Advances on research of structure and function of puromycin sensitive aminopeptidase / 药学学报

Puromycin-sensitive aminopeptidase (PSAP) belongs to the M1 family of aminopeptidases, characterized by the N-terminal substrate binding sequence GAMEN, the enzyme activity center HEXXH(X)18E motif, and the C-terminal ERAP-1-like superfamily structural domain. Encoded by the gene NPEPPS located at 17q21.32, PSAP consists of 919 amino acids and is widely distributed throughout the human body, with the highest expression in the brain, followed by the heart and skeletal muscle. It is also found in the liver, renal tubular epithelium, small intestine, large intestine epithelium, and gastric epithelial cells. PSAP primarily relies on its aminopeptidase hydrolytic activity to remove toxic protein aggregates such as Tau, poly Q, and Cu, Zn-superoxide dismutase 1, making it an important factor in the development of diseases such as Alzheimer's disease, Huntington's chorea, and tumors. Existing PSAP inhibitors include bestatin, amastatin, leuhistin, actinonin, and purinomycin, some of which are already available or in clinical trials. This review provides an overview of the structural and biological functions of M1 family aminopeptidases, with a focus on PSAP, to facilitate further research and targeted drug development.

Novel Class of Central Renin Angiotensin Aldosterone System Inhibitor: Firibastat

Hypertension is one of the most important risk factors for the development of ischemic heart diseases, stroke, disability, vascular demen?a, heart failure, renal dysfunc?on, re?nopathy, and premature death. Despite the use of two or more blood pressure lowering medica?ons, a considerable propor?on of pa?ents show poor control. Current an?hypertensive medica?ons show the limita?on of use and effect in obese popula?on, certain races like black popula?on and also in renal impairment. Thus, there is an impending need to develop novel classes of an?hypertensive agents ac?ng on new targets with diversified mechanisms of ac?on to more effec?vely manage raised blood pressure. With the introduc?on of the recent concept of overac?ve brain renin angiotensin system in cardiovascular disorders, a?empts have been made to iden?fy a molecule with the poten?al of inhibi?ng aminopep?dases involved in the forma?on of Angiotensin III. A novel aminopep?dase A inhibitor, also a prodrug Firibastat is currently undergoing development in Phase III clinical trials for hypertension as well as chronic heart failure. We hereby, provide an updated summary of evidence generated so far with Firibastat and also a glimpse into the therapeu?c poten?al of this novel candidate extending beyond the spectrum of essen?al hypertension

An analytical review of vector- and pathogen-based transmission-blocking vaccine for malaria control

Malaria is a vector borne disease, considered to be one of the most serious public health problems. The present review focused on the blocking of parasite development in mosquito vectors; one broad strategy for achieving this is Transmission Blocking Vaccines (TBV). The TBVs usually rely on immunization of vertebrate hosts with molecules derived from the vector or pathogen to reduce pathogen transmission from infected to uninfected hosts. Most of the studies on the TBVs are based on the antibodies targeted against the surface antigens of sexual stages of malaria parasite, but it is meagre to develop mosquito-based vaccine in this regard. Vector-based TBVs include surface proteins that are expressed by the mosquito midgut digestive enzymes which are induced upon blood-feeding, and receptors expressed on the epithelial line of the tissue. Many proteins are reported that can act as candidates for transmission-blocking vaccines. This review aims to summarize the vector midgut-based proteins identified till date, that can block the development and maturity of sexual stages of the parasite within mosquitoes as targets for transmission-blocking vaccine development. The TBVs intervention can block transmission of different malaria parasite species in various species of mosquitoes with future application perspective worldwide.

Molecular cloning and characterization of a novel aspartyl aminopeptidase from Trichinella spiralis

@#Trichinellosis is an important zoonotic parasitic disease worldwide and is principally caused by ingesting animal meat containing Trichinella infective larvae. Aspartyl aminopeptidase is an intracytoplasmic metalloproteinase that specifically hydrolyzes the N-terminus of polypeptides free of acidic amino acids (aspartic acid and glutamate), and plays an important role in the metabolism, growth and development of organisms. In this study, a novel T. spiralis aspartyl aminopeptidase (TsAAP) was cloned and expressed, and its biological properties and roles in worm growth and development were investigated. The results revealed that TsAAP transcription and expression in diverse T. spiralis stages were detected by RT-PCR and Western blotting, and primarily localized at cuticle, stichosome and intrauterine embryos of this nematode by immunofluorescence test. rTsAAP has the enzymatic activity of native AAP to hydrolyze the substrate H-Glu-pNA. There was a specific binding between rTsAAP and murine erythrocyte, and the binding site was localized in erythrocyte membrane proteins. Silencing of TsAAP gene by specific dsRNA significantly reduced the TsAAP expression, enzymatic activity, intestinal worm burdens and female fecundity. The results demonstrated that TsAAP participates in the growth, development and fecundity of T. spiralis and it might be a potential target molecule for anti-Trichinella vaccines.

Genome-wide analysis of various paralogs of aminopeptidase N (APN) gene in Anopheles gambiae (Diptera: Culicidae)

Malaria continues to be a life threatening infectious disease throughout the tropical region of the world.aminopeptidase N1 (APN1) is one of the best choices for developing new Malaria Transmission-blockingvaccines. In this study an attempt has been made to overview genome-wide identification of APN genes inAnopheles gambiae. A total of eighteen A. gambiae APN sequences were found that contain conserved HEXXHand GAMEN signature sequences, indicate that large numbers of APN isomers present in mosquitoes. MultipleAPN paralogs exist as a gene cluster may propose that huge synthesis of APNs is required for rapid digestion ofpeptides over a brief period. Gene structure study shows high sequence variations among them. Protein–proteininteractions show that APN1 is highly connected protein, supporting their role as hub with other five types ofAPNs involved in glutathione metabolism, act as hub protein and disruption of one of these proteins may affectthe whole pathway

Blocking of methionine aminopeptidase-2 by TNP-470 induces apoptosis and increases chemosensitivity of cholangiocarcinoma

Context: Resistance of cancer cells to chemotherapeutic drugs is a major pitfall of the failure of chemotherapy treatment for cholangiocarcinoma (CCA). A new therapeutic strategy that can improve treatment efficacy is mandatory for CCA patients. Our previous findings demonstrated the overexpression of methionine aminopeptidase-2 (MetAP2) in CCA patients. In addition, supplementation of TNP-470, a MetAP2 inhibitor, significantly inhibited the growth and metastatic activities of CCA cell lines. However, the molecular mechanism of antitumor activity of TNP-470 and the synergistic antitumor activity of TNP-470 combined with chemotherapeutic drugs are still unknown. Aims: The aim of this study is to evaluate the molecular mechanism of anticancer activity and the potential use of TNP-470 as a chemosensitizing agent in CCA cell lines. Materials and Methods: Cell cycle and apoptosis of CCA cell lines were evaluated using flow cytometry with propidium iodide staining. Expression of apoptosis regulatory proteins was measured by Western blotting. The chemosensitizing effect of TNP-470 was determined using combination index. Results: TNP-470 inhibited the growth of CCA cells via induction of apoptosis through activation of the p38-phosphorylation and up- and down-regulation of Bax and Bcl-xL, respectively. Furthermore, TNP-470 significantly enhanced the antitumor activity of 5-fluorouracil, cisplatin, doxorubicin, and gemcitabine. Conclusions: The present results show that TNP-470 could be a potential therapeutic or adjuvant agent for CCA

Application of cholyglycine in common hepatic diseases / 中国医师杂志

Objective To observe the changes of glycocholic acid (CG) and evaluate the diagnostic value of CG combined with total bile acid (TBA) and leucine aminopeptidase (LAP) in various liver diseases.Methods From October 2016 to March 2017,210 serum samples of healthy people,asymptomatic hepatitis B virus (HBV) infected,hepatitis,biliary obstruction,hepatocirrhosis and primary hepatocellular carcinoma patients were collected.CG and LAP were detected by corresponding kits,and liver function,coagulation function and other indicators of patients were collected and analyzed statistically.Results The serum level of CG were elevated in the 4 liver disease groups and differed statistically from the normal group or the asymptomatic HBV infected group.CG level was positively correlated with LAP (r =0.380,P ＜ 0.01).In liver function indexes,CG was correlated with total bilirubin (TB),direct bilirubin (DB),TBA and alkaline phosphatase (AKP).At the same time,CG was correlated with fibrinogen(Fib),thrombin time(TT).LAP and TBA were introduced into regression equation Y =-0.835 + 0.157X1 +0.312X2 (X1:LAP,X2:TBA,R2 =0.685) as final variables in multivariate linear regression to analyse the influencing factors of CG.Receiver operator characteristic (ROC) curve analysis showed that CG had the strongest ability to diagnose liver diseases in combination with LAP.Conclusions The change of CG level is of great significance in all kinds of liver diseases.The combination of LAP has the strongest ability to diagnose liver diseases.

Interaction of Bombyx mori aminopeptidase N and cadherin-like protein with Bacillus thuringiensis Cry1Ac toxin / 生物工程学报

Bacillus thuringiensis (Bt) produces Cry toxins that are widely used as insecticides in agriculture and forestry. Receptors are important to elucidate the mode of interaction with Cry toxins and toxicity in lepidopteran insects. Here, we purified the Cry toxin from Bt and identified this toxin by flight mass spectrometry as Cry1Ac, and then recombinantly expressed aminopeptidase N (BmAPN6) and repeat domains of cadherin-like protein (CaLP) of B. mori. Using co-immunoprecipitation (co-IP), Far-Western blotting, and enzyme-linked immunosorbent assays (ELISAs), we identified the interaction between Cry1Ac and BmAPN6. Furthermore, analysis of the cytotoxic activity of Cry1Ac toxin in Sf9 cells showed that BmAPN6 directly interacted with Cry1Ac toxin to induce morphological aberrations and cell lysis. We also used co-IP, Far-Western blotting and ELISAs to analyze the interactions of Cry1Ac with three binding sites corresponding to cadherin repeat (CR) 7 CR11, and CR12 of CaLP. Notably, the three repeat domains were essential Cry1Ac binding components in CaLP. These results indicated that BmAPN6 and CaLP served as a functional receptor involved in Bt Cry1Ac toxin pathogenicity. These findings represent an important advancement in our understanding of the mechanisms of Cry1Ac toxicity and provide promising candidate targets for gene editing to enhance resistance to pathogens and increase the economic value of B. mori.

Characterization of a recombinant aminopeptidase Lmo1711 from Listeria monocytogenes / 生物工程学报

We aimed to obtain the recombinant aminopeptidase encoded by Listeria monocytogenes (L. monocytogenes) gene lmo1711, and characterized the enzyme. First, the amino acid sequences of Lmo1711 from L. monocytogenes EGD-e and its homologues in other microbial species were aligned and the putative active sites were analyzed. The putative model of Lmo1711 was constructed through the SWISS-MODEL Workspace. Then, the plasmid pET30a-Lmo1711 was constructed and transformed into E. coli for expression of the recombinant Lmo1711. The his-tagged soluble protein was purified using the nickel-chelated affinity column chromatography. With the amino acid-p-nitroaniline as the substrate, Lmo1711 hydrolyzed the substrate to free p-nitroaniline monomers, whose absorbance measured at 405 nm reflected the aminopeptidase activity. The specificity of Lmo1711 to substrates was then examined by changing various substrates, and the effect of metal ions on the catalytic efficiency of this enzyme was further determined. Based on the bioinformatics data, Lmo1711 is a member of the M29 family aminopeptidases, containing a highly conserved catalytic motif (Glu-Glu-His-Tyr-His-Asp) with typical structure arrangements of the peptidase family. The recombinant Lmo1711 with a size of about 49.3 kDa exhibited aminopeptidase activity and had a selectivity to the substrates, with the highest degree of affinity for leucine-p-nitroaniline. Interestingly, the enzymatic activity of Lmo1711 can be activated by Cd²⁺, Zn²⁺, and is strongly stimulated by Co²⁺. We here, for the first time demonstrate that L. monocytogenes lmo1711 encodes a cobalt-activated aminopeptidase of M29 family.

Relationship between left atrial diameter with serum glutamyl transpeptidase level in patients with essential hypertension / 中国基层医药

Objective To analyze the relationship and clinical significance of serum glutamyl transpeptidase (GGT) level with left atrial diameter.Methods All the newly diagnosed 200 essential hypertension patients with complete data were selected.They were divided into normal left atrial group and enlarged left atrial group based on the size of left atrial diameter.Fasting blood glucose,serum lipid,routine laboratory tests,hepatic and renal function and blood pressure were measured by routine methods,and compared between the two groups.Results The GGT level in the enlarged left atrial group was lower than that in the normal left atrial group among essential hypertension patients [(21.56 ± 11.95) U/L vs.(37.28 ± 12.64) U/L] (P =0.001).Spearman correlation showed that GGT level was negatively associated with left atrial diameter(r =-0.413,P =0.002).Multiple linear regression analysis showed that the serum GGT was also negatively correlated with left atrial diameter(β =-0.394,95 ％ CI:-0.131,-0.692;P =0.005).Conclusion Our study demonstrated that the level of GGT was negatively correlated with left atrial diameter among essential hypertension patients,and monitoring the changes of serum liver enzyme may have significant effect on the early detection of enlarged left atrial diameter.

Application of leucine aminopeptidase in biliary obstructive diseases / 中国医师杂志

Objective To investigate the role of leucine aminopeptidase in biliary obstructive dis-ease, and to evaluate the value of leucine aminopeptidase and its combination with alkaline phosphatase (AKP), glutamine transferase and 5′-nucleotidase (5′-NT) in diagnosis and treatment of bile duct obstruc-tion. Methods A total of 181 cases were collected, who were diagnosed as healthy, asymptomatic HBV carriers and patients with hepatitis, biliary obstruction, liver cirrhosis and primary liver cancer samples at Xiangya Hospital of Central South University from October 2016 to March 2017. The leucine aminopeptidase (LAP), AKP, gamma glutamyl transpeptidase (GGT) and 5′-NT were detected with the corresponding kits, and analyzed with different statistical methods. Results The highest level of LAP was in patients with biliary obstruction, compared to other groups, and the differences were statistically significant (P<0. 05). In biliary obstruction group, LAP and AKP, GGT and 5′-NT were correlated ( r=0. 690, P<0. 01; r=0. 864, P<0. 01;r=0. 735, P<0. 01). Receiver operating characteristic (ROC), curve area (AUC) of LAP, 5′-NT, GGT and AKP in the diagnosis of biliary obstruction were 0. 945 and 0. 898, 0. 942 and 0. 916;the AUC of LAP combined with 5′-NT, GGT and AKP was 0. 966;and the AUC of LAP combined with 5′-NT was 0. 968. Conclusions LAP can be used as a preliminary index of differential diagnosis of biliary obstructive disease, and its diagnostic value could be improved when combined with 5-NT.

The relationship of expressions of ERP57 and ERAP1 and clinicopathological features in patients with breast cancer / 天津医药

Objective To observe the expressions of endoplasmic reticulum chaperone (ERP57) and endoplasmic reticulum aminopep-tidase (ERAP1) in female breast cancer, and to explore their relationship with clinical pathological parameters of breast cancer. Methods A total of 124 samples of breast cancer and 24 samples of breast fibroadenoma were collected in the Affiliated Tumor Hospital of Xinjiang Medical University from January 2011 to December 2015. The expressions of ERP57 and ERAP1 were detected by immunohistochemistry SP method. The patients were divided into two groups according to the clinicopathological parameters. The differences of ERP57 and ERAP1 expression were analyzed between the groups. Results The positive expression rates of ERP57 were 58.8% (73/124) and 100% (24/24) in breast cancer and breast fibroadenoma samples, respectively. The difference was statistically significant (χ2=15.061, P14%, and which was significantly higher in patient with non-triple negative than that in patients with the triple negative (P<0.05). Conclusion The low expression levels of ERP57 and ERAP1 may play an important role in the carcinogenesis of breast cancer, and which may be valuable in judging the malignant degree and prognosis of breast cancer.

Interaction of aminopeptidase (BmAPN5) and parasporal crystal (PC) toxin isolated from Bacillus bombysepticus / 生物工程学报

Aminopeptidase N (APN) belonging to zinc-dependent metalloproteinase, not only catalyzes protein proteolytic process, but also is involved in the pathogenic process as the receptor of pathogenic toxin. In Bombyx mori, APN gene family consists of 16 members, of which BmAPN4 binds trypsin-activated parasporal crystal (PC) toxin isolated from Bacillus bombysepticus (Bb). In order to verify whether or not other APNs interact with PC toxin during the pathogenesis of Bb, we cloned BmAPN5, a member of aminopeptidase family, from the silkworm midgut. The full length of BmAPN5 is 3313 bp, encoding 953 amino acids, containing a zinc peptidase_M1 and ERAP1_C domains. A recombinant GST-BmAPN5 was purified by a prokaryotic expression system. Far-Western blotting, co-immunoprecipitation and ELISA. Binding saturation assays demonstrated that PC after activated by trypsin could be bound by BmAPN5. Additionally, cytotoxic activity of trypsin-activated PC in Sf9 cells transfected with BmAPN5 showed that cells exhibited dramatic cytological changes, including swelling and lysis, revealing BmAPN5 serves as a functional receptor that participates in Bb and PC pathogenicity. These provide some clues for further exploring the pathogenesis relationships of Bb and host.

A preliminary study on the interaction between Asn-Gly-Arg (NGR)-modified multifunctional nanoparticles and vascular epithelial cells

Previously developed Asn-Gly-Arg (NGR) peptide-modified multifunctional poly(ethyleneimine)-poly(ethylene glycol) (PEI-PEG)-based nanoparticles (TPIC) have been considered to be promising carriers for the co-delivery of DNA and doxorubicin (DOX). As a continued effort, the aim of the present study was to further evaluate the interaction between TPIC and human umbilical vein endothelial cells (HUVEC) to better understand the cellular entry mechanism. In the present investigation, experiments relevant to co-localization, endocytosis inhibitors and factors influencing the internalization were performed. Without any treatment, there was no co-localization between aminopeptidase N/CD13 (APN/CD13) and caveolin 1 (CAV1). However, co-localization between CD13 and CAV1 was observed when cells were incubated with an anti-CD13 antibody or TPIC. As compared with antibody treatment, TPIC accelerated the speed and enhanced the degree of co-localization. TPIC entered HUVEC not only together with CD13 but also together with CAV1. However, this internalization was not dependent on the enzyme activity of CD13 but could be inhibited by methyl--eyclodextfin (MCD), further identifying the involvement of caveolae-mediated endocytosis (CvME). This conclusion was also verified by endocytosis inhibitor experiments.

A PCR-RFLP method for detection of the LNPEP encoding human insulin-regulated aminopeptidase (IRAP) rs4869317 polymorphism.

Background & objectives: Insulin regulated aminopeptidase (IRAP) has been related to certain pathologies such as breast cancer, Alzheimer´s disease and septic shock. IRAP is encoded by the leucyl/cystinyl aminopeptidase (LNPEP) gene. The genetic variation in the LNPEP gene has been analyzed in relation with the mortality and vasopressin clearance in septic shock. The LNPEP rs4869317 SNP (single nucleotide polymorphism) was the most significantly associated SNP with vasopressinase activity, being TT genotype associated with increased mortality. The objective of the present study was to develop a simple method to allow a quick and affordable genotyping for the rs4869317 SNP of LNPEP gene. Methods: Blood DNA samples were obtained from randomly selected healthy volunteers (n=28). A pair of primers was designed to amplify an 834 bp region of the LNPEP gene containing the rs4869317 SNP. The two alleles (T or A) were detected by digestion of the PCR products with the PacI restriction endonuclease. This enzyme only cuts the PCR products when the adenine is present in the SNP. Results: All individuals showed RFPL (restriction fragment length polymorphism) fragments for the expected genotypes (TT, TA or AA). The methodology was validated by sequencing of the amplified DNAs from several ‘T/T’ and ‘A/A’ homozygotes and ‘T/A’ heterozygotes. The results from both methods showed agreement. Interpretation & conclusions: The PCR-RFLP is a simple and reliable method that allows a quick genotyping for the rs4869317 SNP of LNPEP gene. The study of this polymorphism could be useful in future investigations to analyze the role of genetic variants of IRAP in several physiological/pathological conditions.

The influence of spleen aminopeptidase lyophilized powder on serum levels of TGF -β1,MCP -1,SDF -1 in pediatric asthma / 中国基层医药

Objective To investigate the influence of spleen aminopeptidase lyophilized powder on serum levels of transforming growth factor -β1 (TGF -β1),monocyte chemoattractant protein -1 (MCP -1),stromal cell derived factor 1 (SDF -1 )in pediatric asthma.Methods 128 patients with asthma were randomly divided into observation group(64 cases)and control group (64 cases).Two groups of children were given symptomatic treat-ment.The control group was orally administered montelukast,the observation group was treated with montelukast and splenic ammonia lyophilized powder for 3 months.The levels of TGF -β1,MCP -1,SDF -1 of the two groups were compared before and after treatment.Results After treatment,the asthma control test table (ACT)score,expiratoryvolume in one second (FEV1 )and peak expiratory flow rate (PEF)in the observation group were (24.25 ± 3.98)points (80.25 ±4.25)%,(7.25 ±0.69)L/min,which were significantly higher than those in the control group [(20.12 ±4.02)points,(75.02 ±3.96)%,(5.82 ±0.70)L/min,t =7.203,6.757,14.459,26.677,P <0.01].After treatment,the serum levels of TGF -β1,MCP -1,SDF -1 of the observation group were (42.23 ± 6.02)ng/mL,(48.56 ±3.96)pg/mL,(252.36 ±32.22)ng/L,which were significantly lower than those in the con-trol group [(42.23 ±6.02)ng/mL,(59.02 ±4.22)pg/mL,(425.25 ±40.62)ng/L,t =6.757,14.459,26.677,all P <0.01].Conclusion Montelukast combined with splenic aminopeptidase lyophilized powder for asthma can effec-tively reduce serum TGF -β1,MCP -1,SDF -1 levels and improve clinical symptoms and lung function,improve the treatment of children.

Evaluation on diagnostic value of leucine aminopeptidase in hyperthyroidism / 国际检验医学杂志

Objective To detect serum leucine aminopeptidase (LAP) level in the patients with hyperthyroidism for investiga‐ting the changes of LAP in the patients with thyroid dysfunction and its clinical significance .Methods 117 patients with hyperthy‐roidism were taken as the test group and 109 healthy people as the control group .The differences of various laboratory indexes were comparatively analyzed and the correlation between LAP with FT 3 ,FT4 and TSH was analyzed .117 patients with hyperthyroidism were divided into the liver damage group(52 cases) and non‐liver damage group(65 cases) and performed the LAP determination . Results The serum LAP ,FT3 ,FT4 and TSH levels in the hyperthyroidism whole group ,hyperthyroidism liver damage group and hyperthyroidism non‐liver damage group had statistically significant differences compared with those in the control group (P0 .05) .Conclusion The serum LAP content is closely related with the thyroid hormones and has certain clinical reference value for the diagnosis ,disease condition evaluation and medication .Lap can serve as an independent diagnostic indicator .

Placental Leucine Aminopeptidase/Oxytocinase Expression in Miscarriage.

Objectives: To evaluate the role of placental leucine aminopeptidase (P-LAP) in miscarriage and searching to select the gene of this enzyme in miscarriage to exclude direct or indirect effects of abortion. Methods: Total RNA is purified from the fresh placental tissue sample according to the protocol of the QIAamp®RNA Tissues Mini Kit (Qiagen). The sample is visualized by 0.7% agrose gel containing. Total RNA is reverse-transcribed RT-PCR carried out on the previously extracted RNA samples using (QIAGEN One Step RT –PCR Kit). Aliquots (1ml) of RT reaction samples are amplified by PCR, the PCR products (10μl) per lane are resolved by using electrophoresis on 2.0% agrose gel .Later the product is detected and examined under UV transiluminator. Results: The obtained results indicate that there is an expression of P-LAP mRNAs in placentas of normal pregnancy women (28±SE0.45) and there is a decrease in miscarriage. Furthermore, there is a difference between single miscarriage and those with recurrent miscarriage, the mean values in single miscarriage (1st and 2nd) are (16.1%±SE0.84) and (13%±SE0.24) respectively while the mean values in recurrent miscarriage (1st and 2nd) are (12%±SE0.19) and (9%±SE0.52) respectively. The expression of P-LAP is significantly lower (p=0.05) in miscarriage and highly significant decrease in recurrent than in single miscarriage women. Conclusion: The decrease of P-LAP mRNA levels in miscarriage placentas could be a sign that p-LAP function is an important step in pregnancy regulation.

Aminopeptidase N: A therapeutic target in human liver cancer stem cells / 国际药学研究杂志

Liver cancer stem cells (LCSC) play the critical role in hepatocellular carcinoma development and maintenance. They are generally dormant or slowly cycling tumor cells that have the ability to reconstitute tumors. LCSC associate closely with tumor resistance to chemo/radiation therapy, tumor relapse and metastasis, and can be identified and separated with some special surface markers from hepatocellular carcinoma, such as CD133, CD90, CD44, CD24 and EpCAM to investigate the biological behaviors of them. Early studies showed that these markers can be regarded as special surface markers of liver cancer stem cells. Recent studies found that aminopeptidase N (APN, CD13+) cells in hepatocellular carcinoma have biological characteristics of stem cells and demonstrated that CD13 is a marker for semiquiescent CSC in human liver cancer cell lines and clinical samples and that targeting these cells might provide a way to treat this disease. In this review, we introduce the structure and the main function of CD13, liver cancer stem cells source and identification, CD13+ CSC in hepatocellular carcinoma and combination therapy in the treatment of liver cancer.

Aminopeptidase N:a therapeutic target in human liver cancer stem cells / 国际药学研究杂志

Liver cancer stem cells (LCSC)play the critical role in hepatocellular carcinoma development and maintenance. They are generally dormant or slowly cycling tumor cells that have the ability to reconstitute tumors. LCSC associate closely with tumor resistance to chemo/radiation therapy , tumor relapse and metastasis, and can be identified and separated with some special surface markers from hepatocellular carcinoma, such as CD133, CD90, CD44, CD24 and EpCAM to investigate the biological behaviors of them. Early studies showed that these markers can be regarded as special surface markers of liver cancer stem cells. Recent studies found that aminopeptidase N (APN,CD13+)cells in hepatocellular carcinoma have biological characteristics of stem cells and demonstrated that CD13 is a marker for semiquiescent CSC in human liver cancer cell lines and clinical samples and that targeting these cells might provide a way to treat this disease. In this review,we introduce the structure and the main function of CD13,liver cancer stem cells source and identification,CD13 + CSC in hepatocellular carcinoma and combination therapy in the treatment of liver cancer.