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Leucine rich repeat LGI family member 3: Integrative analyses reveal its prognostic association with non-small cell lung cancer.

ABSTRACT: Leucine rich repeat LGI family member 3 (LGI3) is a member of the LGI protein family. Our previous studies reported that LGI3 was expressed in adipose tissues, brain and skin, where it served roles as a multifunctional cytokine and pro-inflammatory adipokine. It was hypothesized that LGI3 may be involved in cytokine networks in cancer. The present study aimed to analyze differentially expressed genes in non-small cell lung cancer (NSCLC) tissues and NSCLC cohort data, to evaluate the prognostic role of LGI3. Expression microarray and NSCLC cohort data were statistically analyzed by bioinformatic methods, and protein-protein interactions, functional enrichment and pathway, gene coexpression network (GCN) and prognostic association analyses were performed. The results demonstrated that the expression levels of LGI3 and its receptor a disintegrin and metalloproteinase domain-containing protein 22 were significantly decreased in NSCLC tissues. A total of two upregulated genes and 11 downregulated genes in NSCLC tissues were identified as LGI3-regulated genes. Protein-protein interaction network analysis demonstrated that all LGI3-regulated genes that were altered in NSCLC were involved in a protein-protein interaction network cluster. Functional enrichment, Kyoto Encyclopedia of Genes and Genomes pathway and GCN analyses demonstrated the association of these genes with the immune and inflammatory responses, angiogenesis, the tumor necrosis factor pathway, and chemokine and peroxisome proliferator-activated receptor signaling pathways. Analysis of NSCLC cohorts revealed that low expression levels of LGI3 was significantly associated with poor prognosis of NSCLC. Analysis of the somatic mutations of the LGI3 gene in NSCLC revealed that the amino acid residues altered in NSCLC included two single nucleotide polymorphism sites and three phylogenetically coevolved amino acid residues. Taken together, these results suggest that LGI3 may be a potential prognostic marker of NSCLC.

SUBMITTER: Kim DS

PROVIDER: S-EPMC6704323 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Leucine rich repeat LGI family member 3: Integrative analyses reveal its prognostic association with non-small cell lung cancer.

Kim Dong-Seok DS Kwon Nyoun Soo NS Yun Hye-Young HY

Oncology letters 20190722 3

Leucine rich repeat LGI family member 3 (LGI3) is a member of the LGI protein family. Our previous studies reported that LGI3 was expressed in adipose tissues, brain and skin, where it served roles as a multifunctional cytokine and pro-inflammatory adipokine. It was hypothesized that LGI3 may be involved in cytokine networks in cancer. The present study aimed to analyze differentially expressed genes in non-small cell lung cancer (NSCLC) tissues and NSCLC cohort data, to evaluate the prognostic ...[more]

PMID: 31452819

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Project description:LGI family member 3 (LGI3) is a member of the LGI protein family. In our previous studies, LGI3 was determined to be expressed in adipose tissues, skin and the brain, where it served as a pleiotropic cytokine. The results indicated that LGI3 levels are increased in adipose tissues of obese individuals in comparison with control individuals and that LGI3 suppressed adipogenesis via its receptor, disintegrin and metalloproteinase domain-containing protein 23. Additionally, it was reported that LGI3 upregulates tumor necrosis factor-α and downregulated adiponectin and hypothesized that LGI3 may act as a proinflammatory adipokine involved in adipose tissue inflammation. In the present study, cytokine arrays were used to analyze cytokine levels in adipose tissues and plasma of LGI3-knockout mice and signaling protein arrays used to analyze the expression and phosphorylation of these proteins in LGI3-treated preadipocytes. The results suggested that expression levels of 129 gene products (24 cytokines and 105 signaling proteins) were altered in response to LGI3 deficiency or LGI3 treatment, respectively. Protein-protein interaction network analysis of LGI3-regulated gene products revealed that 94% of the gene products (21 cytokines and 100 signaling proteins) formed an interaction network cluster. Functional enrichment analysis for the LGI3-regulated gene products, including those from our previous studies, revealed an association with numerous biological processes, including inflammatory responses, cellular differentiation and development and metabolic regulation. Gene co-expression network analysis revealed that these LGI3-regulated gene products were involved in various biological processes in an overlapping and differential manner between subcutaneous and visceral adipose tissues. Notably, inflammatory responses were more strongly associated with the LGI3-regulated gene co-expression network in visceral adipose tissues than in subcutaneous adipose tissues. Analysis of expression quantitative trait loci identified four single nucleotide variants that affect expression of LGI3 in an adipose depot-specific manner. Taken together, the results suggested that LGI3 may serve depot-specific roles as an adipokine in adipose tissues.

Project description:BACKGROUND:Leucine-rich glioma-inactivated (LGI) proteins play a critical role in synaptic transmission. Dysfunction of these genes and encoded proteins is associated with neurological disorders such as genetic epilepsy or autoimmune limbic encephalitis in animals and human. Familial spontaneous epileptic cats (FSECs) are the only feline strain and animal model of familial temporal lobe epilepsy. The seizure semiology of FSECs comprises recurrent limbic seizures with or without evolution into generalized epileptic seizures, while cats with antibodies against voltage-gated potassium channel complexed/LGI1 show limbic encephalitis and recurrent limbic seizures. However, it remains unclear whether the genetics underlying FSECs are associated with LGI family genes. In the present study, we cloned and characterized the feline LGI1-4 genes and examined their association with FSECs. Conventional PCR techniques were performed for cloning and mutational analysis. Characterization was predicted using bioinformatics software. RESULTS:The cDNAs of feline LGI1-4 contained 1674-bp, 1650-bp, 1647-bp, and 1617-bp open reading frames, respectively, and encoded proteins comprising 557, 549, 548, and 538 amino acid residues, respectively. The feline LGI1-4 putative protein sequences showed high homology with Homo sapiens, Canis familiaris, Bos taurus, Sus scrofa, and Equus caballus (92%-100%). Mutational analysis in 8 FSECs and 8 controls for LGI family genes revealed 3 non-synonymous and 14 synonymous single nucleotide polymorphisms in the coding region. Only one non-synonymous single nucleotide polymorphism in LGI4 was found in 3 out of 8 FSECs. Using three separate computational tools, this mutation was not predicted to be disease causing. No co-segregation of the disease was found with any variant. CONCLUSIONS:We cloned the cDNAs of the four feline LGI genes, analyzed the amino acid sequences, and revealed that epilepsy in FSEC is not a monogenic disorder associated with LGI genes.

Dataset Information

Leucine rich repeat LGI family member 3: Integrative analyses reveal its prognostic association with non-small cell lung cancer.

Publications

Leucine rich repeat LGI family member 3: Integrative analyses reveal its prognostic association with non-small cell lung cancer.

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