Gene Summary

Gene:LAMC2; laminin subunit gamma 2
Aliases: B2T, CSF, EBR2, BM600, EBR2A, LAMB2T, LAMNB2
Summary:Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins, composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively), have a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. Several isoforms of each chain have been described. Different alpha, beta and gamma chain isomers combine to give rise to different heterotrimeric laminin isoforms which are designated by Arabic numerals in the order of their discovery, i.e. alpha1beta1gamma1 heterotrimer is laminin 1. The biological functions of the different chains and trimer molecules are largely unknown, but some of the chains have been shown to differ with respect to their tissue distribution, presumably reflecting diverse functions in vivo. This gene encodes the gamma chain isoform laminin, gamma 2. The gamma 2 chain, formerly thought to be a truncated version of beta chain (B2t), is highly homologous to the gamma 1 chain; however, it lacks domain VI, and domains V, IV and III are shorter. It is expressed in several fetal tissues but differently from gamma 1, and is specifically localized to epithelial cells in skin, lung and kidney. The gamma 2 chain together with alpha 3 and beta 3 chains constitute laminin 5 (earlier known as kalinin), which is an integral part of the anchoring filaments that connect epithelial cells to the underlying basement membrane. The epithelium-specific expression of the gamma 2 chain implied its role as an epithelium attachment molecule, and mutations in this gene have been associated with junctional epidermolysis bullosa, a skin disease characterized by blisters due to disruption of the epidermal-dermal junction. Two transcript variants resulting from alternative splicing of the 3' terminal exon, and encoding different isoforms of gamma 2 chain, have been described. The two variants are differentially expressed in embryonic tissues, however, the biological significance of the two forms is not known. Transcript variants utilizing alternative polyA_signal have also been noted in literature. [provided by RefSeq, Aug 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:laminin subunit gamma-2
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: LAMC2 (cancer-related)

Henrik Heiland D, Ravi VM, Behringer SP, et al.
Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma.
Nat Commun. 2019; 10(1):2541 [PubMed] Free Access to Full Article Related Publications
Reactive astrocytes evolve after brain injury, inflammatory and degenerative diseases, whereby they undergo transcriptomic re-programming. In malignant brain tumors, their function and crosstalk to other components of the environment is poorly understood. Here we report a distinct transcriptional phenotype of reactive astrocytes from glioblastoma linked to JAK/STAT pathway activation. Subsequently, we investigate the origin of astrocytic transformation by a microglia loss-of-function model in a human organotypic slice model with injected tumor cells. RNA-seq based gene expression analysis of astrocytes reveals a distinct astrocytic phenotype caused by the coexistence of microglia and astrocytes in the tumor environment, which leads to a large release of anti-inflammatory cytokines such as TGFβ, IL10 and G-CSF. Inhibition of the JAK/STAT pathway shifts the balance of pro- and anti-inflammatory cytokines towards a pro-inflammatory environment. The complex interaction of astrocytes and microglia cells promotes an immunosuppressive environment, suggesting that tumor-associated astrocytes contribute to anti-inflammatory responses.

Hori S, Miyake M, Onishi S, et al.
Evaluation of pro‑ and anti‑tumor effects induced by three colony‑stimulating factors, G‑CSF, GM‑CSF and M‑CSF, in bladder cancer cells: Is G‑CSF a friend of bladder cancer cells?
Int J Oncol. 2019; 54(6):2237-2249 [PubMed] Related Publications
Cytotoxic chemotherapy is the standard treatment for patients with advanced bladder cancer. However, this treatment can cause transient and prolonged neutropenia, which can result in fatal infection. Three recombinant human colony‑stimulating factors (CSFs), granulocyte CSF (G‑CSF), granulocyte‑macrophage CSF (GM‑CSF), and macrophage CSF (M‑CSF), are currently available to reduce the duration and degree of neutropenia. The present study investigated the pro‑ and anti‑tumor effects of these three CSFs and the changes in molecular profiles. Xenograft tumors in athymic mice were generated by subcutaneously inoculating the human bladder cancer cell lines MGH‑U3 and UM‑UC‑3. A total of 2 weeks after cell inoculation, mice were randomly divided into four groups (control, G‑CSF, GM‑CSF and M‑CSF) and treated thrice a week for 2 weeks. Tumor growth during monitoring and tumor weight at the time of euthanization were significantly higher in mice treated with G‑CSF and lower in mice treated with GM‑CSF compared with the control mice. Tumors were examined by immunostaining with antibodies against proteins associated tumor proliferation (Ki‑67), angiogenesis [CD31 and vascular endothelial growth factor (VEGF)], anti‑immunity (CD204) and epithelial‑mesenchymal transition (EMT; E‑cadherin). Immunohistochemical staining revealed that tumor proliferation, angiogenesis, recruitment of M2 macrophages and EMT were promoted by G‑CSF, whereas lymphangiogenesis and recruitment of M2 macrophages were inhibited by GM‑CSF. Treatment‑associated changes in serum pro‑ and anti‑tumoral cytokines and chemokines were evaluated by enzyme‑linked immunosorbent assay (ELISA)‑based arrays. In the ELISA for serum, the levels of cytokines associated with angiogenesis (interleukin‑6 and VEGF), and EMT (transforming growth factor‑β1 and ‑β2) were elevated in mice treated with G‑CSF. Treatment with GM‑CSF and M‑CSF also affected the level of these cytokines characteristically. The current results indicate that administration of exogenous G‑CSF to patients with bladder cancer promotes tumor growth through promotion of cell proliferation, angiogenesis, recruitment of M2 macrophages and enhancement of EMT through the modulation of the tumor microenvironment.

Zhao H, Ma M, Zhang L, et al.
Diagnosis of central nervous system lymphoma via cerebrospinal fluid cytology: a case report.
BMC Neurol. 2019; 19(1):90 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Primary central nervous system lymphoma (PCNSL) is the most prevalent brain, spinal cord, eyes, and leptomeningeal lymphoma. It is often misdiagnosed due to an unspecific presentation or unavailable biopsy and results in a poor prognosis. Although the craniocerebral imaging examination of PCNSL has some characteristics, it is limited, and atypical cases are especially difficult to identify with intracranial tumours and other diseases. The biopsy, as the gold standard for PCNSL diagnosis, is not eligible for all patients suspected of having PCNSL.
CASE PRESENTATION: This report documents a woman who presented with a three-month history of numbness and weakness in the right leg. She was treated with drugs at a local hospital for one month. She developed demyelination lesions and her symptoms were aggravated. The patient was admitted to the Department of Nerve Infection and Immunology at Tiantan Hospital. Head magnetic resonance imaging (MRI) enhanced scanning indicated significant inflammatory demyelinating disease, and lymphoma was not excluded. CSF revealed a high protein level and CSF cytology detected abnormal cells, PCNSL was eventually presumed according to positive CSF cytology and cytological detection of the cerebrospinal fluid flow.
CONCLUSIONS: PCNSL is a highly invasive tumour. With the development of technologies such as cerebrospinal fluid cytology and flow cytology, CSF analysis has become one of the definite diagnosis methods, and the tumour cell finding in CSF is the only reliable basis for diagnosis. Flow cytometric analysis and gene rearrangement testing also provide objective evidence.

Bencheikh L, Diop MK, Rivière J, et al.
Dynamic gene regulation by nuclear colony-stimulating factor 1 receptor in human monocytes and macrophages.
Nat Commun. 2019; 10(1):1935 [PubMed] Free Access to Full Article Related Publications
Despite their location at the cell surface, several receptor tyrosine kinases (RTK) are also found in the nucleus, as either intracellular domains or full length proteins. However, their potential nuclear functions remain poorly understood. Here we find that a fraction of full length Colony Stimulating Factor-1 Receptor (CSF-1R), an RTK involved in monocyte/macrophage generation, migrates to the nucleus upon CSF-1 stimulation in human primary monocytes. Chromatin-immunoprecipitation identifies the preferential recruitment of CSF-1R to intergenic regions, where it co-localizes with H3K4me1 and interacts with the transcription factor EGR1. When monocytes are differentiated into macrophages with CSF-1, CSF-1R is redirected to transcription starting sites, colocalizes with H3K4me3, and interacts with ELK and YY1 transcription factors. CSF-1R expression and chromatin recruitment is modulated by small molecule CSF-1R inhibitors and altered in monocytes from chronic myelomonocytic leukemia patients. Unraveling this dynamic non-canonical CSF-1R function suggests new avenues to explore the poorly understood functions of this receptor and its ligands.

Tiwari A, Mukherjee B, Hassan MK, et al.
Reduced FRG1 expression promotes prostate cancer progression and affects prostate cancer cell migration and invasion.
BMC Cancer. 2019; 19(1):346 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Prostate cancer is the most common form of cancer in males and accounts for high cancer related deaths. Therapeutic advancement in prostate cancer has not been able to reduce the mortality burden of prostate cancer, which warrants further research. FRG1 which affects angiogenesis and cell migration in Xenopus, can be a potential player in tumorigenesis. In this study, we investigated the role of FRG1 in prostate cancer progression.
METHODS: Immunohistochemistry was performed to determine FRG1 expression in patient samples. FRG1 expression perturbation was done to investigate the effect of FRG1 on cell proliferation, migration and invasion, in DU145, PC3 and LNCaP cells. To understand the mechanism, we checked expression of various cytokines and MMPs by q-RT PCR, signaling molecules by western blot, in FRG1 perturbation sets. Results were validated by use of pharmacological inhibitor and activator and, western blot.
RESULTS: In prostate cancer tissue, FRG1 levels were significantly reduced, compared to the uninvolved counterpart. FRG1 expression showed variable effect on PC3 and DU145 cell proliferation. FRG1 levels consistently affected cell migration and invasion, in both DU145 and PC3 cells. Ectopic expression of FRG1 led to significant reduction in cell migration and invasion in both DU145 and PC3 cells, reverse trends were observed with FRG1 knockdown. In androgen receptor positive cell line LNCaP, FRG1 doesn't affect any of the cell properties. FRG1 knockdown led to significantly enhanced expression of GM-CSF, MMP1, PDGFA and CXCL1, in PC3 cells and, in DU145, it led to higher expression of GM-CSF, MMP1 and PLGF. Interestingly, FRG1 knockdown in both the cell lines led to activation of p38 MAPK. Pharmacological activation of p38 MAPK led to increase in the expression of GM-CSF and PLGF in DU145 whereas in PC3 it led to enhanced expression of GM-CSF, MMP1 and CXCL1. On the other hand, inhibition of p38 MAPK led to reduction in the expression of above mentioned cytokines.
CONCLUSION: FRG1 expression is reduced in prostate adenocarcinoma tissue. FRG1 expression affects migration and invasion in AR negative prostate cancer cells through known MMPs and cytokines, which may be mediated primarily via p38 MAPK activation.

Salvagno C, Ciampricotti M, Tuit S, et al.
Therapeutic targeting of macrophages enhances chemotherapy efficacy by unleashing type I interferon response.
Nat Cell Biol. 2019; 21(4):511-521 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
Recent studies have revealed a role for macrophages and neutrophils in limiting chemotherapy efficacy; however, the mechanisms underlying the therapeutic benefit of myeloid-targeting agents in combination with chemotherapy are incompletely understood. Here, we show that targeting tumour-associated macrophages by colony-stimulating factor-1 receptor (CSF-1R) blockade in the K14cre;Cdh1

Guo X, Cui J, Zhao Y, et al.
The therapeutic value of cerebrospinal fluid ctDNA detection by next-generation sequencing for meningeal carcinomatosis: a case report.
BMC Neurol. 2019; 19(1):38 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
BACKGROUND: It is usually very complicated to treat meningeal carcinomatosis, and it is important to treat it as soon as possible.
CASE PRESENTATION: The 19-Del mutation was found in the exon for the epidermal growth factor receptor gene in the pleural effusion of a patient on March 11th, 2015. He took 250 mg of oral gefitinib once a day for 11 months beginning in December of 2015. On the 3rd of November 2016, he arrived at the hospital and presented with dizziness, headache and transient blurred vision. At this time, he began to take 4 mg of oral zoledronic acid once a month to prevent bone metastases. The result of a cytology exam of the cerebrospinal fluid showed that the man had meningeal carcinomatosis. The 19-Del mutation and the 20-T790 M mutation in the exon of the epidermal growth factor receptor gene was found by the next generation sequencing of the CSF. Then, he discontinued taking gefitinib and began to take 90-100 mg of oral AZD9291 once a day in November 2016. After adjusting the medication dose based on the NGS, his headache was noticeably reduced, and his condition gradually stabilized.
CONCLUSIONS: Cerebrospinal fluid ctDNA detection by next generation sequencing may become a suitable biomarker to monitor clinical treatment response in meningeal carcinomatosis.

Hua F, Tian Y, Gao Y, et al.
Colony‑stimulating factor 1 receptor inhibition blocks macrophage infiltration and endometrial cancer cell proliferation.
Mol Med Rep. 2019; 19(4):3139-3147 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
Tumor‑associated macrophages (TAMs) promote the progression of endometrial cancer (EC), but the mechanism of TAM in EC cell proliferation remains unclear. It was found that colony stimulating factor (CSF)‑1 and CSF‑1 receptor (CSF‑1R) were highly expressed in EC tissues of patients and two EC cell lines (ECC‑1 and HEC‑1A). Using wound‑healing and chemotactic migration assays to evaluate the role of EC cells in the induction of macrophage migration, it was found that the supernatant of EC cells promoted macrophage cell line (U937) migration; however, the migration capacity of U937 weakened when CSF‑1R was blocked. Subsequently, inhibition of CSF‑1 expression in EC cells also restrained U937 migration. Additionally, blocking CSF‑1R by PLX3397 treatment in U937 cells inhibited EC cell proliferation in a co‑culture system by inhibiting the expression of proliferation‑associated proteins (Janus kinase‑1, phosphoinositide 3‑kinase, AKT, cyclin kinase 2, 4 and retinoblastoma‑associated protein). Together, these results demonstrated that CSF‑1 secreted by EC cells promoted macrophage migration; similarly, CSF‑1‑stimulated macrophages promoted EC cell proliferation. These results suggested that the interaction between CSF‑1 and its receptor served an important role in promoting macrophage infiltration and progression of EC.

Yeo C, Lee HJ, Lee EO
Serum promotes vasculogenic mimicry through the EphA2/VE-cadherin/AKT pathway in PC-3 human prostate cancer cells.
Life Sci. 2019; 221:267-273 [PubMed] Related Publications
AIMS: Serum is widely used for in vitro cell culture of eukaryotic cells. Although serum is well known to affect various biological activities in cancer cells, its effect in vasculogenic mimicry (VM) is not yet fully defined. Thus, this study investigated the role of serum in VM in human prostate cancer (PCa) PC-3 cells.
MAIN METHODS: Invasion assay and 3D culture VM tube formation assay are performed. VM-related molecules are checked by western blot and reverse transcriptase-polymerase chain reaction. Nuclear twist is detected by confocal after twist-FITC/DAPI double staining.
KEY FINDINGS: Serum dramatically induced not only invasion but also VM. Serum increased the phosphorylation of erythropoietin-producing hepatocellular A2 (EphA2) without affecting EphA2 expression. Both the protein and mRNA expression levels of vascular endothelial cadherin (VE-cadherin) are up-regulated by serum. Twist expression was increased in the nucleus by serum. Serum activated AKT through phosphorylation, despite the unchanged AKT expression. Serum caused an increase in matrix metalloproteinase-2 (MMP-2) and laminin subunit 5 gamma-2 (LAMC2) protein expressions. Wortmannin, a phosphoinositide-3-kinase inhibitor, significantly decreased serum-induced invasion and VM.
SIGNIFICANCE: These results demonstrated that serum activates EphA2 and up-regulates twist/VE-cadherin, which in turn activate AKT that up-regulates MMP-2 and LAMC2, thereby inducing the invasion and VM of human PCa PC-3 cells.

Yan J, Zhao Q, Gabrusiewicz K, et al.
FGL2 promotes tumor progression in the CNS by suppressing CD103
Nat Commun. 2019; 10(1):448 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
Few studies implicate immunoregulatory gene expression in tumor cells in arbitrating brain tumor progression. Here we show that fibrinogen-like protein 2 (FGL2) is highly expressed in glioma stem cells and primary glioblastoma (GBM) cells. FGL2 knockout in tumor cells did not affect tumor-cell proliferation in vitro or tumor progression in immunodeficient mice but completely impaired GBM progression in immune-competent mice. This impairment was reversed in mice with a defect in dendritic cells (DCs) or CD103

Miller AM, Shah RH, Pentsova EI, et al.
Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid.
Nature. 2019; 565(7741):654-658 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
Diffuse gliomas are the most common malignant brain tumours in adults and include glioblastomas and World Health Organization (WHO) grade II and grade III tumours (sometimes referred to as lower-grade gliomas). Genetic tumour profiling is used to classify disease and guide therapy

You GR, Cheng AJ, Lee LY, et al.
Prognostic signature associated with radioresistance in head and neck cancer via transcriptomic and bioinformatic analyses.
BMC Cancer. 2019; 19(1):64 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
BACKGROUND: Radiotherapy is an indispensable treatment modality in head and neck cancer (HNC), while radioresistance is the major cause of treatment failure. The aim of this study is to identify a prognostic molecular signature associated with radio-resistance in HNC for further clinical applications.
METHODS: Affymetrix cDNA microarrays were used to globally survey different transcriptomes between HNC cell lines and isogenic radioresistant sublines. The KEGG and Partek bioinformatic analytical methods were used to assess functional pathways associated with radioresistance. The SurvExpress web tool was applied to study the clinical association between gene expression profiles and patient survival using The Cancer Genome Atlas (TCGA)-head and neck squamous cell carcinoma (HNSCC) dataset (n = 283). The Kaplan-Meier survival analyses were further validated after retrieving clinical data from the TCGA-HNSCC dataset (n = 502) via the Genomic Data Commons (GDC)-Data-Portal of National Cancer Institute. A panel maker molecule was generated to assess the efficacy of prognostic prediction for radiotherapy in HNC patients.
RESULTS: In total, the expression of 255 molecules was found to be significantly altered in the radioresistant cell sublines, with 155 molecules up-regulated 100 down-regulated. Four core functional pathways were identified to enrich the up-regulated genes and were significantly associated with a worse prognosis in HNC patients, as the modulation of cellular focal adhesion, the PI3K-Akt signaling pathway, the HIF-1 signaling pathway, and the regulation of stem cell pluripotency. Total of 16 up-regulated genes in the 4 core pathways were defined, and 11 over-expressed molecules showed correlated with poor survival (TCGA-HNSCC dataset, n = 283). Among these, 4 molecules were independently validated as key molecules associated with poor survival in HNC patients receiving radiotherapy (TCGA-HNSCC dataset, n = 502), as IGF1R (p = 0.0454, HR = 1.43), LAMC2 (p = 0.0235, HR = 1.50), ITGB1 (p = 0.0336, HR = 1.46), and IL-6 (p = 0.0033, HR = 1.68). Furthermore, the combined use of these 4 markers product an excellent result to predict worse radiotherapeutic outcome in HNC (p < 0.0001, HR = 2.44).
CONCLUSIONS: Four core functional pathways and 4 key molecular markers significantly contributed to radioresistance in HNC. These molecular signatures may be used as a predictive biomarker panel, which can be further applied in personalized radiotherapy or as radio-sensitizing targets to treat refractory HNC.

Shvachko LP, Zavelevich MP, Gluzman DF, et al.
Vitamin Е activates expression of С/EBP alpha transcription factor and G-CSF receptor in leukemic K562 cells.
Exp Oncol. 2018; 40(4):328-331 [PubMed] Related Publications
BACKGROUND: Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder associated with the activity of BCR-ABL fusion oncogene. Tyrosine kinase inhibitors are the current treatment of CML, but secondary mutations finally contribute to therapy resistance and blast crisis of the disease. The search for the novel compounds for the effective control of CML is now in the spotlight. The progression of CML to blast crisis is correlated with down-modulation of C/EBP alpha. Therefore, C/EBP alpha may be considered as a putative target in differentiation therapies in myeloid leukemias. The aim of the study was to assess the potential of vitamin E as the possible inducer of C/EBP alpha expression in BCR-ABL-positive CML K562 cells.
MATERIALS AND METHODS: RNA extracted from K562 cells cultured with valproic acid or vitamin E was converted to cDNA, RT-PCR reactions were carried out using HotStarTaq DNA polymerase with primers for C/EBP alpha and granulocyte colony-stimulating factor receptor (G-CSFR).
RESULTS: We have not found detectable expression of C/EBP alpha in K562 cells. Upon 48-h culture with vitamin E at a dose of 100 µM, K562 cells expressed both C/EBP alpha and G-CSFR.
CONCLUSION: Vitamin E restored the expression of C/EBP alpha mRNA in chronic myelogenous leukemia K562 cells. In this setting, G-CSFR expression in vitamin E treated K562 cells seems to suggest the activation to granulocytic differentiation. It should be further elucidated whether such effects of vitamin E on C/EBP alpha transcription factor are direct or mediated indirectly due to antioxidant properties of vitamin E.

Ma W, He H, Wang H
Oncolytic herpes simplex virus and immunotherapy.
BMC Immunol. 2018; 19(1):40 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
BACKGROUND: Oncolytic viruses have been proposed to be employed as a potential treatment of cancer. Well targeted, they will serve the purpose of cracking tumor cells without causing damage to normal cells. In this category of oncolytic viral drugs human pathogens herpes simplex virus (HSV) is especially suitable for the cause. Although most viral infection causes antiviral reaction in the host, HSV has multiple mechanisms to evade those responses. Powerful anti-tumor effect can thus be achieved via genetic manipulation of the HSV genes involved in this evading mechanism, namely deletions or mutations that adapt its function towards a tumor microenvironment. Currently, oncolytic HSV (oHSV) is widely use in clinical; moreover, there's hope that its curative effect will be further enhanced through the combination of oHSV with both traditional and emerging therapeutics.
RESULTS: In this review, we provide a summary of the HSV host antiviral response evasion mechanism, HSV expresses immune evasion genes such as ICP34.5, ICP0, Us3, which are involved in inducing and activating host responses, so that the virus can evade the immune system and establish effective long-term latent infection; we outlined details of the oHSV strains generated by removing genes critical to viral replication such as ICP34.5, ICP0, and inserting therapeutic genes such as LacZ, granulocyte macrophage colony-stimulating factor (GM-CSF); security and limitation of some oHSV such G207, 1716, OncoVEX, NV1020, HF10, G47 in clinical application; and the achievements of oHSV combined with immunotherapy and chemotherapy.
CONCLUSION: We reviewed the immunotherapy mechanism of the oHSV and provided a series of cases. We also pointed out that an in-depth study of the application of oHSV in cancer treatment will potentially benefits cancer patients more.

Komohara Y, Noyori O, Saito Y, et al.
Potential anti-lymphoma effect of M-CSFR inhibitor in adult T-cell leukemia/lymphoma.
J Clin Exp Hematop. 2018; 58(4):152-160 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
The c-fms proto-oncogene is also known as macrophage colony stimulating factor receptor (M-CSFR) or colony-stimulating factor-1 receptor (CSF-1R), and is expressed on several types of malignant tumor cells and myeloid cells. In the present study, we found that overexpression of M-CSFR was present in adult T-cell leukemia/lymphoma (ATLL) cases. M-CSFR signaling was associated with lymphoma cell proliferation, and M-CSFR inhibition induced apoptosis in lymphoma cells. The ATLL cell line ATL-T expressed M-CSF/CSF-1 and interleukin (IL)-34, which are both M-CSFR ligands. M-CSF and IL-34 expression was seen in ATLL cases, and co-expression of these ligands was detected in 11 of 13 ATLL cases. M-CSFR inhibition suppressed programmed death-1 and -2 ligand in ATL-T cells and macrophages stimulated with conditioned medium from ATL-T cells. Thus, an M-CSFR inhibitor may be useful as additional therapy against ATLL due to direct and indirect mechanisms.

Liu M, Sun X, Shi S
MORC2 Enhances Tumor Growth by Promoting Angiogenesis and Tumor-Associated Macrophage Recruitment via Wnt/β-Catenin in Lung Cancer.
Cell Physiol Biochem. 2018; 51(4):1679-1694 [PubMed] Related Publications
BACKGROUND/AIMS: In this study, we aimed to investigate how MORC family CW-type zinc finger 2 (MORC2) affects tumor progression of lung cancer.
METHODS: The MORC2 level was analyzed by real-time RT-PCR and immunohistochemistry (IHC) in normal control tissues and lung cancers. LL/2 cells overexpressing MORC2 were used to study how MORC2 expression influences lung cancer progression. The effects of MORC2 on cell viability, migration and invasion were assessed by MTT assay, Western blotting, and transwell assays, respectively. Afterwards, the effects of MORC2 on the activation of the Wnt/β-catenin pathway were explored by Western blotting. The effects of MORC2 on tumor-associated macrophages (TAM) were determined by immunofluorescence (IF) staining, real-time RT-PCR and Western blotting.
RESULTS: Our results showed that MORC2 was upregulated in lung cancers relative to adjacent tissues. The results also demonstrated that MORC2 promoted lung cancer tumor growth in vivo. Additionally, MORC2 overexpression stimulated the upregulation of vascular endothelial growth factor (VEGF), driving angiogenesis. MORC2 overexpression in LL/2 also increased the amount of aldehyde dehydrogenase-1 (ALDH1) protein, indicating that MORC2 increased cancer stem cell features. We further determined that MORC2 activated Wnt/β-catenin signaling in lung cancer cells. Upregulation of macrophage-recruiting genes including VEGF and Macrophage-specific colony stimulating factor (CSF-1) recruits TAMs to the tumor site, which has the net effect of promoting additional tumor growth and metastasis.
CONCLUSION: Our data suggest that MORC2 overexpression can drive lung cancer growth by stimulating the recruitment of TAMs in addition to angiogenesis and that activation of Wnt/β-signaling may be a key pathway underlying this phenotype that is amenable to pharmacological intervention.

Huang R, Ge M, Zhou X, et al.
Epidermal Growth Factor Receptor Mutation Detection in Cerebrospinal Fluid of Lung Adenocarcinoma Patients with Leptomeningeal Metastasis.
Cancer Biother Radiopharm. 2019; 34(2):128-133 [PubMed] Related Publications
BACKGROUND: Epidermal growth factor receptor (EGFR) mutations are associated with leptomeningeal metastases (LM) of nonsmall cell lung cancer and sensitivity to tyrosine kinase inhibitor (TKI) treatment. Owing to the difficulty of obtaining carcinomatous meningeal tissue for analysis, cerebrospinal fluid (CSF) might be an alternative.
OBJECTIVE: To investigate the EGFR mutation detection in the CSF of lung adenocarcinoma patients with LM.
METHODS: Twenty-five lung adenocarcinoma patients with LM diagnosed by CSF cytology were retrospectively evaluated. The results of EGFR mutation detection in CSF, the treatment plan, and clinical outcome information were recorded.
RESULTS: Nineteen patients had a known EGFR status in their primary tumors. Twenty patients received EGFR mutation analysis in CSF after LM diagnosis and 14 of them with a known EGFR mutation status of both primary tumors and CSF. Ten (71.4%) had the same EGFR gene status. In primary tumors, no T790M mutations were detected, whereas in CSF, 2 L858R cases and 1 19del case had T790M mutations at the same time. The detection rate of T790M mutations in CSF was 18.1% (2 of 11) in all cases with EGFR-sensitive mutations in the primary lesion.
CONCLUSIONS: EGFR mutation detection in CSF of lung adenocarcinoma patients with LM might be an alternative when leptomeningeal biopsy cannot be applied and may help to guide TKI treatments.

Orciani M, Caffarini M, Torresetti M, et al.
Breast Implant Texturization Does Not Affect the Crosstalk Between MSC and ALCL Cells.
Inflammation. 2019; 42(2):721-730 [PubMed] Related Publications
In the last decade, there has been a growing interest about the possible association between anaplastic large cell lymphoma (ALCL) and breast implants (BIA-ALCL). Many variables, such as breast implants texturization, have been investigated. Breast implants often lead to the formation of a periprosthetic capsule, characterized by inflammation. The presence of the inflamed capsule has been found in the majority of patients with BIA-ALCL. Inflammation may be sustained or counteracted by mesenchymal stem cells (MSCs) by the secretion of pro- or anti-inflammatory cytokines. MSCs were isolated from three capsules surrounding micro-textured (micro-MSCs) and from three capsules surrounding macro-textured (macro-MSCs) implants; after characterization, MSCs were co-cultured with KI-JK cells (a cell line derived from the cutaneous form of ALCL). The secretion of cytokines related to inflammation, the proliferation rate, and the expression of genes referred to pro-tumoral mechanisms were evaluated. Co-cultures of KI-JK cells with micro- or macro-MSCs gave the same results about the secretion of cytokines (increase of IL10, G-CSF, and TGF-β1 and decrease of IL4, IL5, IL12, IL13, IL17A, IFN-γ (p < 0.05) with respect to mock sample), expression of selected genes (increase for ACVR1, VEGF, TGF-βR2, CXCL12, and MKi67 (p < 0.05) with respect to control sample), and the proliferation rate (no variation between mock and co-cultured samples). Our results suggest that MSCs derived from capsules surrounding micro- and macro-textured implants display the same effects on the ALCL cells.

Zhao L, Chi W, Cao H, et al.
Screening and clinical significance of tumor markers in head and neck squamous cell carcinoma through bioinformatics analysis.
Mol Med Rep. 2019; 19(1):143-154 [PubMed] Article available free on PMC after 18/09/2019 Related Publications
In order to identify potential diagnostic and prognostic biomarkers, and treatment targets for head and neck squamous cell carcinoma (HNSCC), the present study obtained the gene expression profiles in HNSCC through public data mining, and core genes were identified using a series of bioinformatics analysis methods and databases. A total of nine hub genes (SPP1, ITGA6, TMPRSS11D, MMP1, LAMC2, FAT1, ACTA1, SERPINE1 and CEACAM1) were identified to be significantly correlated with HNSCC. Furthermore, overall survival analysis demonstrated that the expression values of hub genes were associated with overall survival in HNSCC. Furthermore, certain of the identified genes, including, TMPRSS11D, ACTA1 and CEACAM1, have not been thoroughly investigated in HNSCC previously. Taken together, the nine hub genes obtained by screening in the present study may serve as potential tumor markers and important prognostic indicators for HNSCC.

Zeng C, Chen L, Chen B, et al.
Th17 cells were recruited and accumulated in the cerebrospinal fluid and correlated with the poor prognosis of anti-NMDAR encephalitis.
Acta Biochim Biophys Sin (Shanghai). 2018; 50(12):1266-1273 [PubMed] Related Publications
Anti-N-methyl-D-aspartate-receptor (NMDAR) encephalitis is an autoimmune disorder characterized by memory deficits, psychiatric symptoms, and autonomic instability. The lack of suitable biomarkers targeting anti-NMDAR encephalitis makes the immunotherapy and prognosis challenging. In this study, we found that the Th17 cells were significantly accumulated in the cerebrospinal fluid (CSF) of anti-NMDAR encephalitis patients than that of control individuals. The concentration of the cytokines and chemokines including interleukin (IL)-1β, IL-17, IL-6, and CXCL-13 were significantly increased in the CSF of anti-NMDAR encephalitis patients. IL-6 and IL-17 were found to promote the differentiation of CD4+ T cells into Th17 lineage. The chemotaxis assay showed that CCL20 and CCL22 play essential roles in the migration of Th17 cells. Notably, the correlation between the expression of IL-17 and the outcome of anti-NMDAR encephalitis patients was analyzed. The data showed that high level of IL-17 was significantly correlated with the limited response to the treatment and relapse of anti-NMDAR encephalitis patients. Our results suggested the potential important involvement of IL-17 in anti-NMDAR encephalitis.

Bagley SJ, Hwang WT, Brem S, et al.
RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma.
J Neurooncol. 2019; 141(1):95-102 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
INTRODUCTION: We sought to determine which therapeutically targetable immune checkpoints, costimulatory signals, and other tumor microenvironment (TME) factors are independently associated with immune cytolytic activity (CYT), a gene expression signature of activated effector T cells, in human glioblastoma (GBM).
METHODS: GlioVis was accessed for RNA-seq data from The Cancer Genome Atlas (TCGA). For subjects with treatment-naïve, primary GBM, we quantified mRNA expression of 28 therapeutically targetable TME factors. CYT (geometric mean of GZMA and PRF1 expression) was calculated for each tumor. Multiple linear regression was performed to determine the relationship between the dependent variable (CYT) and mRNA expression of each of the 28 factors. Variables associated with CYT in multivariate analysis were subsequently evaluated for this association in an independent cohort of newly diagnosed GBMs from the Chinese Glioma Cooperative Group (CGCG).
RESULTS: 109 TCGA tumors were analyzed. The final multiple linear regression model included the following variables, each positively associated with CYT except VEGF-A (negative association): CSF-1 (p = 0.003), CD137 (p = 0.042), VEGF-A (p < 0.001), CTLA4 (p = 0.028), CD40 (p = 0.023), GITR (p = 0.020), IL6 (p = 0.02), and OX40 (p < 0.001). In CGCG (n = 52), each of these variables remained significantly associated with CYT in univariate analysis except for VEGF-A. In multivariate analysis, only CTLA4 and CD40 remained statistically significant.
CONCLUSIONS: Using multivariate modeling of RNA-seq gene expression data, we identified therapeutically targetable TME factors that are independently associated with intratumoral cytolytic T-cell activity in human GBM. As a myriad of systemic immunotherapies are now available for investigation, our results could inform rational combinations for evaluation in GBM.

Ravindranathan S, Nguyen KG, Kurtz SL, et al.
Tumor-derived granulocyte colony-stimulating factor diminishes efficacy of breast tumor cell vaccines.
Breast Cancer Res. 2018; 20(1):126 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
BACKGROUND: Although metastasis is ultimately responsible for about 90% of breast cancer mortality, the vast majority of breast-cancer-related deaths are due to progressive recurrences from non-metastatic disease. Current adjuvant therapies are unable to prevent progressive recurrences for a significant fraction of patients with breast cancer. Autologous tumor cell vaccines (ATCVs) are a safe and potentially useful strategy to prevent breast cancer recurrence, in a personalized and patient-specific manner, following standard-of-care tumor resection. Given the high intra-patient and inter-patient heterogeneity in breast cancer, it is important to understand which factors influence the immunogenicity of breast tumor cells in order to maximize ATCV effectiveness.
METHODS: The relative immunogenicity of two murine breast carcinomas, 4T1 and EMT6, were compared in a prophylactic vaccination-tumor challenge model. Differences in cell surface expression of antigen-presentation-related and costimulatory molecules were compared along with immunosuppressive cytokine production. CRISPR/Cas9 technology was used to modulate tumor-derived cytokine secretion. The impacts of cytokine deletion on splenomegaly, myeloid-derived suppressor cell (MDSC) accumulation and ATCV immunogenicity were assessed.
RESULTS: Mice vaccinated with an EMT6 vaccine exhibited significantly greater protective immunity than mice vaccinated with a 4T1 vaccine. Hybrid vaccination studies revealed that the 4T1 vaccination induced both local and systemic immune impairments. Although there were significant differences between EMT6 and 4T1 in the expression of costimulatory molecules, major disparities in the secretion of immunosuppressive cytokines likely accounts for differences in immunogenicity between the cell lines. Ablation of one cytokine in particular, granulocyte-colony stimulating factor (G-CSF), reversed MDSC accumulation and splenomegaly in the 4T1 model. Furthermore, G-CSF inhibition enhanced the immunogenicity of a 4T1-based vaccine to the extent that all vaccinated mice developed complete protective immunity.
CONCLUSIONS: Breast cancer cells that express high levels of G-CSF have the potential to diminish or abrogate the efficacy of breast cancer ATCVs. Fortunately, this study demonstrates that genetic ablation of immunosuppressive cytokines, such as G-CSF, can enhance the immunogenicity of breast cancer cell-based vaccines. Strategies that combine inhibition of immunosuppressive factors with immune stimulatory co-formulations already under development may help ATCVs reach their full potential.

Luo W, Yu H, Zou X, et al.
Long non-coding RNA taurine-upregulated gene 1 correlates with unfavorable prognosis in patients with refractory or relapsed acute myeloid leukemia treated by purine analogue based chemotherapy regimens.
Cancer Biomark. 2018; 23(4):485-494 [PubMed] Related Publications
OBJECTIVE: This study aimed to explore the correlation of long non-coding RNA taurine-upregulated gene 1 (lncRNA TUG1) expression with clinicopathological features and its predictive value for treatment response and survival profiles in refractory or relapsed acute myeloid leukemia (R/R AML) patients.
METHODS: Seventy three R/R AML patients who received cladribine combined with cytarabine and granulocyte colony-stimulating factor (G-CSF) (CLAG) or fludarabine combined with cytarabine and G-CSF (FLAG) based chemotherapy and 37 non-malignant controls were recruited. LncRNA TUG1 expression was detected in bone marrow sample obtained before treatment. Complete response (CR), partial response (PR), overall response rate (ORR) and overall survival (OS) were evaluated.
RESULTS: LncRNA TUG1 expression was upregulated in R/R AML patients compared to controls. It was also elevated in R/R AML patients with age ⩾ 60 years (vs. age < 60 years, P= 0.030) and in patients with secondary AML (vs. primary AML, P= 0.035). R/R AML patients with lncRNA TUG1 high expression achieved numerically lower CR (P= 0.053), decreased ORR (P= 0.028) and shorter OS (P< 0.001) than patients with lncRNA TUG1 low expression. Univariate logistic regression and COX's regression disclosed that lncRNA TUG1 high expression correlated with declined ORR, numerically decreased CR, and reduced OS. Furthermore, multivariate analyses verified that lncRNA TUG1 high expression was an independent predictive factor for decreased ORR and worse OS.
CONCLUSIONS: In conclusion, lncRNA TUG1 expression was elevated in R/R AML patients, and it might serve as a potential biomarker for poor prognosis in R/R AML patients treated with CLAG or FLAG based chemotherapy.

Woo HH, Chambers SK
Human ALKBH3-induced m
Biochim Biophys Acta Gene Regul Mech. 2019; 1862(1):35-46 [PubMed] Related Publications
In ovarian and breast cancers, the actions of the cytokine CSF-1 lead to poor prognosis. CSF-1 expression can be regulated post-transcriptionally. RNA methylation is another layer of posttranscriptional regulation. The methylation of N

Negoro Y, Yano R, Yoshimura M, et al.
Influence of UGT1A1 polymorphism on etoposide plus platinum-induced neutropenia in Japanese patients with small-cell lung cancer.
Int J Clin Oncol. 2019; 24(3):256-261 [PubMed] Related Publications
BACKGROUND: The association between UGT1A1 polymorphism and etoposide-induced toxicities is still not clear. The aim of this study was to assess the association between uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphism and severe hematologic toxicities in Japanese patients receiving etoposide plus platinum chemotherapy for small-cell lung cancer.
METHODS: This retrospective analysis included patients with small-cell lung cancer who had received their first-line chemotherapy with etoposide plus cisplatin or carboplatin, between October 2008 and April 2018, at the University of Fukui Hospital. The relationship between UGT1A1 polymorphisms and first-cycle neutropenia as well as thrombocytopenia was evaluated.
RESULTS: A total of 55 patients were enrolled. The incidence of grade 4 neutropenia during the first cycle of etoposide-based chemotherapy was higher in patients with homozygous (hmz) polymorphisms for UGT1A1*28 and *6 (*28/*28, *6/*6, and *6/*28) than in patients with wild-type (wt) (*1/*1) and heterozygous (htz) (*1/*28 and *1/*6) polymorphisms (88% vs 43% P = 0.03). The incidence of febrile neutropenia and grade 4 thrombocytopenia, however, was not significantly different. Multivariate analysis suggested that grade 4 neutropenia associated significantly with an hmz UGT1A1 genotype [odds ratio (OR) 11.3; P = 0.04] and administration of granulocyte colony-stimulating factor (G-CSF) before the neutrophil counts dropped to < 500 cells/µL (OR; P = 0.01).
CONCLUSIONS: UGT1A1*28 and UGT1A1*6 mutations might be regarded as predictors for etoposide-induced grade 4 neutropenia.

Majkowska-Pilip A, Koźmiński P, Wawrzynowska A, et al.
Application of Neurokinin-1 Receptor in Targeted Strategies for Glioma Treatment. Part I: Synthesis and Evaluation of Substance P Fragments Labeled with
Molecules. 2018; 23(10) [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Gliomas, particularly WHO grade IV glioblastoma multiforme, are one of the most common and aggressive primary tumors of the central nervous system. The neuropeptide, substance P (SP), is the physiological ligand of the neurokinin-1 (NK-1) receptor that is consistently overexpressed in glioblastoma cells. The aim of this work was to study physico-chemical and biological properties of different SP analogues labeled with technetium-99m and lutetium-177 radionuclides. The synthesized compounds were characterized in vitro by partition coefficients (log

Kahn SA, Wang X, Nitta RT, et al.
Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma.
Nat Commun. 2018; 9(1):4121 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Medulloblastoma is the most common malignant brain tumor of childhood. Group 3 medulloblastoma, the most aggressive molecular subtype, frequently disseminates through the leptomeningeal cerebral spinal fluid (CSF) spaces in the brain and spinal cord. The mechanism of dissemination through the CSF remains poorly understood, and the molecular pathways involved in medulloblastoma metastasis and self-renewal are largely unknown. Here we show that NOTCH1 signaling pathway regulates both the initiation of metastasis and the self-renewal of medulloblastoma. We identify a mechanism in which NOTCH1 activates BMI1 through the activation of TWIST1. NOTCH1 expression and activity are directly related to medulloblastoma metastasis and decreased survival rate of tumor-bearing mice. Finally, medulloblastoma-bearing mice intrathecally treated with anti-NRR1, a NOTCH1 blocking antibody, present lower frequency of spinal metastasis and higher survival rate. These findings identify NOTCH1 as a pivotal driver of Group 3 medulloblastoma metastasis and self-renewal, supporting the development of therapies targeting this pathway.

Song J, Wu S, Xia X, et al.
Cell adhesion-related gene somatic mutations are enriched in aggressive papillary thyroid microcarcinomas.
J Transl Med. 2018; 16(1):269 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
BACKGROUND: Approximately half of the documented increases in differentiated thyroid carcinoma is due to identification of papillary thyroid microcarcinomas (PTMCs). Knowing whether PTMC is aggressive is required for proper treatment, but until now, there has been no method for assessing these traits and understanding the underlying mechanisms for aggressiveness.
METHODS: We performed whole-exome sequencing of 16 PTMCs and matched normal thyroid tissues and GO/KEGG analysis to study genetic alterations and biological consequences associated with aggressive PTMCs, and then sequenced these genes using a next-generation gene-panel approach in an additional 70 PTMC samples including aggressive (n = 50) and non-aggressive (n = 20) groups.
RESULTS: We identified 254 somatic mutations of 234 genes, for which 178 mutations in 168 genes were found in the aggressive group, and 76 mutations in 74 genes were found in the non-aggressive group. Several recurrent mutations in BRAF, VCAN, ALDH1L1, and MUC5B were identified, and many novel but infrequent mutations in other genes were also found. The aggressive cohort had more mutational burdens than the non-aggressive group (P = 0.004). Nonsynonymous mutations of 13 genes (MUC5B, TNN, SSPO, PPFIA1, PCDHGA2, ITGA8, ITGA4, DCHS1, CRNN, ROCK1, RELN, LAMC2, and AEBP1) were involved in cell adhesion, and these were only present in the aggressive group. Targeted sequencing of these genes revealed significant enrichment in the aggressive group (P = 0.000004).
CONCLUSION: PTC may have evolved from PTMC due to sharing similar gene mutations, and the accumulation of such mutations promoted the aggressiveness of PTMC. Gene mutants associated with cell adhesion may be used to predict PTMC aggressiveness and allow more selective treatment.

Yang T, Zhang Z, Zhang J, et al.
The rs2147578 C > G polymorphism in the Inc-LAMC2-1:1 gene is associated with increased neuroblastoma risk in the Henan children.
BMC Cancer. 2018; 18(1):948 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
BACKGROUND: The rs2147578 C > G polymorphism in the long non-coding RNA gene Lnc-LAMC2-1:1 is associated with increased susceptibility to a few types of cancers. However, its role in neuroblastoma has not been evaluated yet.
METHODS: We investigated the association between the lnc-LAMC2-1:1 rs2147578 C > G polymorphism and neuroblastoma susceptibility in Chinese Han populations. A total of 393 neuroblastoma cases and 812 healthy individuals from the Henan and Guangdong provinces were enrolled and subjected to genotyping. Odds ratio (OR) and 95% confidence interval (CI) were used to determine the strength of the association of interest.
RESULTS: Combined analysis revealed that the lnc-LAMC2-1:1 rs2147578 C > G polymorphism was associated with increased neuroblastoma susceptibility (CG vs. CC: adjusted OR = 1.33, 95% CI = 1.01-1.75, P = 0.045; CG/GG vs. CC: adjusted OR = 1.34, 95% CI = 1.03-1.74, P = 0.028). In stratification analysis, children under 18 months with rs2147578 CG/GG genotypes had an increased neuroblastoma risk (adjusted OR = 1.70, 95% CI = 1.08-2.67, P = 0.022). Females with rs2147578 CG/GG genotypes also had increased neuroblastoma susceptibility (adjusted OR = 2.08, 95% CI = 1.37-3.18, P = 0.0007). In addition, children with lnc-LAMC2-1:1 rs2147578 CG/GG genotypes were prone to develop earlier stages of neuroblastoma (adjusted OR = 1.46, 95% CI = 1.01-2.12, P = 0.046).
CONCLUSIONS: The Lnc-LAMC2-1:1 rs2147578 C > G polymorphism may contribute to increased neuroblastoma susceptibility in children of Henan province.

Zhao C, Zou H, Zhang J, et al.
An integrated methylation and gene expression microarray analysis reveals significant prognostic biomarkers in oral squamous cell carcinoma.
Oncol Rep. 2018; 40(5):2637-2647 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Oral squamous cell carcinoma (OSCC) is a life‑threatening disease with a poor prognosis. Although previous studies have reported that the methylation of certain genes is associated with the pathogenesis of OSCC, the methylation of genes that have relevance to OSCC progression is not clearly documented. The present study aimed to gain insights into the mechanisms underlying DNA methylation regulation associated with OSCC progression and to identify potential prognostic markers for OSCC treatment. DNA methylation dataset GSE41114 and gene expression dataset GSE74530 were downloaded from the Gene Expression Omnibus database. The global methylation status of OSCC tumor samples and normal control samples was determined, and differentially methylated genes (DMGs) in OSCC samples compared with control samples were identified. The mRNA expression data were then integrated to identify differentially expressed genes (DEGs) in OSCC samples compared with control samples. Overlapping genes between DEGs and DMGs were identified, and functional enrichment analysis was performed. In addition, survival analysis of the overlapping genes was performed to screen genes with prognostic significance in OSCC. A total of 40,115 differential methylation CpG sites spanning 3,360 DMGs were identified; CpG sites in the promoter, gene body and intergenic regions were generally highly hypermethylated or hypomethylated. Additionally, 508 DEGs in OSCC samples were identified, including 332 upregulated and 176 downregulated genes. A total of 82 overlapping genes between DEGs and DMGs were found, which were mainly involved in protein metabolism, regulation of the metabolic process and the immune system. Additionally, differential methylation or expression of several genes, including fibroblast activation protein α (FAP), interferon α inducible protein 27 (IFI27), laminin subunit γ2 (LAMC2), matrix metallopeptidase 1 (MMP1), serine peptidase inhibitor Kazal‑type 5 (SPINK5) and zinc finger protein 662 (ZNF662), was significantly associated with the survival of OSCC patients, and their differential expression in OSCC patients was further confirmed by reverse transcription‑quantitative polymerase chain reaction in OSCC and normal oral cell lines. Overall, FAP, IFI27, LAMC2, MMP1, SPINK5 and ZNF662 genes caused by epigenetic changes via DNA methylation may be associated with the development and progression of OSCC, and should be valuable OSCC therapeutic biomarkers.

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