Omnibus proteome-wide association study identifies 43 risk genes for Alzheimer disease dementia.

Transcriptome-wide association study (TWAS) tools have been applied to conduct proteome-wide association studies (PWASs) by integrating proteomics data with genome-wide association study (GWAS) summary data. The genetic effects of PWAS-identified significant genes are potentially mediated through genetically regulated protein abundance, thus informing the underlying disease mechanisms better than GWAS loci. However, existing TWAS/PWAS tools are limited by considering only one statistical model. We propose an omnibus PWAS pipeline to account for multiple statistical models and demonstrate improved performance by simulation and application studies of Alzheimer disease (AD) dementia. We employ the Aggregated Cauchy Association Test to derive omnibus PWAS (PWAS-O) p values from PWAS p values obtained by three existing tools assuming complementary statistical models-TIGAR, PrediXcan, and FUSION. Our simulation studies demonstrated improved power, with well-calibrated type I error, for PWAS-O over all three individual tools. We applied PWAS-O to studying AD dementia with reference proteomic data profiled from dorsolateral prefrontal cortex of postmortem brains from individuals of European ancestry. We identified 43 risk genes, including 5 not identified by previous studies, which are interconnected through a protein-protein interaction network that includes the well-known AD risk genes TOMM40, APOC1, and APOC2. We also validated causal genetic effects mediated through the proteome for 27 (63%) PWAS-O risk genes, providing insights into the underlying biological mechanisms of AD dementia and highlighting promising targets for therapeutic development. PWAS-O can be easily applied to studying other complex diseases.

M2 macrophage exosome-derived Apoc1 promotes ferroptosis resistance in osteosarcoma by inhibiting ACSF2 deubiquitination.

Osteosarcoma (OS) is the most common primary malignant tumor of bone. The aim of this study was to investigate the regulatory mechanisms of M2 macrophage exosomes (M2-Exos) in ferroptosis in OS. A mouse model was established to investigate the in vivo role of M2-Exos. We investigated their effects on ferroptosis in OS using erastin, a ferroptosis activator, and deferoxamine mesylate, an iron chelator. In vitro, we investigated whether the Apoc1/Acyl-CoA Synthetase Family Member 2 (ACSF2) axis mediates these effects, using shApoc1 and shACSF2. The mechanisms whereby Apoc1 regulates ACSF2 were examined using cyclohexanone, a protein synthesis inhibitor, and MG132, a proteasomal inhibitor. M2-Exos reversed the inhibitory effects of erastin on OS cells, thus enhancing their viability, migration, invasion, proliferation, and reducing ferroptosis. Apoc1 was highly expressed in M2-Exos, and interfering with this expression reversed the effects of M2-Exos on OS cells. ACSF2 mediated the effects of M2-Exos-derived Apoc1. Apoc1 interacted with ACSF2, which, in turn, interacted with USP40. Apoc1 overexpression increased ACSF2 ubiquitination, promoting its degradation, whereas USP40 overexpression inhibited ACSF2 ubiquitination and promoted its expression. Apoc1 overexpression inhibited ACSF2 binding to USP40. M2-Exos-derived Apoc1 promoted ferroptosis resistance by inhibiting USP40 binding to ACSF2 and promoting ACSF2 ubiquitination and degradation, thus enhancing OS development.

Shexiang tongxin dropping pill alleviates myocardial injury induced by coronary microembolization by down-regulating APOC1 to inhibit STAT3 signaling pathway.

AIM: This study determines to validate the mechanism of Shexiang Tongxin dropping pill (STDP) in attenuating coronary microembolization (CME) induced myocardial injury. METHODS: CME rat models were established and underwent corresponding treating. Gene chip analysis was performed in rat myocardial tissues for GO and KEGG enrichment analysis. The differentially expressed genes were detected by qRT-PCR. H&E staining and ELISA were used for pathological analysis and detection of troponin (cTnI) and Creatine Kinase Isoenzyme (CK-MB). Lipopolysaccharide (LPS) treated primary cardiomyocytes were used to mimic inflammatory in vitro models. Cell viability and apoptosis of cardiomyocytes were determined by MTT and flow cytometry. The expressions of inflammatory cytokines, apoptotic proteins and proteins related to the STAT3 signal pathway were detected by western blot. APOC1 mRNA expression was detected by qRT-PCR. Immunofluorescence (IF) was used for subcellular localization of p-STAT3 and the binding of APOC1 with STAT3 was verified using Co-IP. RESULTS: STDP can attenuate myocardial injury in CME rat models, and lead to decreased expression of APOC1 and suppressed STAT3 signal pathway. In vitro models found STDP can suppress the cell viability and cell apoptosis of primary cardiomyocytes, in addition to suppressing the secretions of IL-6, IL-1ß and TNF-α, while the protective effect of STDP can be reversed by overexpression of APOC1. Co-IP found that APOC1 can bind STAT3 directly. APOC1 can increase p-STAT3 expression in the nucleus to activate the STAT3 signal pathway. CONCLUSIONS: STDP can suppress APOC1 and STAT3 signal pathway to inhibit inflammation and cell apoptosis of cardiomyocytes. APOC1 may be one of the key regulatory factors in CME-induced myocardial injury.

APOC1 reduced anti-PD-1 immunotherapy of nonsmall cell lung cancer via the transformation of M2 into M1 macrophages by ferroptosis by NRF2/HO-1.

The treatment strategy for nonsmall cell lung cancer (NSCLC) has always been a hot topic of concern, and its treatment strategies are also emerging. This experiment wants to know the effects of apolipoprotein C1 (APOC1) in immunotherapy of NSCLC. APOC1 mRNA and protein expression were upregulated in lung cancer tissue of patients with NSCLC. programmed cell death protein 1 (PD-1) mRNA expression was negatively correlated with PD-1 mRNA expression in patients. The survival rate of APOC1 high expression was lower than that of low expression in patients with NSCLC. APOC1 gene reduced the transformation of M2 into M1 macrophages (TMMM). APOC1 gene promoted cell growth, and the gene reduced ferroptosis of NSCLC. APOC1-induced nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (NRF2/HO-1) signaling pathway. Sh-APOC1 gene reduced cell growth in mice of NSCLC through the inhibition of NRF2/HO-1 signaling pathway. The inhibition of NRF2 reduced the TMMM by APOC1. The activation of NRF2 reduced the TMMM by si-APOC1. In conclusion, APOC1 reduced anti-PD-1 immunotherapy of NSCLC via the TMMM by ferroptosis by NRF2/HO-1, suggesting that targeting this mechanism of APOC1 may be a feasible strategy for anti-PD-1 immunotherapy for NSCLC.

ZNF460 mediates epithelial-mesenchymal transition to promote gastric cancer progression by transactivating APOC1 expression.

Zinc finger protein 460 (ZNF460) is closely related to the progression of a variety of human cancers. However, the biological role of ZNF460 in gastric cancer remains fully unrevealed. This study aimed to investigate the role and potential mechanism of ZNF460 in gastric cancer. In this study, we discovered a significant up-regulation of ZNF460 in gastric cancer and that ZNF460 expression correlated with tumor grade, lymph node metastasis, and H. pylon infection in gastric cancer through UALCAN database. Functionally, Diminished ZNF460 expression inhibited gastric cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro and suppressed tumor growth in vivo. Mechanistically, ZNF460 combined with apolipoprotein C1 (APOC1) promoter to facilitate APOC1 transcription, and accelerated EMT, thereby promoting the progression of gastric cancer. In conclusion, our study confirmed that ZNF460 promotes gastric cancer progression, which might serve as a novel target for gastric cancer treatment.

ApoC1 promotes glioma metastasis by enhancing epithelial-mesenchymal transition and activating the STAT3 pathway.

OBJECTIVE: One of the apolipoprotein's members, apolipoprotein C1 (ApoC1), is critical in the metabolism of both very-low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) cholesterols. Multiple studies have recently revealed that ApoC1 may be a viable therapeutic target in solid malignancies. However, the motor protein ApoC1's specific role and mechanism in glioblastoma remain unknown. METHODS: In this study, the Cancer Genome Atlas (TCGA) database was used to look at the level of ApoC1 in glioma tissues and normal tissues, as well as how it related to the prognosis of glioma. Glioma cell lines (U87 and U251) were subjected to a wide range of experiments to determine the involvement of ApoC1 in cell proliferation, migration, and invasion. RESULTS: Cell proliferation, migration, and invasion decreased in glioma cell lines when ApoC1 was silenced. Furthermore, ApoC1 increased glioma cell metastasis through the epithelial-mesenchymal transition (EMT), while ApoC1 deletion reduced this impact. Additionally, APOC1 influenced the evolution of glioma by affecting the STAT3 pathway. In addition, APOC1 knockdown reduced the activation of the phosphorylated-total signal transducer and activator of transcription (STAT3) in the glioma cells. ApoC1-induced glioma cell metastatic ability was prevented by niclosamide (a STAT3 inhibitor). CONCLUSIONS: These results uncover that ApoC1 may serve as a biomarker or therapeutic target for future fundamental study or clinical treatment of glioma.

Role of apolipoprotein C1 in lipoprotein metabolism, atherosclerosis and diabetes: a systematic review.

Apolipoprotein C1 (apoC1) is a small size apolipoprotein whose exact role is not totally clarified but which seems to modulate significantly the metabolism of lipoproteins. ApoC1 is involved in the metabolism of triglyceride-rich lipoproteins by inhibiting the binding of very low density lipoproteins (VLDL) to VLDL-receptor (VLDL-R), to low density lipoprotein receptor (LDL-R) and to LDL receptor related protein (LRP), by reducing the activity of lipoprotein lipase (LPL) and by stimulating VLDL production, all these effects leading to increase plasma triglycerides. ApoC1 takes also part in the metabolism of high density lipoproteins (HDL) by inhibiting Cholesterol Ester Transfer Protein (CETP). The functionality of apoC1 on CETP activity is impaired in diabetes that might account, at least in part, for the increased plasma CETP activity observed in patients with diabetes. Its different effects on lipoprotein metabolism with a possible role in the modulation of inflammation makes the net impact of apoC1 on cardiometabolic risk difficult to figure out and apoC1 might be considered as pro-atherogenic or anti-atherogenic depending on the overall metabolic context. Making the link between total plasma apoC1 levels and the risk of cardio-metabolic diseases is difficult due to the high exchangeability of this small protein whose biological effects might depend essentially on its association with VLDL or HDL. The role of apoC1 in humans is not entirely elucidated and further studies are needed to determine its precise role in lipid metabolism and its possible pleiotropic effects on inflammation and vascular wall biology. In this review, we will present data on apoC1 structure and distribution among lipoproteins, on the effects of apoC1 on VLDL metabolism and HDL metabolism and we will discuss the possible links between apoC1, atherosclerosis and diabetes.

Systematic pan-cancer analysis identifies APOC1 as an immunological biomarker which regulates macrophage polarization and promotes tumor metastasis.

Apolipoprotein C1 (APOC1) has been found to play an essential part in proliferation and metastasis of numerous cancers, but related mechanism has not been elucidated, especially its function and role in tumor immunity. Through systematic pan-cancer analysis, we identified that APOC1 was closely associated with the infiltration of various immune cells in multiple cancers. Besides, APOC1 was significantly co-expressed with the immune checkpoints, major histocompatibility complex (MHC) molecules, chemokines and other immune-related genes. Furthermore, single-cell sequencing analysis suggested that the vast majority of APOC1 was expressed in macrophages or tumor-associated macrophages (TAMs). Additionally, the expression of APOC1 was significantly related to the prognosis of different cancers. Since APOC1 was most significantly abnormally expressed in renal cell cancer (RCC), subsequent experiments were carried out in RCC to explore the role of APOC1 in tumor immunity. The expression of APOC1 was significantly elevated in the tumor and serum of RCC patients. Besides, APOC1 was mainly expressed in the macrophage and it was closely related to the immune cell infiltration of RCC. Co-culture with RCC cells could induce the generation of TAMs with M2 phenotype which be blocked by silencing APOC1. The expression of APOC1 was elevated in the M2 or TAMs and APOC1 promoted M2 polarization of macrophages through interacting with CD163 and CD206. Furthermore, macrophages overexpressing APOC1 promoted the metastasis of RCC cells via secreting CCL5. Together, these data indicate that APOC1 is an immunological biomarker which regulates macrophage polarization and promotes tumor metastasis.

Apolipoprotein C1 promotes glioblastoma tumorigenesis by reducing KEAP1/NRF2 and CBS-regulated ferroptosis.

Glioblastoma (GBM), a malignant brain tumor, is a world-wide health problem because of its poor prognosis and high rates of recurrence and mortality. Apolipoprotein C1 (APOC1) is the smallest of apolipoproteins, implicated in many diseases. Recent studies have shown that APOC1 promotes tumorigenesis and development of several types of cancer. In this study we investigated the role of APOC1 in GBM tumorigenesis. Using in silico assays we showed that APOC1 was highly expressed in GBM tissues and its expression was closely related to GBM progression. We showed that APOC1 protein expression was markedly increased in four GBM cell lines (U251, U138, A172 and U87) compared to the normal brain glia cell lines (HEB, HA1800). In U251 cells, overexpression of APOC1 promoted cell proliferation, migration, invasion and colony information, which was reversed by APOC1 knockdown. APOC1 knockdown also markedly inhibited the growth of GBM xenografts in the ventricle of nude mice. We further demonstrated that APOC1 reduced ferroptosis by inhibiting KEAP1, promoting nuclear translocation of NRF2 and increasing expression of HO-1 and NQO1 in GBM cells. APOC1 also induced ferroptosis resistance by increasing cystathionine beta-synthase (CBS) expression, which promoted trans-sulfuration and increased GSH synthesis, ultimately leading to an increase in glutathione peroxidase-4 (GPX4). Thus, APOC1 plays a key role in GBM tumorigenesis, conferring resistance to ferroptosis, and may be a promising therapeutic target for GBM.

Construction of a novel mRNA-miRNA-lncRNA network and identification of potential regulatory axis associated with prognosis in colorectal cancer liver metastases.

Liver metastasis is a leading cause of death in patients with colorectal cancer (CRC). Increasing evidence demonstrates that competing endogenous RNA (ceRNA) networks play important roles in malignant cancers. The purpose of this study was to identify molecular markers and build a ceRNA network as a significant predictor of colorectal liver metastases (CRLM). By integrated bioinformatics analysis, we found that apolipoprotein C1 (APOC1) was upregulated in CRLM and associated with prognosis in patients with CRC and thereby established an APOC1-dependent ceRNA network. By survival analysis, expression analysis, and correlation analysis of each element in the ceRNA network, we identified that ZEB1-AS1, miR-335-5p and APOC1 regulated each other. We further experimentally confirmed that ZEB1-AS1 promoted a CRC progression via regulating the expression of miR-335-5p that controlled the expression of APOC1. Our findings indicate that the ZEB1-AS1-miR-335-5p-APOC1 ceRNA regulatory network is significantly valuable for better prognosis of patients with CRC and as a new therapeutic target for the treatment of CRLM.

Overexpression of Apolipoprotein C1 (APOC1) in Clear Cell Renal Cell Carcinoma and Its Prognostic Significance.

BACKGROUND The aims of this study included 3 aspects: 1) assessing the expression of Apolipoprotein C1 (APOC1) in clear cell renal cell carcinoma (ccRCC) and normal groups; 2) evaluating the prognostic significance of APOC1 expression in the overall survival (OS) of ccRCC patients; and 3) exploring APOC1-related signaling pathways. MATERIAL AND METHODS The APOC1 expression value and clinical data of ccRCC patients were obtained from the cBioPortal database. We then evaluated the association of APOC1 expression with clinical characteristics of ccRCC patients. We also assessed the correlation between APOC1 expression and clinical outcome using Kaplan-Meier method. Our work then verified the independent prognostic factors of ccRCC by Cox regression analysis. Finally, the potential role of genes co-expressed with APOC1 was revealed via functional enrichment analysis. RESULTS Bioinformatic data revealed that APOC1 was expressed at higher levels in ccRCC tissue than in the normal group (all P<0.05). The high expression of APOC1 was associated with unfavorable prognosis of female patients (P<0.01), but not of male patients. APOC1 high expression also shortened the survival time of ccRCC patients age ≥60 years old (P<0.05). Cox regression analysis further indicated that APOC1 expression was an independent prognostic factor for OS of ccRCC patients. Additionally, we found that APOC1 expression was significantly associated with sex, grade, clinical stage, and T stage. Finally, enrichment analysis suggested that APOC1-associated pathways were involved in tumor growth and metastasis. CONCLUSIONS The current study indicated that APOC1 was highly expressed in ccRCC and was significantly associated with key clinical features. APOC1 appears to be an independent prognostic factor in patients with ccRCC. Importantly, APOC1 might be a potential therapeutic target for ccRCC via regulating pathways involved in cell growth and metastasis.

Bayesian Genome-wide TWAS Method to Leverage both cis- and trans-eQTL Information through Summary Statistics.

Transcriptome-wide association studies (TWASs) have been widely used to integrate gene expression and genetic data for studying complex traits. Due to the computational burden, existing TWAS methods do not assess distant trans-expression quantitative trait loci (eQTL) that are known to explain important expression variation for most genes. We propose a Bayesian genome-wide TWAS (BGW-TWAS) method that leverages both cis- and trans-eQTL information for a TWAS. Our BGW-TWAS method is based on Bayesian variable selection regression, which not only accounts for cis- and trans-eQTL of the target gene but also enables efficient computation by using summary statistics from standard eQTL analyses. Our simulation studies illustrated that BGW-TWASs achieved higher power compared to existing TWAS methods that do not assess trans-eQTL information. We further applied BWG-TWAS to individual-level GWAS data (N = ∼3.3K), which identified significant associations between the genetically regulated gene expression (GReX) of ZC3H12B and Alzheimer dementia (AD) (p value = 5.42 × 10-13), neurofibrillary tangle density (p value = 1.89 × 10-6), and global measure of AD pathology (p value = 9.59 × 10-7). These associations for ZC3H12B were completely driven by trans-eQTL. Additionally, the GReX of KCTD12 was found to be significantly associated with ß-amyloid (p value = 3.44 × 10-8) which was driven by both cis- and trans-eQTL. Four of the top driven trans-eQTL of ZC3H12B are located within APOC1, a known major risk gene of AD and blood lipids. Additionally, by applying BGW-TWAS with summary-level GWAS data of AD (N = ∼54K), we identified 13 significant genes including known GWAS risk genes HLA-DRB1 and APOC1, as well as ZC3H12B.

ApoC1 promotes the metastasis of clear cell renal cell carcinoma via activation of STAT3.

Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer and frequently diagnosed at an advanced stage. It is prone to develop unpredictable metastases even with proper treatment. Antiangiogenic therapy is the most effective medical treatment for metastatic ccRCC. Thus, exploration of novel approaches to inhibit angiogenesis and metastasis may potentially lead to a better therapeutic option for ccRCC. Among all the types of cancer, renal cancer samples exhibited the maximum upregulation of ApoC1 as referred to in the Oncomine database. The expression of ApoC1 was increased accompanied by ccRCC progression. A high level of ApoC1 was closely related to poor survival time in ccRCC patients. Furthermore, ApoC1 was over-expressed in the highly invasive ccRCC cells as compared to that in the low-invasive ccRCC cells. Besides, ApoC1 promoted metastasis of ccRCC cells via EMT pathway, whereas depletion of ApoC1 alleviated these effects. ApoC1 as a novel pro-metastatic factor facilitates the activation of STAT3 and enhances the metastasis of ccRCC cells. Meanwhile, ApoC1 in the exosomes were transferred from the ccRCC cells to the vascular endothelial cells and promoted metastasis of the ccRCC cells via activating STAT3. Finally, the metastatic potential of the ccRCC cells driven by ApoC1 was suppressed by DPP-4 inhibition. Our study not only identifies a novel ApoC1-STAT3 pathway in ccRCC metastasis but also provides direction for the exploration of novel strategies to predict and treat metastatic ccRCC in the future.

Apolipoprotein C1: Its Pleiotropic Effects in Lipid Metabolism and Beyond.

Apolipoprotein C1 (apoC1), the smallest of all apolipoproteins, participates in lipid transport and metabolism. In humans, APOC1 gene is in linkage disequilibrium with APOE gene on chromosome 19, a proximity that spurred its investigation. Apolipoprotein C1 associates with triglyceride-rich lipoproteins and HDL and exchanges between lipoprotein classes. These interactions occur via amphipathic helix motifs, as demonstrated by biophysical studies on the wild-type polypeptide and representative mutants. Apolipoprotein C1 acts on lipoprotein receptors by inhibiting binding mediated by apolipoprotein E, and modulating the activities of several enzymes. Thus, apoC1 downregulates lipoprotein lipase, hepatic lipase, phospholipase A2, cholesterylester transfer protein, and activates lecithin-cholesterol acyl transferase. By controlling the plasma levels of lipids, apoC1 relates directly to cardiovascular physiology, but its activity extends beyond, to inflammation and immunity, sepsis, diabetes, cancer, viral infectivity, and-not last-to cognition. Such correlations were established based on studies using transgenic mice, associated in the recent years with GWAS, transcriptomic and proteomic analyses. The presence of a duplicate gene, pseudogene APOC1P, stimulated evolutionary studies and more recently, the regulatory properties of the corresponding non-coding RNA are steadily emerging. Nonetheless, this prototypical apolipoprotein is still underexplored and deserves further research for understanding its physiology and exploiting its therapeutic potential.

Assessment of ApoC1, LuzP6, C12orf75 and OCC-1 in cystic glioblastoma using MALDI-TOF mass spectrometry, immunohistochemistry and qRT-PCR.

Mass spectrometric analysis of glioblastoma cyst fluids has disclosed a protein peak with m/z 6424-6433. Among the proteins, potentially generating this peak are ApoC1 and LuzP6. To further elucidate protein expression of glioblastoma cells, we analyzed MALDI-TOF results of cyst fluid, performed immunohistochemistry and mRNA analysis. MALDI-TOF protein extraction from 24 glioblastoma cyst fluids was performed with a weak cation exchange. 50 glioblastoma samples were stained with two custom-made antibodies against LuzP6 and commercial antibodies against ApoC1, C12orf75 and OCC-1 and analyzed. For mRNA detection, 16 tissue samples were stored in RNAlater, extracted using the miRNeasy kit and reversely transcribed. For 12 patients, synopsis of results from all three examinations was possible. MALDI-TOF confirmed the peak at 6433 Da in 75% of samples. Immunohistochemically, LuzP6 was detected in 92% (LuzP61-29) and 96% (LuzP630-58) of samples and ApoC1 in 66%. Mean mRNA levels were highest for ApoC1, followed by LuzP6. No correlation between mRNA expression, immunohistochemical staining and intensity of the MALDI-TOF peaks was found. An unequivocal identification of one protein as the source for the 6433 peak is not possible, but our results point to ApoC1 and LuzP6 as the underlying proteins.

Characterization of apolipoprotein C1 in hepatitis C virus infection and morphogenesis.

Previous studies have shown that apolipoprotein C1 (apoC1)-specific antibodies precipitated hepatitis C virus (HCV) and neutralized HCV infectivity, suggesting that apoC1 is a HCV component. However, the importance of apoC1 in the HCV life cycle has not been experimentally examined. In the present study, we sought to determine the role of apoC1 in the HCV infection and morphogenesis by knocking out the apoC1 gene using the CRISPR/Cas9 system. Strikingly, apoC1 gene knockout markedly enhanced apoE expression. As a result, apoC1 gene knockout per se didn't significantly affect HCV infection or morphogenesis, probably ascribing to its redundant functions with apoE. However, knockout of apoC1 gene potentiated the impairment of HCV infection and/or morphogenesis by apoE-specific small interfering RNAs. Additionally, a recombinant apoC1 protein efficiently blocked HCV infection. Collectively, these findings suggest that apoC1 and apoE have redundant functions in the HCV infection and morphogenesis.

ANP32A regulates histone H3 acetylation and promotes leukemogenesis.

Deregulation of key regulators of histone modification is important in the initiation and progression of human leukemia. Acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) participates in histone acetylation and its role in acute myeloid leukemia remains unclear. Here we observed significant upregulation of ANP32A in primary AML cells, which was essential for AML cell proliferation, survival, and colony formation. Integrative analysis of the genome-wide histone H3 acetylation and gene expression demonstrated that ANP32A deficiency reduced histone H3 acetylation, in accordance with changes in gene expression. Notably, significant histone H3 acetylation enrichment was associated with mRNA changes in lipid-related genes, including APOC1, PCSK9, P2RX1, and LPPR3. Indeed, over-expression of APOC1 partially compensated the proliferation-defect phenotype in ANP32A deficient AML cells while APOC1 knockdown alone mimicked the effect of ANP32A deficiency. Collectively, our data indicate that ANP32A is a novel regulator of histone H3 acetylation and promotes leukemogenesis.

Truncated apolipoprotein C-I induces apoptosis in neuroblastoma by activating caspases in the extrinsic and intrinsic pathways.

Truncated apolipoprotein C-I is a post-translationally modified protein characterized by the loss of threonine and proline residues from the N-terminus of the mature peptide. The truncated peptide is involved in many physiological and pathological processes in vivo and is related to malignant diseases. The aim of the present study was to assess the effects of the truncated peptide on tumorigenesis in neuroblastoma. The truncated peptide was chemically synthesized, and a signal peptide was used as the negative control. The results of the CCK-8 assay showed that the truncated peptide selectively inhibited cell proliferation compared with the signal peptide, and inhibited migration and invasion as determined by wound healing and Transwell assays. Flow cytometry analysis demonstrated that the truncated peptide induced apoptosis and cell cycle arrest in the S phase. Bax, Bim, and tBid upregulation, and Bcl­2 and Bcl­xl downregulation were associated with permeabilization of the mitochondrial membrane, as detected by the JC-1 assay and the release of cytochrome c and apoptosis. Activation of caspase­8 was associated with activation of cell death receptors such as the tumor necrosis factor receptor. PARP cleavage indicated apoptosis, and DNA damage was observed in the TUNEL assay. The results showed that the truncated apoC-I induced apoptosis in neuroblastoma by the extrinsic and intrinsic pathways. The anticancer effects were confirmed in vivo in a xenograft mouse model. In conclusion, the endogenous protein apoC-I may be a new promising therapeutic target to suppress tumor growth.

Apolipoprotein C-I mediates Wnt/Ctnnb1 signaling during neural border formation and is required for neural crest development.

In vertebrates, the neural crest and placodes originate in the neural border, which is located between the neural plate and epidermal ectoderm. The neural crest and placodes give rise to a vast array of cell types. Formation of neural crest is a multi-step process, in which Wnt signals are used reiteratively, but it is currently not clear if a Wnt signal is required for neural border formation. Here, we have identified apolipoprotein C-I (apoc1) in a screen for genes regulated by Wnt/Ctnnb1 signaling in late blastula stage Xenopus tropicalis embryos. We show that Xenopus laevis apoc1 encodes a small, secreted protein, and is induced by Wnt/Ctnnb1 signaling. Depletion of Apoc1 protein results in a neural border formation defect and loss of border fates, including neural crest cells. However, unlike another Wnt/Ctnnb1 target, gbx2.2, apoc1 is not required for patterning of the neural border. We further show that gbx2.2 and apoc1 are independently regulated by Wnt signaling. Our results thus suggest that Wnt regulates border formation and patterning by distinct genetic mechanisms.

Apolipoprotein C-I plays a role in the pathogenesis of glomerulosclerosis.

Diabetic nephropathy is the leading cause of end-stage renal disease. Diabetic patients have increased plasma concentrations of apolipoprotein C-I (apoCI), and meta-analyses found that a polymorphism in APOC1 is associated with an increased risk of developing nephropathy. To investigate whether overexpressing apoCI contributes to the development of kidney damage, we studied renal tissue and peritoneal macrophages from APOC1 transgenic (APOC1-tg) mice and wild-type littermates. In addition, we examined renal material from autopsied diabetic patients with and without diabetic nephropathy and from autopsied control subjects. We found that APOC1-tg mice, but not wild-type mice, develop albuminuria, renal dysfunction, and glomerulosclerosis with increased numbers of glomerular M1 macrophages. Moreover, compared to wild-type macrophages, stimulated macrophages isolated from APOC1-tg mice have increased cytokine expression, including TNF-alpha and TGF-beta, both of which are known to increase the production of extracellular matrix proteins in mesangial cells. These results suggest that APOC1 expression induces glomerulosclerosis, potentially by increasing the cytokine response in macrophages. Furthermore, we detected apoCI in the kidneys of diabetic patients, but not in control kidneys. Moreover, patients with diabetic nephropathy have significantly more apoCI present in glomeruli compared to diabetic patients without nephropathy, suggesting that apoCI could be involved in the development of diabetic nephropathy. ApoCI co-localized with macrophages. Therefore, apoCI is a promising new therapeutic target for patients at risk of developing nephropathy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.