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Background
We investigated the expression status of AGBL2 and its inhibitor latexin in breast cancer stem cells and its clinical implications in order to lay a foundation for managing breast cancer.
Methods
CD44+/CD24- tumor cells (CSC) from clinical specimens were sorted using flow cytometry. AGBL2 expression status was detected in CSC and 126 br...
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Citations
... AGBL Carboxypeptidase 2 (AGBL2), also known as Cytoplasmic Carboxypeptidase 2 (CCP2), has been recently identi ed as a microtubule carboxypeptidase. Emerging evidence has revealed that AGBL2 plays a contributory role in the development of various tumors, including those of the liver, breast, and kidney [17,18,19] . It has been associated with the promotion of tumorigenesis and correlated with unfavorable prognosis in patients. ...
Background
AGBL2's role in tumorigenesis and cancer progression has been reported in several cancer studies, and it is closely associated with α-tubulin detyrosination. The roles of AGBL2 and α-tubulin detyrosination in renal cell carcinoma (RCC) pathogenesis remain unclear and require further investigation.
Methods
In this study, we conducted an analysis of AGBL2 expression differences between renal clear cell carcinoma tissues and normal tissues using data from The Cancer Genome Atlas (TCGA). We performed a comprehensive prognostic analysis of AGBL2 in Kidney Renal Clear Cell Carcinoma(KIRC) using univariate and multivariate Cox regression. Based on the results of the Cox analysis, we constructed a prognostic model to assess its predictive capabilities. Receiver Operating Characteristic (ROC) analysis confirmed the diagnostic value of AGBL2 in renal cancer. We conducted further validation by analyzing cancer tissue samples and renal cancer cell lines, which confirmed the role of AGBL2 in promoting RCC cell proliferation and migration through in vitro experiments. Additionally, we verified the impact of AGBL2's detyrosination on α-tubulin using the tubulin carboxypeptidase (TCP) inhibitor parthenolide. Finally, we performed sequencing analysis on AGBL2 knockdown 786-O cells to investigate the correlation between AGBL2, immune infiltration, and AKT phosphorylation. Moreover, we experimentally demonstrated the enhancing effect of AGBL2 on AKT phosphorylation.
Results
TCGA analysis revealed a significant increase in AGBL2 expression in RCC patients, which was correlated with poorer overall survival (OS), disease-specific survival (DSS), and progression-free intervals (PFI). According to the analysis results, we constructed column-line plots to predict the 1-, 3-, and 5-year survival outcomes in RCC patients. Additionally, the calibration plots assessing the model's performance exhibited favorable agreement with the predicted outcomes. And the ROC curves showed that AGBL2 showed good diagnostic performance in KIRC (AUC = 0.836)). Cell phenotyping assays revealed that AGBL2 knockdown in RCC cells significantly inhibited cell proliferation and migration. Conversely, overexpression of AGBL2 resulted in increased cell proliferation and migration in RCC cells. We observed that AGBL2 is predominantly located in the nucleus and can elevate the detyrosination level of α-tubulin in RCC cells. Moreover, the enhancement of RCC cell proliferation and migration by AGBL2 was partially inhibited after treatment with the TCP inhibitor parthenolide. Analysis of the sequencing data revealed that AGBL2 is associated with a diverse array of biological processes, encompassing signal transduction and immune infiltration. Interestingly, AGBL2 expression exhibited a negative correlation with the majority of immune cell infiltrations. Additionally, AGBL2 was found to enhance the phosphorylation of AKT in RCC cells.
Conclusion
Our study suggests that AGBL2 fosters RCC cell proliferation and migration by enhancing α-tubulin detyrosination. Moreover, elevated AGBL2 expression increases phosphorylation of AKT in RCC cells
... Third down-regulated protein NADH dehydrogenase 1 alpha subcomplex subunit 10, involved in electron transport respiratory chain. Zhang et al. (2014) significantly found its association with the downregulation of mRNA expression levels in human squamous cell carcinoma. ...
This study aimed to characterize differentially expressed proteins in malignant ovarian tissue to find out potential novel biomarkers in ovarian cancer (OC). We enrolled 20 ovarian cancer patients (40-65 years) and an equal number of age-matched healthy women to get malignant and healthy ovarian tissue samples for protein extraction and quantification after tissue lysis. The protein profile was analyzed using two-dimensional gel electrophoresis followed by MALDI-TOF mass spectrometry. Based on the information thus obtained, the proteins were identified using the relevant software and protein databank to analyze the malignant and non-malignant ovarian tissue samples (n = 20/group). In this proteomic analysis of the ovarian tissue, 112 proteins were detected. Based on a minimum of ≥ 1.5-fold expression difference (p-value ≤ 0.05; FDR ≤ 0.05 and PMF ≥ 79), 17 proteins were found to be upregulated while 27 were downregulated in the malignant ovarian tissue. Six of these proteins have not been previously reported in ovarian cancer. Out of these, three are upregulated while the other three are downregulated. The upregulated proteins are centrosomal protein of 290 kDa (Cep290), uncharacterized protein C1orf109 (C1orf109) and GTPase-activating Rap/Ran-GAP domain-like protein 3 (GARNL3), and the three downregulated proteins identified are actin-related protein 3 (ARP3), cytosolic carboxypeptidase 3 (AGBL3) and NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 10 (NDUFA10). This proteomic mapping not only provides data on protein profiling of ovarian cancer in Pakistani population for the first time but also reports six novel differentially expressed proteins, which have not been previously reported in ovarian cancer patients. They may serve as potential novel biomarkers after further validation for early diagnosis and prognosis of ovarian cancer. It also provides additional data to improve existing knowledge of already reported protein ovarian cancer biomarkers.
... Furthermore, detyrosinated tubulins are more resistant to microtubule-targeting agents (17). Previous studies demonstrated that AGBL2 promotes tumorigenesis and cancer progression in breast cancer, prostate cancer and hepatocellular carcinoma (8,18) and could be considered as a potential biomarker for lymph node metastasis and chemotherapy resistance in breast cancer (19). In addition, AGBL2 promotes hepatocellular carcinoma cancer cell growth via IRGM-regulated autophagy. ...
... These results confirmed that AGBL2 could serve a crucial role in tumorigenesis promotion of ovarian carcinoma. Previous studies demonstrated that AGBL2 high expression is a prognostic marker of cancer and is associated with poor clinical outcome in patients with hepatocellular carcinoma and breast cancer (18,19). Similarly, the results from this study indicated that AGBL2 high expression could predict poor overall survival in patients with ovarian carcinomas, and that AGBL2 may be considered as an independent prognostic marker. ...
The putative oncogenic role of ATP/GTP binding protein like 2 (AGBL2) in catalyzing α-tubulin detyrosination has recently been characterized in cancer. However, the status of AGBL2 expression in ovarian cancer and its potential clinical and prognostic significance remain unclear. In the present study, immunohistochemistry staining investigated the protein expression level of AGBL2 in paraffin-embedded pathological specimens from 30 normal ovaries, 35 ovarian cystadenomas, 38 borderline ovarian tumors and 165 invasive ovarian carcinomas. The association between AGBL2 expression and clinicopathological characteristics of patients was evaluated using the χ2 test or Fisher's exact test. The survival status of patients was assessed by receiver-operator curve analysis. The results demonstrated that high expression of AGBL2 was observed in 9% of cystadenomas cases, 21% of borderline tumors cases and 38% of ovarian carcinomas cases; however AGBL2 expression was not high in normal ovarian tissues (P<0.01). Furthermore, the results demonstrated that high expression of AGBL2 was associated with tumor histological grade, advanced pT/pN/pM and cancer stage according to the International Federation of Gynecology and Obstetrics (P<0.05). Following univariate survival analysis of the ovarian carcinoma groups, high expression of AGBL2 was significantly associated with shorter patient survival (P<0.001). In addition, multivariate analysis revealed that AGBL2 could be identified as a potential independent prognostic factor for overall survival in patients with ovarian carcinoma (P=0.004). Furthermore, the results demonstrated that AGBL2 expression was significantly associated with the expression of immunity related GTPase M (IRGM) (P=0.013) and LC3A/B (P=0.004). IRGM expression level was also significantly associated with LC3A/B expression level (P=0.023). These findings demonstrated that AGBL2 expression was high in ovarian carcinomas, which suggested that AGBL2 may participate in the acquisition of an aggressive phenotype and may therefore serve as an independent prognostic molecular marker.
... Other studies suggest that increased LXN expression is associated with inflammatory responses such as acute pancreatitis and inflammatory lung disease 8 . In mouse models, LXN is found to be both highly expressed in inflammatory Mast cells and is induced following stimulation of mouse macrophages 9,10 Several additional studies have also linked loss of LXN expression with numerous human malignancies, such as leukeamia 11 , melanoma 12 , hepatocellular carcinoma 13 and pancreatic ductal adenocarcinoma (PDAC) 14 . For example, LXN expression was shown to significantly correlate with tumour size, histological grade, metastasis and clinical stage in PDAC, indicating that LXN may function as a tumour suppressor 15 . ...
... LXN has been reported to be a predominantly cytosolic protein in the leukeamic cell line FDC-P1, in murine HSCs and also in primary human breast adenocarcinoma 14,17,25 . However, Oldridge et al. (2013) presented preliminary data to suggest that LXN may be a nuclear protein in the prostate. ...
Loss of latexin (LXN) expression negatively correlates with the prognosis of several human cancers. Despite association with numerous processes including haematopoietic stem cell (HSC) fate, inflammation and tumour suppression, a clearly defined biological role for LXN is still lacking. Therefore, we sought to understand LXN expression and function in the normal and malignant prostate to assess its potential as a therapeutic target. Our data demonstrate that LXN is highly expressed in normal prostate luminal cells but downregulated in high Gleason grade cancers. LXN protein is both cytosolic and secreted by prostate cells and expression is directly and potently upregulated by all-trans retinoic acid (atRA). Whilst overexpression of LXN in prostate epithelial basal cells did not affect cell fate, LXN overexpression in the luminal cancer line LNCaP reduced plating efficiency. Transcriptome analysis revealed that LXN overexpression had no direct effects on gene expression but had significant indirect effects on important genes involved in both retinoid metabolism and IFN-associated inflammatory responses. These data highlight a potential role for LXN in retinoid signaling and inflammatory pathways. Investigating the effects of LXN on immune cell function in the tumour microenvironment (TME) may reveal how observed intratumoural loss of LXN affects the prognosis of many adenocarcinomas.
... After pruning, we found 4 loci that were associated with both AD and fasting glucose at the genome-wide significance level in the cross-trait meta-analysis ( Table 2). The first locus (index SNP: rs10501320, P meta = 2.80 × 10 − 16 ) was in close proximity to genes MADD, ACP2 and AGBL2, which was found to play roles in insulin sensitivity (Wagner et al. 2011), lysosome and cerebellar function (van de Bunt et al. 2015) and immune complexes (Zhang et al. 2014). The second loci (index SNP: rs12805422, P meta = 1.57 ...
A growing number of studies clearly demonstrate a substantial link between metabolic dysfunction and the risk of Alzheimer’s disease (AD), especially glucose-related dysfunction; one hypothesis for this comorbidity is the presence of a common genetic etiology. We conducted a large-scale cross-trait GWAS to investigate the genetic overlap between AD and ten metabolic traits. Among all the metabolic traits, fasting glucose, fasting insulin and HDL were found to be genetically associated with AD. Local genetic covariance analysis found that 19q13 region had strong local genetic correlation between AD and T2D (P = 6.78 × 10− 22), LDL (P = 1.74 × 10− 253) and HDL (P = 7.94 × 10− 18). Cross-trait meta-analysis identified 4 loci that were associated with AD and fasting glucose, 3 loci that were associated with AD and fasting insulin, and 20 loci that were associated with AD and HDL (Pmeta < 1.6 × 10− 8, single trait P < 0.05). Functional analysis revealed that the shared genes are enriched in amyloid metabolic process, lipoprotein remodeling and other related biological pathways; also in pancreas, liver, blood and other tissues. Our work identifies common genetic architectures shared between AD and fasting glucose, fasting insulin and HDL, and sheds light on molecular mechanisms underlying the association between metabolic dysregulation and AD.
... Stem cells which represent only a very small percentage of the total tumor mass, have been found to be the source of some, and possibly most, cancers (2). ...
... Moreover, AGBL2 protein was found to be related to clinical stage, histological stage, and lymph node metastasis. (2). ...
... Studies showed elevated CXCL1 is associated with tumor progression and poor prognosis in cancers; 55,56 and the overexpression of ATF5 or AGBL2 enhances malignancy in cancer cells. 57,58 The mechanisms of SRSF1 within different cellular compartments need to be further studied. ...
Serine/arginine‐rich splicing factor 1 (SRSF1) has been linked to various human cancers including pediatric acute lymphoblastic leukemia (ALL). Our previous study has shown that SRSF1 potentially contributes to leukemogenesis, however its underlying mechanism remains unclear. In this study, leukemic cells were isolated from pediatric ALL bone marrow samples, followed by immune‐precipitation assays and mass spectrum analysis specific to SRSF1. Subcellular localization of the SRSF1 protein and its mutants were analyzed by immunofluorescence staining. Cell growth, colony formation, cell apoptosis and cell cycle were investigated using stable leukemic cell lines generated with lentivirus‐mediated overexpressed wild‐type or mutant plasmids. Cytotoxicity of the Tie2 kinase inhibitor was also evaluated. Our results showed the phosphorylation of SRSF1 at tyrosine 19 (Tyr‐19) was identified in newly diagnosed ALL samples, but not in complete remission and normal control samples. Compared to the SRSF1‐wild type cells, the missense mutants of the Tyr‐19 phosphorylation affected the subcellular localization of SRSF1. In addition, the Tyr‐19 phosphorylation of SRSF1 also led to increased cell proliferation and enhanced colony‐forming properties by promoting cell cycle. Remarkably, we further identified the kinase Tie2 as a potential therapeutic target in leukemia cells. In conclusion, we identify for the first time that the phosphorylation state of SRSF1 is linked to different phases in pediatric ALL. The Tyr‐19 phosphorylation of SRSF1 disrupts its subcellular localization and promotes proliferation in leukemia cells by driving cell‐cycle progression. Inhibitors targeting Tie2 kinase that may catalyze Tyr‐19 phosphorylation of SRSF1 offer a promising therapeutic target for treatment of pediatric ALL.
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... LXN has homology to two other proteins/genes, tazarotene-induced gene 1 (TIG1) and cystatin C, both of which have been reported to be tumor suppressors (36,37). LXN expression has been suggested to be a tumor suppressor itself as it has been shown to inhibit tumor cell growth in gastric cancer (14), leukemia (15), melanoma (16), PCa (38), hepatocellular carcinoma (39) and breast cancer (40). In addition to being a potential tumor suppressor, LXN negatively regulates hematopoietic stem cell self-renewal in mice, resulting in an inverse relationship between LXN expression and HSC population size (17,18,41). ...
... It has been previously demonstrated that hypermethylation of CpG islands was found to be highly correlated with the transcriptional silencing of LXN gene (14)(15)(16). Furthermore, consistent with its role as tumor suppressor, the LXN gene has been shown to be silenced by methylation in several different cancers (14)(15)(16)(38)(39)(40). Our findings that demethylation treatment of the PCa cells restored LXN expression are consistent with these previous reports suggesting that methylation of the LXN gene contributes to its downregulation in the chemoresistant PCa cells. ...
Although docetaxel is the standard of care for advanced prostate cancer, most patients develop resistance to docetaxel. Therefore, elucidating the mechanism that underlies resistance to docetaxel is critical to enhance therapeutic intervention. Mining cDNA microarray from the PC-3 prostate cancer cell line and its docetaxel-resistant derivative (PC3-TxR) revealed decreased latexin (LXN) expression in the resistant cells. LXN expression was inversely correlated with taxane resistance in a panel of prostate cancer cell lines. LXN knockdown conferred docetaxel resistance to prostate cancer cells in vitro and in vivo, whereas LXN overexpression reduced docetaxel resistance in several prostate cancer cell lines. A mouse model of prostate cancer demonstrated that prostate cancer cells developed resistance to docetaxel in the bone microenvironment, but not the soft tissue microenvironment. This was associated with decreased LXN expression in prostate cancer cells in the bone microenvironment compared with the soft tissue microenvironment. It was identified that bone stromal cells decreased LXN expression through methylation and induced chemoresistance in prostate cancer in vitro. These findings reveal that a subset of prostate cancer develops docetaxel resistance through loss of LXN expression associated with methylation and that the bone microenvironment promotes this drug resistance phenotype.
Implications: This study suggests that the LXN pathway should be further explored as a viable target for preventing or reversing taxane resistance in prostate cancer. Mol Cancer Res; 15(4); 457–66. ©2017 AACR.
... Furthermore, they showed that Lxn has a tumor-suppressive role and that it negatively regulates the expression of tumor-sustaining stem cell factors (19). Recently, Lxn has been demonstrated to be a tumor-suppressor gene in gastric cancer (38), hepatocellular carcinoma (39), melanoma (19), leukemia (40), prostate (41) and breast cancer (42). Our previous study revealed that Lxn induced the apoptosis and inhibited the proliferation of CD133 + MIA PaCa-2 pancreatic cancer cells (20). ...
Recent studies suggest that latexin (Lxn) expression is involved in stem cell regulation and that it plays significant roles in tumor cell migration and invasion. The clinicopathological significance of Lxn expression and its possible correlation with CD133 expression in pancreatic ductal adenocarcinoma (PDAC) is currently unknown. In the present study, immunohistochemical analysis was performed to determine Lxn and CD133 expression in 43 PDAC patient samples and in 32 corresponding adjacent non-cancerous samples. The results were analyzed and compared with patient age, gender, tumor site and size, histological grade, clinical stage and overall mean survival time. Lxn expression was clearly decreased in the PDAC tissues compared with that in the adjacent non-cancerous tissues, while CD133 expression was increased. Low Lxn expression in the PDAC tissues was significantly correlated with tumor size (P=0.002), histological grade (P=0.000), metastasis (P=0.007) and clinical stage (P=0.018), but not with age (P=0.451), gender (P=0.395) or tumor site (P=0.697). Kaplan-Meier survival analysis revealed that low Lxn expression was significantly correlated with reduced overall survival time (P=0.000). Furthermore, Lxn expression was found to be inversely correlated with CD133 expression (r=-0.485, P=0.001). Furthermore, CD133-positive MIA PaCa-2 pancreatic tumor cells were sorted by magnetic-activated cell sorting (MACS), and those that overexpressed Lxn exhibited a significantly higher rate of apoptosis and lower proliferative activity. Our findings suggest that Lxn may function as a tumor suppressor that targets CD133-positive pancreatic cancer cells.
Vascular dementia (VaD) is the second leading type of dementia after Alzheimer's disease plaguing the aging population. Acupuncture has served as alternative and complementary medicine in the world for a long time and its use for VaD is based on a large body of preclinical and clinical researches. The mechanisms that underlie the protective effects of acupuncture are slowly beginning to be understood. Acupuncture influences multiple aspects of the pathological process of VaD. It improves cognitive function through protecting cerebral neurons from oxidative stress, apoptosis, and neuroinflammation, regulating glucose metabolism and neurotransmitters. Acupuncture may also improve synaptic plasticity and blood vessel function. It is likely that no single factor can explain the protection provided by acupuncture. This review provides a comprehensive overview of established and recent findings in animal-based researches aiming to elucidate the complex mechanisms of acupuncture on VaD.
