and apoptosis are mediated by Fra-1 upregulation and binding to YKL-40 in A549 cells.

Acute respiratory distress syndrome (ARDS) is a multifactorial syndrome that leads to increased morbidity and mortality in infants and children. The identification of novel biomarkers is critical for the treatment of ARDS. The present study aimed to investigate the effects of chitinase-3-like-1 protein (CHI3L1 or YKL-40) in an in vitro model of ARDS and to explore the potential underlying mechanisms. The in vitro model of ARDS was established in A549 alveolar epithelial type II cells, which were treated by lipopolysaccharide (LPS) to induce inflammation. Transfection was performed to alter YKL-40 expression. The mRNA and protein expression of YKL-40 was determined using reverse transcription-quantitative PCR and western blotting, respectively. Cell Counting Kit-8 and TUNEL assays were used to evaluate the cell viability and apoptosis, respectively. The production of cytokines was evaluated using specific ELISA kits. The relationship between YKL-40 and Fos-related antigen 1 (Fra-1) was verified using luciferase reporter and chromatin immunoprecipitation assays. The expression of the apoptotic proteins was detected using western blotting. The expression levels of YKL-40 and Fra-1 were increased in LPS-treated A549 cells. Higher levels of pro-inflammatory cytokines and induction of cell apoptosis were observed in LPS-treated A549 cells compared with the control. YKL-40 knockdown in LPS-treated A549 cells significantly decreased the production of pro-inflammatory cytokines and reduced cell apoptosis, whereas it concomitantly caused upregulation of Bax and downregulation of Bcl-2, cleaved caspase-3 and cleaved caspase-9. In addition, Fra-1 could directly bind to YKL-40 promoter and regulate its expression level. Overexpression of YKL-40 partly decreased the inhibitory effects of Fra-1 knockdown on the inflammatory response and induction of apoptosis. In summary, the findings from the present study indicated that Fra-1 could bind to YKL-40 and regulate its expression, whereas YKL-40 knockdown could further suppress LPS-induced inflammatory response and apoptosis in A549 cells. These data may provide novel evidence on the diagnosis and therapy of ARDS.

Serum YKL-40 Levels Predict Endotypes and Associate with Postoperative Recurrence in Patients with Chronic Rhinosinusitis with Nasal Polyps.

BackgroundChronic rhinosinusitis with nasal polyps (CRSwNP) is a global health concern with high heterogeneity and rate of postoperative recidivation. YKL-40 is a pivotal pro-inflammatory mediator to promote Th2 immune response which is involved in many inflammatory diseases. This study aimed to investigate the predictive value of serum YKL-40 in CRSwNP endotypes and postoperative recurrence.MethodsWe recruited 80 primary CRSwNP, 40 recurrent CRSwNP patients and 40 healthy controls (HCs) in this study, and the serum and tissue specimens were collected. The middle turbinate mucosa tissue collected from patients undergoing septoplasty was used as control. Serum YKL-40 concentrations were detected by enzyme-linked immunosorbent assay (ELISA), and tissue YKL-40 mRNA and protein levels were examined using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The difference of YKL-40 expression was compared among different group. Multivariate analysis and receiver operating characteristic (ROC) curve were performed to evaluate the value of serum YKL-40 in discriminating eosinophilic CRSwNP (eCRSwNP) and predicting postoperative recurrence.ResultsThe serum YKL-40 levels in CRSwNP patients were higher than HCs, especially in eCRSwNP patients (p < 0.05). The elevated YKL-40 levels positively correlated with blood eosinophil percentage, tissue eosinophil counts and percentages (p < 0.05). The serum YKL-40 levels in recurrent CRSwNP patients were markedly enhanced than primary CRSwNP patients (p < 0.05). The YKL-40 mRNA and protein levels were significantly elevated in CRSwNP patients compared to HCs, especially in eCRSwNP and recurrent CRSwNP group. Multivariate analysis and ROC curve exhibited that serum YKL-40 might be a promising indicator in distinguishing CRSwNP endotypes and predicting postoperative recurrence.ConclusionOur data suggested that YKL-40 might be unregulated in CRSwNP and associated with mucosal eosinophilia and recurrence. Serum YKL-40 appeared to a novel biomarker for predicting CRSwNP endotypes and postoperative recurrence of CRSwNP.

Elevated YKL-40 serum levels may contribute to wet age-related macular degeneration via the ERK1/2 pathway.

Choroidal neovascularization (CNV) is a key characteristic of wet age‐related macular degeneration (AMD) that can lead to severe vision loss in the elderly. Anti‐VEGF therapy is currently the premier strategy for wet AMD, but it has limited efficacy. Previous studies have shown that chitinase‐3‐like‐1 (YKL‐40) can promote microangiogenesis and inflammation, but its effect on CNV formation has not yet been studied. Here, we investigated the potential role of YKL‐40 in wet AMD and the underlying mechanism(s). We report that the serum expression of YKL‐40 in wet AMD patients was significantly higher than that in control patients and was positively correlated with VEGF expression, indicating that YKL‐40 may participate in the development of wet AMD. In addition, YKL‐40 and VEGF expression levels were observed to be increased and the ERK1/2 pathway activated in the neuroretinal (NR) and RPE/choroid tissues of mice with laser‐induced CNV. The YKL‐40 and phosphorylated protein levels of the ERK1/2 pathway were decreased after intravitreal injection with an anti‐YKL‐40 antibody, suggesting that anti‐YKL‐40 could inhibit the activation of the ERK1/2 pathway. These results indicate that YKL‐40 may serve as a novel target for the diagnosis and treatment of wet AMD.

Up-regulated YKL-40 is associated with poor prognosis of HCC patients with hepatitis B related cirrhosis

IntroductionTo investigate clinical significance of YKL-40 in hepatocellular carcinoma (HCC) patients with hepatitis B (HBV) related cirrhosis.Material and methodsThe present prospective observational study included 129 cases of HCC patients. Besides, 152 patients with only hepatitis B related cirrhosis and 110 HCC patients with no cirrhosis were also enrolled during the same period. Additionally, 100 healthy individuals were enrolled as control. Serum YKL-40 levels were determined using ELISA method. Levels of serum albumin, total bilirubin, alanine aminotransferase (ALT) and aspartate transaminase (AST) as well as HCC related biomarkers of alpha fetoprotein (AFP), des-γ-carboxy prothrombin (DCP), gamma glutamyltransferase (GCT-II), α-L-Fucosidase (AFU), CEA and CA19-9 were measured using an automatic biochemical analyzer. Patients’ demographic and clinical characteristics were collected and analyzed.ResultsThe expression of YKL-40 was the highest in HCC patients with HBV-related cirrhosis and the lowest in the healthy control, and the difference was significant compared with other groups. And HCC patients showed markedly higher YKL-40 levels than the HBV-related cirrhosis patients. Patients with higher expression of YKL-40 showed higher ratio of TNM IV, lymphatic metastasis and Child-Pugh C, and higher serum levels of AFP, AFU and CA19-9 than those in the patients with lower levels of YKL-40. YKL-40 level was positively correlated with AFP and AFU. Survival analysis showed patients with higher expression of YKL-40 had shorter 1-year survival time than the patients with lower YKL-40.ConclusionsYKL-40 was elevated in HCC patients with HBV-related cirrhosis and high expression of YKL-40 predicted poor prognosis and shorter 1-year survival.

Metformin-loaded lecithin nanoparticles induce colorectal cancer cytotoxicity via epigenetic modulation of noncoding RNAs.

Colorectal cancer (CRC) is major aliment around the word, with a cumulative rate of mortality. Metformin (MT) was recently approved as anticancer drug against solid tumors, such as CRC. Resistance to MT therapy remains to be a challenging matter facing the development of possible anti-cancer strategy. To circumvent this problem, MT nano-encapsulation has been introduced to sensitize resistant cancer cells. The purpose of the current study is to explore the MT's aptitude encapsulated in lecithin (LC) and chitosan (CS) nanoparticles to inhibit CRC proliferation through modulations of long noncoding RNAs (lncRNAs), micro RNAs (miRNAs), and some biochemical markers. Cytotoxic screenings of the newly synthesized MT-based regimens; MT, MT-LC NPs (NP1), MT-CS NPs (NP2), and MT-LC-CS NPs (NP3) against colorectal cancerous Caco-2 and HCT116 cell lines versus normal WI-38 cells were performed. The epigenetic mechanistic effects of these proposed regimens on lncRNAs and miRNAs were investigated. Additionally, some protein levels were assessed in CRC cells upon treatments; YKL-40, PPARγ, E-cadherin(ECN), and VEGF. We resulted that NP1 recorded the highest significant cytotoxic effect on CRC cells. HCT116 cells were more sensitive to the NP1 compared to Caco-2 cells. Intriguingly, it was suggested that NP1 tackled the CRC cells through down-regulation of the H19, HOTTIP, HULC, LINC00641, miR-200, miR-92a, miR-21, YKL-40, PPARγ, and VEGF expressions, as well as up-regulation of the miR-944 and ECN expressions. We concluded that the NP1 can potentially be cytotoxic to CRC cells in-vitro by modulating noncoding RNA.

YKL-40 protein expression in human tumor samples and human tumor cell line xenografts: implications for its use in tumor models

BackgroundYKL-40, also known as non-enzymatic chitinase-3 like-protein-1 (CHI3L1), is a glycoprotein expressed and secreted mainly by inflammatory cells and tumor cells. Accordingly, several studies demonstrated elevated YKL-40 serum levels in cancer patients and found YKL-40 to be correlated with a poor prognosis and disease severity in some tumor entities. YKL-40 was suggested to be involved in angiogenesis and extracellular matrix remodeling. As yet, however, its precise biological function remains elusive.MethodsAs YKL-40 protein expression has only been investigated in few malignancies, we employed immunohistochemical detection in a large multi-tumor tissue microarray consisting of 2,310 samples from 72 different tumor entities. In addition, YKL-40 protein expression was determined in primary mouse xenograft tumors derived from human cancer cell lines.ResultsYKL-40 could be detected in almost all cancer entities and was differently expressed depending on tumor stage and subtype (e.g., thyroid cancer, colorectal cancer, gastric cancer and ovarian cancer). While YKL-40 was absent in in vitro grown human cancer cell lines, YKL-40 expression was upregulated in xenograft tumor tissues in vivo.ConclusionsThese data provide new insights into YKL-40 expression at the protein level in various tumor entities and its regulation in tumor models. Our data suggest that upregulation of YKL-40 expression is a common feature in vivo and is finely regulated by tumor cell-microenvironment interactions.

Silencing YKL-40 gene can inhibit inflammatory factor expression and affects the effect of THP-1 cells on endometrial cancer.

To investigate the effect of silencing the YKL-40 gene on the expression of inflammatory factors and the effect of silencing the YKL-40 gene of THP-1 cells on endometrial cancer. We used a siRNA targeting a sequence in YKL-40 (si-YKL-40) to transfect HEC-1A and THP-1 cells. Quantitative real-time polymerase chain reaction assay was performed to investigate the mRNA levels of YKL-40, IL-8 and MMP-9 in HEC-1A and THP-1 cells. Migration, and invasion assays were performed to identify the effects of co-culture with THP-1 cells that silenced YKL-40 gene on the migration and invasion capacity of HEC-1A cells. Tube formation ability were detected by Matrigel-based angiogenesis assay. We successfully transfected HEC-1A and THP-1 cells with lentivirus to silence the YKL-40 gene. Compared with the blank control group and NC group, the expression of YKL-40, IL-8 and MMP-9 which were examined by qRT-PCR in YKL-40-siRNA group was significantly reduced in the two cell lines; after co-cultured with the supernatant of transfected THP-1 cells, the migration and invasion ability of HEC-1A cells in YKL-40-siRNA group was significantly reduced; the number of tubes in the YKL-40-siRNA group was significantly reduced, the spacing between the tubes was significantly increased, and the structure of tubes was incomplete. Silencing the YKL-40 gene in THP-1 cells can inhibit the expression of inflammatory factors, the invasion and migration of human endometrial cancer cells and the capacity of vitro angiogenic. And YKL-40 gene as a marker of inflammation may be an effective therapeutic target for endometrial cancer.

Prognostic Impact of YKL-40 Immunohistochemical Expression in Patients with Colorectal Cancer.

This study aims to examine the clinicopathological and prognostic significance of the YKL-40 immunohistochemical expression of tumor and immune cells through human colorectal cancer (CRC) tissue. We performed immunohistochemistry for YKL-40 and investigated the clinicopathological and prognostic impact of the YKL-40 expression of tumor (T-YKL-40) and immune cells (I-YKL-40) in CRC. We also evaluated the correlation between YKL-40 and PD-L1 expression and the immunoscore. YKL-40 was expressed in 22.6% and 64.2% of T-YKL-40 and I-YKL-40, respectively, out of the 265 CRC tissues. The I-YKL-40 expression significantly correlated with well and moderately differentiated tumors. The PD-L1 expression in immune cells significantly correlated with the I-YKL-40 expression, but not T-YKL-40 expression (p = 0.020 and p = 0.846, respectively). The I-YKL-40 expression significantly correlated with a worse overall survival rate but not recurrence-free survival (p = 0.047 and p = 0.080, respectively). However, there was no significant correlation between the T-YKL-40 expression and survival. In CRCs with a high immunoscore, patients with I-YKL-40 expression demonstrated worse overall and recurrence-free survival than those without I-YKL-40 expression. Our results demonstrated that I-YKL-40 expression significantly correlated with tumor differentiation and PD-L1 expression in immune cells. I-YKL-40 expression can be useful for the prognostic stratification of CRC patients.

High YKL-40 serum levels and its expression in the muscle tissues of patients with antisynthetase syndrome

BackgroundThe protein chitinase-3-like-1 (YKL-40) is rarely analyzed in patients with myositis. Therefore, we aimed to evaluate YKL-40 serum levels; correlate them with laboratory and clinical parameters, disease status, and treatment schemes; and analyze the YKL-40 expression in the muscle tissues of patients with antisynthetase syndrome (ASSD).MethodsThis cross-sectional single-center study included 64 adult patients with ASSD who were age-, gender-, and ethnicity-matched to 64 healthy control individuals. Their YKL-40 serum levels were analyzed using the Enzyme-Linked Immunosorbent Assay (ELISA) kit method, while YKL-40 expression in muscle tissues was analyzed using an immunohistochemical technique. Disease status was assessed using the International Myositis Assessment and Clinical Studies Group (IMACS) set scores.ResultsThe patients’ mean age was 44.8 ± 11.8 years, and median disease duration was 1.5 (0.0–4.0) years. These patients were predominantly female (82.8%) and Caucasian (73.4%). Most patients had stable disease. The median YKL-40 serum level was significantly higher in patients with ASSD when compared to the healthy individuals: 538.4 (363.4–853.1) pg/mL versus 270.0 (201.8–451.9) pg/mL, respectively; P < 0.001. However, YKL-40 serum levels did not correlate with any clinical, laboratory, disease status, or therapeutic parameters (P > 0.050), except tumor necrosis factor alpha (TNF-α) serum levels (Spearman’s correlation, rho = 0.382; P = 0.007). YKL-40 was highly expressed by inflammatory cells found in muscle biopsy specimens.ConclusionsHigh YKL-40 serum levels were observed in patients with ASSD and correlated positively with TNF-α serum levels. Moreover, YKL-40 was expressed by the inflammatory cells of the muscle tissue.

Exosomal lncRNA NEAT1 from cancer-associated fibroblasts facilitates endometrial cancer progression via miR-26a/b-5p-mediated STAT3/YKL-40 signaling pathway

Cancer-associated fibroblasts cells (CAFs) confer a rapid growth and metastasis ability of endometrial cancer (EC) via exosomes-mediated cellular communication. Long non-coding RNA nuclear enriched abundant transcript 1 (lncRNA NEAT1) drives the malignant phenotypes of EC cells. However, the role of exosomal NEAT1 from CAFs in EC progression remains ambiguous, which needs to be investigated. In our study, NEAT1 and YKL-40 were up-regulated, while miR-26a/b-5p was down-regulated in EC tissues. Moreover, NEAT1 expression was increased in CAF-exosomes compared with that in NF-exosomes. In addition, the exosomal NEAT1 derived from CAFs could transfer to EC cells and promote YKL-40 expression. Further exploration showed that exosomal NEAT1 enhanced YKL-40 expression via regulating miR-26a/b-5p-STAT3 axis in EC cells. More importantly, exosomal NEAT1 accelerated in vivo tumor growth via miR-26a/b-5p-STAT3-YKL-40 axis. Taken together, our study reveals that exosomal NEAT1 from CAFs contributes to EC progression via miR-26a/b-5p-mediated STAT3/YKL-40 pathway, which indicates the therapeutic potential of exosomal NEAT1 for treating EC.