Integrative genomic analysis of interleukin‑36RN and its prognostic value in cancer

  • Authors:
    • Zhilei Lv
    • Jinshuo Fan
    • Xiuxiu Zhang
    • Qi Huang
    • Jieli Han
    • Feng Wu
    • Guorong Hu
    • Mengfei Guo
    • Yang Jin
  • View Affiliations

  • Published online on: December 9, 2015     https://doi.org/10.3892/mmr.2015.4667
  • Pages:1404-1412
Metrics: HTML 0 views | PDF 0 views     Cited By (CrossRef): 0 citations

Abstract

Interleukin (IL)‑36RN, previously known as IL1‑F5 and IL‑1δ, shares a 360‑kb region of chromosome 2q13 with members of IL‑1 systems. IL‑36RN encodes an anti‑inflammatory cytokine, IL‑36 receptor antagonist (IL‑36Ra). In spite of IL‑36Ra showing the highest homology to IL‑1 receptor (IL‑1R) antagonist, it differs from the latter in aspects including its binding to IL‑lRrp2 but not to IL‑1R1. IL‑36RN is mainly expressed in epithelial cells and has important roles in inflammatory diseases. In the present study, IL‑36RN was identified in the genomes of 27 species, including human, chimpanzee, mouse, horse and dolphin. Human IL‑36RN was mainly expressed in the eye, head and neck, fetal heart, lung, testis, cervix and placenta; furthermore, it was highly expressed in bladder and parathyroid tumors. Furthermore, a total of 30 single nucleotide polymorphisms causing missense mutations were determined, which are considered to be the causes of various diseases, such as generalized pustular psoriasis. In addition, the link between IL‑36RN and the prognosis of certain cancer types was revealed through meta‑analysis. Tumor‑associated transcriptional factors c‑Fos, activator protein‑1, c‑Jun and nuclear factor κB were found to bind to the upstream region in the IL‑36RN gene. This may indicate that IL‑36RN is involved in tumorigenesis and tumor progression through the regulation of tumor‑associated transcriptional factors. The present study identified IL-36RN in various species and investigated the associations between IL-36RN and cancer prognosis, which would determine whether IL-36RN drove the evolution of the various species with regard to tumorigenesis.

Introduction

Interleukin (IL)-36RN was first discovered as an IL-1 family cytokine, also known as IL-1F5, IL-1δ, IL-1Hy1, FIL-1δ, IL-1H3, IL-1RP3 and IL-1L1 (1,2), which is, together with classic IL-1 members, IL-37 and other IL-36 cytokines (IL-36α, IL-36β and IL-36γ) located in a 360-kb region of chromosome 2q13 (3). IL-36RN was identified to encode anti-inflammatory cytokine IL-36Ra, which is 52% homologous to the IL receptor antagonist (IL-1Ra) (4). IL-36Ra binds to IL-1Rrp2 and inhibits IL-36α, IL-36β and IL-36γ in similar manner to IL-1Ra inhibiting IL-1α and IL-1β (5). In spite of its similar functions to those of IL-1Ra, IL-36Ra itself can induce IL-4 expression in glial cells, while IL-4 is indispensable for the anti-inflammatory activities of IL-36Ra in the brain; however, IL-1Ra has not been found to induce any cytokines (6). To facilitate functional investigations, IL-36 cytokines, including IL-36Ra, were re-named in 2010 with the aim to distinguish them from the IL-1 cytokines (2).

With regard the functions of IL-36, the perturbation of the IL-36 signaling balance contributes to the pathogenesis of immunological and inflammatory diseases (7). The balance can be disrupted by aberrant expression of either agonists or antagonists of IL-36 signaling. The IL-36R signaling agonists IL-36α, -β and -γ are highly expressed in several inflammatory diseases, including chronic obstructive pulmonary disease (8), asthma (9), obesity (10), ankylosing spondylitis (11), rheumatoid arthritis (12) and allergic contact dermatitis (13), and have a significant role in these diseases. As an antagonist of IL-36 signaling, IL-36Ra is also implicated in the pathogenesis of immunological and inflammatory conditions. IL-36Ra expression is associated with Kindler syndrome (14), brain micromotion (15) and psoriasis (16). It was recently shown that mutations of IL36RN are closely associated with a serious disease called general pustular psoriasis (GPP) (1720). Single-nucleotide polymorphisms (SNPs) in the IL-36RN gene can lead to induction of a premature stop-codon, frame-shift mutation or an amino acid substitution, resulting in a misfolded IL-36Ra protein that is less stable and poorly expressed (17,18,20). However, the roles of IL-36Ra in inflammation-associated tumors have not been clearly elucidated, while IL-36 signaling has been implicated in inflammatory diseases; therefore, an integrative analysis of IL-36RN and its prognostic value in cancer is required.

The present study assessed the IL-36RN gene in a wide range of genomes using integrative genomic analyses. Subsequently, functionally relevant SNP analysis and comparative proteomic analysis of IL-36RN were conducted. The conserved transcription-factor binding sites within the upstream region of IL-36RN as well as the prognostic value of IL-36RN in cancer were investigated.

Materials and methods

Identification of the IL-36RN gene in vertebrate genomes and integrative genomic analyses

The nucleotide and amino acid sequences of IL-36RN were obtained from the Ensembl database (www.ensembl.org), based on orthologous and paralogous relationships. The IL-36RN gene sequences subjected to analysis with the Basic Local Alignment Search Tool (BLAST; http://blast.ncbi.nlm.nih.gov/Blast.cgi) against the GenBank database (http://www.ncbi.nlm.nih.gov/genbank/) to confirm that the best hits were the IL36RN genes for the selected species. Conserved transcription-factor binding sites within promoter regions of the human IL-36RN gene were obtained from the DECipherment Of DNA Elements proprietary database (http://www.sabiosciences.com/chipqpcrsearch.php?app=TFBS) of SABiosciences (Qiagen, Hilden, Germany), which combines text mining with data from the genome browser of the University of California, Santa Cruz (https://genome.ucsc.edu/).

Comparative proteomic analysis of the IL-36RN protein

The ClustalW software implemented in MEGA 5.05 (http://www.megasoftware.net/) was used to align the protein-coding sequences of IL-36RN. A maximum likelihood tree of IL-36RN amino acid sequences was constructed using MEGA 5.05 with the Kimura 2-parameter model (21). For the relative support of the internal node, bootstrap analysis was performed with 1,000 replications for ML reconstructions. The positive selection of IL-36RN during evolution (22) was analyzed using the program CodeML implemented in the PAML4.7 software package (http://abacus.gene.ucl.ac.uk/software/paml.html). Codon subsitution models M0 (one ratio), M1a (NearlyNeutral), M2a (PositveSelection), M7 (β) and M8 (β and ω) were used. The site-specific model was generated using likelihood ratio tests to compare the models as previously described (23).

In silico expression analyses of the human IL-36RN gene

The expression profiles of normal human tissues were acquired from GeneAnnot (http://genecards.weizmann.ac.il/geneannot/index.shtml) and ArrayExpress (https://www.ebi.ac.uk/array-express/). Using the human IL-36RN gene (GenBank ID, NC_000002.12) as a query sequence, expressed sequence tags (ESTs) derived from the human IL-36RN gene were identified by BLAST as described previously (24). Virtual northern blot analysis was also performed by searching the uniGene database of the National Center of Biotechnology Information (NCBI) (http://www.ncbi.nlm.nih.gov/unigene). In addition, protein expression profiles of IL-36RN were obtained from the Systematic Protein Investigative Research Environment (25) and the Model Organism Protein Expression Database (26).

Evaluation of functionally relevant SNPs of the human IL-36RN gene and identification of somatic mutations in human cancer

Ensembl (http://www.ensembl.org/index.html) and the NCBI's Database of SNPs (http://www.ncbi.nlm.nih.gov/snp/) were used to obtain functionally relevant SNPs of the human IL-36RN gene as previously described (24,27,28). The SNPs that could disrupt exonic splicing enhancer (ESE)/exonic splicing silencer (ESS) motifs or cause a missense mutation were identified. Somatic mutations of the IL-36RN gene were identified in human cancer types from the Catalogue Of Somatic Mutations In Cancer (COSMIC) database (http://cancer.sanger.ac.uk/cosmic/), which mines complete cancer genomes (29).

Meta-analysis of the prognostic value of the IL-36RN gene in cancer

The PrognoScan database (http://www.prognoscan.org/) (30) contains a large collection of publicly available cancer microarray datasets with clinical annotation, enabling it to also be used as an efficient tool for assessing the association between gene expression and cancer prognosis. During gene analysis, PrognoScan employed the minimum P-value approach for grouping patients for survival analysis. Data was collected for further analysis by searching the IL-36RN gene as a query in PrognoScan.

Results

Comparative proteomic analysis of the IL-36RN protein

All the IL-36RN gene and protein sequences were collected from the Ensembl database and then confirmed by BLAST. The complete IL-36RN genes were identified in human, chimpanzee, gibbon, orangutan, olive baboon, vervet-African green monkey, marmoset, bush baby, tarsier, rabbit, pika, rat, mouse, elephant, cat, dog, panda, ferret, horse, cow, dolphin, guinea pig, sheep, opossum, tasmanian devil, armadillo and tree shrew genomes. The sequence and structural alignment of IL-36RN is illustrated in Fig. 1. Refined phylogentic trees generated using the identified IL-36RN protein amino acid sequences by ML and neighbor-joining (NJ) methods were almost identical; therefore, only the results of the ML method are presented (Fig. 2). It appeared that the IL-36RN protein from the primate lineage forms a species-specific cluster. Site-specific analysis for positive selection was performed for primate, rodent, carnivora, mammalian and mammalian excluding primate lineages. By using any of the six models in the IL-36RN proteins, no positive selection site was identified. Instead, purifying selection was observed among the proteins (data not shown). Furthermore, the exon-intron information was collected from the Ensembl database and presented in Table I and Fig. 3. In most of the mammalian genomes, IL-36RN genes had four exons and three introns of similar length. In the primate lineage, IL-36RN genes showed the same exon lengths and numbers with similar exon-intron conservations (Table I). However, IL-36RN genes had six exons and five introns in pikas and only three exons and two introns in opossums. Furthermore, the tasmanian devil was shown to have five exons and four introns in its IL-36RN genes (Table I and Fig. 3).

Table I

Exon and intron lengths of IL-36RN.

Table I

Exon and intron lengths of IL-36RN.

Species Length (bp)
Exon 1Intron 1Exon 2Intron 2Exon 3Intron 3Exon 4Intron 4Exon 5Intron 5Exon 6Total exons
Armadillo3273486820128756225471
Bushbaby291343861280128199225468
Cat321334861036128202225471
Chimpanzee291384861187128201225468
Cow291334861014128171225468
Dog291553861058128194225468
Dolphin29151886998128171225468
Elephant32151086976128220225471
Ferret321539861032128175225471
Gibbon291382861182128201225468
Guinea Pig321650861282131203225474
Horse291369861050128197225468
Human291384861186128201225468
Marmoset291380861187128201225468
Mouse Lemur291353861264128200225468
Olive baboon291385861197128200222465
Opossum1181450128348219465
Orangutan291384861184128201225468
Panda321579861055128201225471
Pika29797163251421449128161225465
Rabbit291491861141128198225468
Rat322070861069128205225471
Sheep32133286974128174225471
Tarsier291348861774128218225468
Tasmanian devil88143225765538128293216462
Tree Shrew291509861084128237225468
Vervet African green monkey291392861201128201225468
Expression profile of the human IL-36RN gene

A search of the EST sequence database revealed that the human IL-36RN gene was expressed in the placenta, cervix, lung, head and neck, eye, fetal heart and testis, and furthermore, that it was highly expressed in bladder and parathyroid tumors. Examination of microarray analyses and 'virtual northern blot analysis' revealed a predominant expression of IL-36RN in cervix, larynx, lung, mouth, muscle, parathyroid, pharynx, placenta and testis. A search of the PrognoScan database revealed that human IL-36RN was also expressed in bladder, blood, brain, breast, colorectal, esophageal, eye, head and neck, lung, ovarian, skin and soft tissue cancer.

Comparative genomics analysis of human IL-36RN

Activator protein 1 (AP-1), c-Fos, c-Jun and nuclear factor (NF)-κB binding sites were identified within the upstream regions of the transcriptional start site of human IL-36RN.

Functionally relevant SNP evaluation of the human IL-36RN gene and identification of somatic mutations in human cancer

A total of 543 SNPs were identified in the human IL-36RN gene through searching the NCBI SNP and Ensembl databases. Among these SNPs, 30 were functionally relevant, causing missense and nonsense mutations (Table II). As presented in Table III, by searching the COSMIC database, 31 somatic mutations of the IL-36RN gene were identified in cancer.

Table II

Evaluation of the functionally relevant SNP in the human IL-36RN gene.

Table II

Evaluation of the functionally relevant SNP in the human IL-36RN gene.

SNP IDChr 2 position sequenceSequenceTypeAmino acid change
rs143724424113820120 GCTTC[A/G]AGTCGMissenseEK
rs144478519113820124 CGAGT[C/T]GGCTGMissenseSL
rs151325121113819727 CCAAT[C/T]GGTGGMissenseRW
rs387906914113818479 GCTTC[C/T]AGCTGMissenseLP
rs397514629113820154 GTGCA[C/G]GGTGCMissenseTR
rs28938777113819725 CCCCA[A/G]TCGGTMissenseNS
rs77864207113819754 CCCCC[A/G]TCATCMissenseVI
rs139497891113819812 GGAGC[C/T]GACTCMissensePL
rs141341649113820136 CTACC[C/T]GGGCTMissensePL
rs144182857113820031 GCAGC[C/T]AGTGAMissensePL
rs144420774113820103 CATGG[C/G]GCTCAMissenseGA
rs145099228113819721 TGGTC[C/T]CCAATMissensePS
rs147389610113818487 CTGGA[A/G]GGCTGMissenseGR
rs147410197113820087 CCTTC[C/T]ACCGGMissenseYH
rs187015338113818503 AGGGA[A/G]GGTCAMissenseKR
rs199932303113820090 TCTAC[C/T]GGCGGMissenseRW
rs202059991113820222 CCCCC[A/G]TCACAMissenseIV
rs369259981113820048 TGGAG[C/T]TCTATMissenseLF
rs371819085113820091 CTACC[A/G]GCGGGMissenseRQ
rs372880215113819815 GCCGA[C/T]TCTAAMissenseTI
rs374900764113820247 GCAGT[A/G]TGACTMissenseCY
rs375207169113820093 ACCGG[C/T]GGGACMissenseRW
rs375718709113819793 TGTCA[C/T]GTGGGMissenseCR
rs377330697113820172 CGATC[A/G]GCCTGMissenseQR
rs537559199113820044 ATCAT[A/G]GAGCTMissenseMI
rs542606182113820094 CCGGC[A/G]GGACAMissenseRQ
rs545202535113820237 TCTAC[A/T]TCCAGMissenseFI
rs545673991113818451 TGAAG[G/T]TGCTTMissenseVL
rs397514630113817043 GCTTC[C/T]GGTGANonsenseR-Ter
rs368461730113819805 TGGGG[C/T]AGGAGNonsenseQ-Ter

[i] Among the 543 available SNPs identified in the human IL-36RN gene, a total of 30 SNPs were functionally relevant, including 28 SNPs causing missense mutations and 2 SNPs causing nonsense mutations. SNP, single nucleotide polymorphism; Chr 2, chromosome 2.

Table III

Somatic mutations of IL-36RN in tumor tissues.

Table III

Somatic mutations of IL-36RN in tumor tissues.

Position (AA)Mutation (CDS)Mutation (amino acid)Mutation ID (COSM)CountMutation type
3c.9G>Cp.L3LCOSM38366281Substitution-coding silent
5c.15G>Ap.G5GCOSM38945581Substitution-coding silent
6c.17C>Tp.A6VCOSM2402201 Substitution-missense
10c.28C>T p.R10*COSM1267411 Substitution-nonsense
14c.41C>Tp.S14LCOSM7147061 Substitution-missense
15c.44C>Ap.A15ECOSM7147051 Substitution-missense
21c.63G>Tp.L21LCOSM3814741Substitution-coding silent
29c.85G>Ap.G29RCOSM16909461 Substitution-missense
34c.102G>Ap.G34GCOSM38945591Substitution-coding silent
36c.108C>Ap.V36VCOSM1691721Substitution-coding silent
37c.110T>Cp.I37TCOSM40842971 Substitution-missense
46c.137C>Tp.P46LCOSM16909471 Substitution-missense
48c.142C>Tp.R48WCOSM4410161 Substitution-missense
54c.160C>Ap.L54MCOSM3000701 Substitution-missense
54c.160C>Tp.L54LCOSM35654571Substitution-coding silent
55c.164C>Tp.S55FCOSM16909481 Substitution-missense
56c.168C>Ap.P56PCOSM35654581Substitution-coding silent
71c.212G>Ap.G71ECOSM35654591 Substitution-missense
73c.218G>Cp.G73ACOSM15277071 Substitution-missense
86c.258G>Tp.M86ICOSM35654601 Substitution-missense
92c.275C>Ap.A92DCOSM41330121 Substitution-missense
95c.284C>Tp.S95FCOSM35654611 Substitution-missense
97c.290G>Ap.S97NCOSM35654621 Substitution-missense
106c.317G>Ap.G106ECOSM35654631 Substitution-missense
112c.334G>Ap.E112KCOSM1074371 Substitution-missense
117c.350C>Ap.P117QCOSM39610111 Substitution-missense
126c.378A>Gp.E126ECOSM40842981Substitution-coding silent
136c.406C>Ap.L136ICOSM40842991 Substitution-missense
137c.411C>Tp.P137PCOSM35654641Substitution-coding silent
138c.412G>Ap.E138KCOSM2755592 Substitution-missense
142c.425G>Tp.W142LCOSM3366641 Substitution-missense

[i] IL-36RN, interleukin-36RN; COSM, catalogue of somatic mutations; CDS, coding sequences.

Meta-analysis of the prognostic value of IL-36RN gene in cancer

PrognoScan employs the minimum P-value approach for grouping patients with varied cancer types for survival analysis and produces a data-set of results, including cancer type, subtype, endpoint, cohort, contributor, array type, probe ID, number of patients, optimal cut-off point, Pmin and Pcor. For the IL-36RN gene, 7 out of the 84 cancer cases showed correlations between microarray expression in the IL-36RN gene and cancer prognosis (bladder cancer, 1/2; blood cancer, 0/9; brain cancer, 0/4; breast cancer, 1/30; colorectal cancer, 1/9; esophageal cancer, 0/1; eye cancer, 0/1; head and neck cancer, 0/1; lung cancer, 2/15; ovarian cancer, 2/9; skin cancer, 0/1; soft tissue cancer, 0/1) with a 5% significance level (Table IV). Among the two ovarian cancer cases, poor survival in one case was associated with elevated expression of IL-36RN (DUKE-OC), and the other one was associated with decreased expression of IL-36RN (GSE17260). While one case out of nine cases of colorectal cancer showed poor survival associated with decreased expression of IL-36RN, elevated expression of IL-36RN in one case of bladder cancer, one case of breast cancer and two cases of lung cancer was found to be associated with poor survival.

Table IV

Dataset contents from PrognoScan showing an association between microarray expression of IL-36RN and cancer prognosis.

Table IV

Dataset contents from PrognoScan showing an association between microarray expression of IL-36RN and cancer prognosis.

DatabaseCancer typePatients (n)EndpointCut-off pointP-valuePrognosisReference
GSE13507Bladder cancer165Overall survival0.870.0462(32)
GSE12276Breast cancer204Relapse-free survival0.460.0422(33)
GSE17536Colorectal cancer177Overall survival0.210.0331(34)
GSE31210Lung cancera204Overall survival0.84<0.0012(35)
GSE31210Lung cancera204Relapse-free survival0.890.0022(35)
DUKE-OCOvarian cancer133Overall survival0.440.0312
GSE17260Ovarian cancer110Overall survival0.120.0091(36)

a Sub-type, Adenocarcinoma. In total, 7 out of the 84 cancer cases showed correlations between microarray expression in the IL-36RN gene and cancer prognosis (bladder cancer, 1/2; blood cancer, 0/9; brain cancer, 0/4; breast cancer, 1/30; colorectal cancer, 1/9; esophageal cancer, 0/1; eye cancer, 0/1; head and neck cancer, 0/1; lung cancer, 2/15; ovarian cancer, 2/9; skin cancer, 0/1; soft tissue, cancer 0/1) with a 5% significance level.

Discussion

The IL-36RN gene encodes the anti-inflammatory cytokine IL-36Ra, which was previously known as IL-1F5 and later re-defined as a member of the IL-36 cytokine family.

The present study identified IL-36RN from 27 genomes and found that IL-36RN exists in all types of mammals, including primates, rodents and carnivora, as well as elephant, dolphin, sheep, rabbit, horse and armadillo. In the phylogenetic tree, all of the primates were clustered. Furthermore, the exon-intron information indicated that all primates were almost identical with regard to the IL-36RN gene. According to the alignment and phylogenetic tree, IL-36RN was evolutionarily conserved among mammals, indicating a significant biological function of this gene. It is known that IL-36 cytokines are expressed in various tissue types and contribute to inflammatory diseases (7), confirming its biological importance indicated by the present study.

EST sequence analysis revealed that the IL-36RN gene is expressed in the placenta, cervix, lung, head and neck, eye, fetal heart and testis; furthermore, high expression had been detected in bladder and parathyroid tumors. This result implied that IL-36RN is extensively expressed in a large variety of organ and tissue types. A total of 30 SNPs, including 28 SNPs causing missense mutations and 2 SNPs causing nonsense mutations, were analyzed from 543 available SNPs in human IL-36RN genes. Recently, several IL-36RN mutations among the 28 SNPs have been reported as causative genetic defects associated with GPP and related pustular disorders (1820,31), which indicates that changes in IL-36RN SNPs truly contribute to physiological and pathological functions of IL-36Ra. However, another reported IL-36RN mutation in the intron region, rs148755083, which causes GPP (31), was not included in the present study; therefore, further investigation is required to reveal the effects of the other SNPs on the links between IL-36RN and diseases.

In the present study, assessment of the prognostic value of IL-36RN in cancer using the PrognoScan database revealed that IL-36RN is expressed in various cancer types including bladder (32), breast (33), colorectal (34), lung (35) and ovarian cancer (36). In 7 out of 84 cancer cases, IL-36RN was identified as a promising prognostic factor. Furthermore, IL-36RN expression varied among different types of cancer and the prognostic value varied within entries of different databases for the same cancer type. These results suggested that IL-36RN may have multiple roles in cancer development. In addition, 31 somatic mutations of IL-36RN in cancer tissues were identified in the present study. Thus, additional study is required to confirm the preliminary findings of the present study, which indicated that IL-36RN takes part in cancer development, and to assess the underlying mechanisms.

The IL-36RN gene was identified to bind with the AP-1, c-Fos, c-Jun, and NF-κB regulatory transcription factors in the upstream (promoter) region. Transcription factor AP-1 regulates a broad range of genes involved in cell cycle and inflammation. It mediates the anti-apoptotic response to hypoxic conditions and contributes to resistance to chemo- and radiotherapy in colon cancer cells (37), while it influences pivotal regulators of cell proliferation, migration and survival involved in melanoma progression (38) as well as in the carcinogenesis of the respiratory epithelium (39). c-Fos has been found to be associated with lipid- and phospholipid synthesis in several cell types (40) and activates biogenesis in certain types of tumor cell to support tumor growth (41,42). c-Jun is a critical transcription factor involved in major cell-biological activities, including cell proliferation, apoptosis, angiogenesis and invasiveness by specific regulation of epidermal growth factor receptor, keratinocyte growth factor, cyclin D1, p53, proliferin and CD44 (4346). NF-κB is known to be the key regulator of apoptosis and controlled cell suicide by means of controlling pro-apoptotic and anti-apoptotic genes (4750). NF-κB exacerbates inflammation-induced cancer types, while it suppresses chemically induced skin and liver cancers (5153), which suggests that NF-κB has a dual role in cancer. These transcription factors associated with tumorigenesis may represent a link between IL-36RN and tumorigenesis or cancer progression.

In conclusion, the present study investigated IL-36RN in various species and types of cancer at the gene and protein levels, and the results demonstrated that IL-36RN may have an important role in cancer progression through tumor-associated transcription factors and signaling pathways, but this hypothesis requires further investigation.

Acknowledgments

The present study was supported by the National Natural Science Foundation of China (no. 81072400), the Research Fund for the Doctoral Program of Higher Education of China (no. 20130142110066), the Scientific Research Foundation of Hubei Health Department (no. JX5B54), the Natural Science Foundation of Hubei province (no. 2009CDB148), the Wuhan Planning Project of Science and Technology (no. 201161038340-01) and the Independent Innovation Research Foundation of Huazhong University of Science and Technology (no. 2011JC016).

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February 2016
Volume 13 Issue 2

Print ISSN: 1791-2997
Online ISSN:1791-3004

2016 Impact Factor: 1.692
Ranked #19/128 Medicine Research and Experimental
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APA
Lv, Z., Fan, J., Zhang, X., Huang, Q., Han, J., Wu, F. ... Jin, Y. (2016). Integrative genomic analysis of interleukin‑36RN and its prognostic value in cancer. Molecular Medicine Reports, 13, 1404-1412. https://doi.org/10.3892/mmr.2015.4667
MLA
Lv, Z., Fan, J., Zhang, X., Huang, Q., Han, J., Wu, F., Hu, G., Guo, M., Jin, Y."Integrative genomic analysis of interleukin‑36RN and its prognostic value in cancer". Molecular Medicine Reports 13.2 (2016): 1404-1412.
Chicago
Lv, Z., Fan, J., Zhang, X., Huang, Q., Han, J., Wu, F., Hu, G., Guo, M., Jin, Y."Integrative genomic analysis of interleukin‑36RN and its prognostic value in cancer". Molecular Medicine Reports 13, no. 2 (2016): 1404-1412. https://doi.org/10.3892/mmr.2015.4667
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