Gene Summary

Gene:TNF; tumor necrosis factor
Aliases: DIF, TNFA, TNFSF2, TNLG1F, TNF-alpha
Summary:This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance, and cancer. Knockout studies in mice also suggested the neuroprotective function of this cytokine. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tumor necrosis factor
Source:NCBIAccessed: 31 August, 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

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TNF (cancer-related)

Chen C, Ma Y, Li YD, Zhang XC
[Influence of LBP alone or Combined with TRAIL on Apoptosis of MLL Rearranged Leukemic Cells].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2019; 27(4):1104-1110 [PubMed] Related Publications
OBJECTIVE: To investigate the effect of lycium barbarum polysaccharide (LBP) alone or combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the apoptosis of leukemia cell lines with MLL gene-rearrangement, and to explore the cell apoptotic pathway after the combined action.
METHODS: MLL-ALL cell line KOCL44 and KOCL45 were selected as the research object, then the control and experimental groups were set up. The cell survival rate was measured by the trypan blue dye exclusion method, the cell early apoptosis and expression of death receptors on the cell surface were detected by flow cytometry with Annexin-V/PI double staining. The protein level of caspase-8, BID, caspase-3, caspase-9, BAD, BCL-2, as well as mitochondrial and cytosol Cyto-C were detected by Western blot.
RESULTS: LBF combined with TRAIL inhibited the growth of KOCL44 and KOCL-45 cells and showed the synergistic effect, the results of flow cytometry with Amnexiu V/PI double staining were consistent with above-mentioned results. After treatment of KOCL44 and KOCL45 cells with LBF plus TRAIL, the significant expression of DR4 on cell surface was not found, while the expression of DR4 receptor was enhanced significantly, the pro-apoptotic proteins including caspase-8, BID, caspase-3, caspase-9 and BAD were activated significantly and BCL-2 was suppressed significantly with time-dependent manner. The expression of mitochondria cyto-C in KOCL44 and KOCL45 decreased along with prolonging of treatment time (r=-0.95, r=-0.866), while the expression of cytosol cyto-C in KOCL44 and KOCL45 increased along with prolonging of treatment time (r=0.883, r=0.903).
CONCLUSION: The combination of LBP and TRAIL significantly increases the apoptosis of KOCL44 and KOCL45, and the LBP and TRAIL can up-regulate the expression of TRAIL death receptor-DR5 on the cell surface, activate the pathway of caspase and mito-chrondia mitachondria, thus enhance the sensitivity of KOCL44 and KOCL45 to TRAIL induced apoptosis through both mitochondrial and apoptotic pathway.

Honda T, Inagawa H
Usefulness of Monocytes/macrophages Activated With Low-dose Lipopolysaccharide in Tumor Tissue and Adipose Tissue of Obesity.
Anticancer Res. 2019; 39(8):4475-4478 [PubMed] Related Publications
Chronic inflammation is involved in the development of cancer, lifestyle-related diseases, and autoimmune diseases. It also influences the severity of these diseases. Macrophages that accumulate in tumor tissues and adipose tissues of obesity have been shown to increase expression of inflammatory cytokines, thereby inducing inflammatory changes in these tissues. The macrophage phenotype is believed to be important in mediating inflammatory changes in tissues. Recently, monocytes/macrophages activated with low-dose lipopolysaccharide (LPS) were demonstrated to suppress increased expression of monocyte chemotactic protein (MCP)-1 and inflammatory cytokines (interleukin (IL)-1 β, IL-8, and tumor necrosis factor (TNF)-α). By suppressing the increased expression of chemotaxis-related and inflammation-related factors, monocytes/macrophages activated with low-dose LPS are considered to suppress the migration of macrophages into tissues and to regulate inflammatory changes in these tissues, respectively. The effects of macrophages activated with low-dose LPS were different from those of macrophages activated with high-dose LPS. In this review, we discuss the usefulness of monocytes/macrophages activation by low-dose LPS.

Yu QC, Song B, Zou XX, et al.
[Analysis of normal tissues adjacent to the tumour-specific expressed genes in breast cancer].
Yi Chuan. 2019; 41(7):625-633 [PubMed] Related Publications
Normal tissues adjacent to the tumour (NAT) are widely used as controls in comparative studies to search for cancer-associated genes. However, the gene expression profiles between NAT and non-tumour-bearing tissues are different. The presence of NAT-specific expressed genes often hinders traditional transcriptional profiles studies. Further, studies on the differences in gene expression profiles between NAT and tumour-free tissues are infrequently performed. In this study, we sequenced and analysed the transcriptomes of tumour tissues (T), matched NAT and contralateral breast normal tissues (CBN) of 14 breast cancer patients, and identified 102 differentially expressed genes (DEGs) between CBN and NAT. Gene enrichment and protein-protein interaction (PPI) analyses revealed that these DEGs are significantly enriched in TNF (tumour necrosis factor) signalling and EMT (epithelial-mesenchymal transition) gene sets closely associated with oncogenesis. Comparative analyses of the transcriptomic profiles between NAT and CBN, NAT and T identified 23 NAT-specific highly-expressed genes, namely tumour-adjacent speci?cally activated (TASA) genes. These genes were significantly enriched in TNF signalling gene set, and 15 of which have not been previously reported. The results indicate that TASA genes are common in adjacent tissues and are related to the TNF signalling in the immune system. The tumour-adjacent tissues harbour tumour-like expressed genes that could contribute to tumour initiation but are often missed in NAT-T pair-wise studies.

Gong W, Hoffmann JM, Stock S, et al.
Comparison of IL-2 vs IL-7/IL-15 for the generation of NY-ESO-1-specific T cells.
Cancer Immunol Immunother. 2019; 68(7):1195-1209 [PubMed] Related Publications
The anti-tumor efficacy of TCR-engineered T cells in vivo depends largely on less-differentiated subsets such as T cells with naïve-like T cell (T

Yang Q, Li J, Hu Y, et al.
MiR-218-5p Suppresses the Killing Effect of Natural Killer Cell to Lung Adenocarcinoma by Targeting SHMT1.
Yonsei Med J. 2019; 60(6):500-508 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Lung adenocarcinoma (LA) is one of the major types of lung cancer. MicroRNAs (miRNAs) play an essential role in regulating responses of natural killer (NK) cells to cancer malignancy. However, the mechanism of miR-218-5p involved in the killing effect of NK cells to LA cells remains poorly understood.
MATERIALS AND METHODS: The expression of miR-218-5p was examined by quantitative real-time polymerase chain reaction (qRT-PCR). Serine hydroxymethyl transferase 1 (SHMT1) level was detected by qRT-PCR or western blots. Cytokines production of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were detected by ELISA. The killing effect of NK cells to LA cells was investigated using lactate dehydrogenase cytotoxicity assay kit. The interaction of miR-218-5p and SHMT1 was probed by luciferase activity assay. Xenograft model was established to investigate the killing effect of NK cells
RESULTS: miR-218-5p was enhanced and SHMT1 was inhibited in NK cells of LA patients, whereas stimulation of interleukin-2 (IL-2) reversed their abundances. Addition of miR-218-5p reduced IL-2-induced cytokines expression and cytotoxicity in NK-92 against LA cells. Moreover, SHMT1 was negatively regulated by miR-218-5p and attenuated miR-218-5p-mediated effect on cytotoxicity, IFN-γ and TNF-α secretion in IL-2-activated NK cells. In addition, miR-218-5p exhaustion inhibited tumor growth by promoting killing effect of NK cells.
CONCLUSION: miR-218-5p suppresses the killing effect of NK cells to LA cells by targeting SHMT1, providing a potential target for LA treatment by ameliorating NK cells function.

Pradhan N, Parbin S, Kausar C, et al.
Paederia foetida induces anticancer activity by modulating chromatin modification enzymes and altering pro-inflammatory cytokine gene expression in human prostate cancer cells.
Food Chem Toxicol. 2019; 130:161-173 [PubMed] Related Publications
Aberrant epigenetic modifications are responsible for tumor development and cancer progression; however, readily reversible. Bioactive molecules from diets are promising to cure cancer by modulating epigenetic marks and changing immune response. These compounds specifically target the activity of DNMTs and HDACs to cure various human cancers. In view of this, we investigated the anticancer and epigenetic regulatory activities of an edible-plant Paederia foetida. The efficacy of methanolic extract of P. foetida leaves (MEPL) was tested for the modulation of epigenetic factors in gene silencing, i.e. DNMT and HDAC and expression pattern of certain tumor-suppressor genes. After treatment of prostate cancer cells (PC-3 and DU-145) with MEPL, lupeol and β-sitosterol; induction of apoptosis, decrease in cellular-viability and inhibition of cellular-migration were noticed. Simultaneously there was inhibition of DNMT1, HDACs and pro-inflammatory, IL-6, IL1-β, TNF-α and anti-inflammatory, IL-10 genes in cancer and THP1 cell lines. The DNMT1 protein content, enzyme activity and Bcl2 expression decreased significantly; however, expression of E-cadherin (CDH1) and pro-apoptotic gene Bax increased significantly after the treatment of cells with drugs. We conclude plant-derived compounds can be considered to target epigenetic machineries involved with malignant transformation and can open new avenues for cancer therapeutics provoking immune response.

Voorwerk L, Slagter M, Horlings HM, et al.
Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.
Nat Med. 2019; 25(6):920-928 [PubMed] Related Publications
The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low

Cheng J, Li Y, Kong J
Ginkgetin inhibits proliferation of HeLa cells via activation of p38/NF-κB pathway.
Cell Mol Biol (Noisy-le-grand). 2019; 65(4):79-82 [PubMed] Related Publications
Effect of ginkgetin on proliferation of human cervical cancer (HeLa) cells and the underlying mechanism   were investigated. Human cervical cancer (HeLa) cells were cultured at 37 °C in 10 % fetal bovine serum (FBS) supplemented RPMI 1640 medium in a humidified incubator containing 5 % CO2. Cell proliferation was determined using MTT assay, while real-time quantitative polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to determine the levels of expression of interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin 8 (IL-8). The expressions of p38 mitogen-activated protein kinases (p38 MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF- κB) were determined using Western blotting. Treatment of HeLa cells with ginkgetin significantly and time- and dose-dependently inhibited their proliferation (p < 0.05). The invasion of the cells were also significantly and dose-dependently decreased, when compared with control cells (p < 0.05). The expressions of p-p38 and p-NF-κB were significantly and dose-dependently down-regulated, relative to control group (p < 0.05). However, the expressions of p38 and NF-κB in ginkgetin-treated cells were not significantly different from those of control group (p > 0.05). The results of qRT-PCR and ELISA showed that the levels of expression of TNF-α, IL-1β and IL-8 mRNAs were significantly and dose-dependently reduced in HeLa cells after 48 h of treatment with ginkgetin, when compared with the control group (p < 0.05). The anti-proliferative effect of ginkgetin on HeLa cells is exerted via a mechanism involving the p38/NF-κB pathway.

Deng X, Luo Q, Dong F, et al.
[Tristetraprolin inhibits autophagy in cultured lung cancer cells
Nan Fang Yi Ke Da Xue Xue Bao. 2019; 39(3):313-319 [PubMed] Related Publications
OBJECTIVE: To explore the expression of the RNA-binding protein tristetraprolin in lung adenocarcinoma cells and its molecular mechanism for inhibiting autophagy.
METHODS: Quantitative real-time PCR and Western blotting were performed to detect the expression of autophagy-related genes (including Beclin1, LC3-Ⅱ/LC3-Ⅰ and SQSTM1/p62) in cultured lung adenocarcinoma cells at 24, 48 and 72 h after transient transfection with a tristetraprolin-overexpressing plasmid and the empty plasmid. The effects of transfection with the tristetraprolin-overexpressing plasmid and empty plasmids in the presence or absence of tumor necrosis factor-
RESULTS: The expressions of tristetraprolin were significantly reduced at both the mRNA and protein levels in lung adenocarcinoma cells (
CONCLUSIONS: The expression of tristetraprolin is low in lung adenocarcinoma cells. Tristetraprolin overexpression causes inhibition of autophagy in lung adenocarcinoma cells possibly by blocking NF-κB p65 and c-rel nuclear translocation.

de Carvalho LR, Borrego A, Jensen JR, et al.
Genetic Predisposition to Hepatocarcinogenesis in Inbred and Outbred Mouse Lines Selected for High or Low Inflammatory Response.
J Immunol Res. 2019; 2019:5298792 [PubMed] Free Access to Full Article Related Publications
AIRmax and AIRmin mouse strains phenotypically selected for high and low acute inflammatory responsiveness (AIR) are, respectively, susceptible or resistant to developing hepatocellular carcinoma (HCC) induced by the chemical carcinogens urethane and diethylnitrosamine (DEN). Early production of TNF-

Ameri Z, Ghiasi S, Farsinejad A, et al.
Telomerase inhibitor MST-312 induces apoptosis of multiple myeloma cells and down-regulation of anti-apoptotic, proliferative and inflammatory genes.
Life Sci. 2019; 228:66-71 [PubMed] Related Publications
AIMS: The telomerase-based therapy of cancer has received a great deal of attention due to the fact that it is expressed in almost all of the cancer cells while it is inactivated in most of the normal somatic cells. Current investigation was aimed to examine the effects of namely telomerase inhibitor, the MST-312, as a chemically modified derivative of epigallocatechin gallate (EGCG), on human multiple myeloma cell line U-266.
MAIN METHODS: U-266 cells were cultured and then treated by MST-312. The viability of cultured cells was measured by both trypan blue staining and MTT assay techniques. To examine the apoptosis, annexin-V/7-AAD staining using flow cytometry method was employed. To analysis the expression of Bax, Bcl-2, c-Myc, hTERT, IL-6 and TNF-α genes, the quantitative real-time PCR was employed.
KEY FINDINGS: We observed the short-term dose-dependent cytotoxic and apoptotic effect of MST-312 against U-266 myeloma cells. Gene expression analysis indicated that the MST-312-based apoptosis was associated with up-regulation of pro-apoptotic gene (Bax) as well as down-regulation of anti-apoptotic (Bcl-2), proliferative (c-Myc, hTERT) and inflammatory (IL-6, TNF-α) genes.
SIGNIFICANCE: These findings suggest that telomerase-based therapy using MST-312 may represent a novel promising strategy for treatment of multiple myeloma.

Zuo J, Jiang Y, Zhang E, et al.
Synergistic effects of 7-O-geranylquercetin and siRNAs on the treatment of human breast cancer.
Life Sci. 2019; 227:145-152 [PubMed] Related Publications
AIMS: To investigate the antitumor effect of 7-O-geranylquercetin (GQ) combining with survivin siRNA (siSuvi) or IL-10 siRNA (siIL-10) to breast cancer.
MAIN METHODS: Xenograft tumor model was established by subcutaneously inoculating human breast cancer MCF-7 cells in BALB/c nude mice. Transfection efficiency of siRNA mediated by cationic liposome CDO14 in MCF-7 cells and tumor bearing mice was measured by flow cytometer and living imaging sysytem, respectively. Cell viability was detected using CCK-8 assay. Cell apoptosis was determined by Hoechst33342 staining and AV-PI staining. Tumors bearing mice were administered with GQ by gavage, and/or with liposome CDO14 mediated siRNAs via tail intravenous injection. Expression levels of proteins and cytokines were detected by western blot and ELISA, respectively.
KEY FINDINGS: Liposome CDO14 could deliver siRNA to tumor effectively. Combination of GQ and siSuvi promoted the antiproliferation and pro-apoptosis effects of GQ or siSuvi to MCF-7 cells, and reduced the level of survivin and raised the level of caspase-7 in cells. GQ combining with siSuvi inhibited the growth of tumor, down-regulated the expression of survivin and up-regulated the expression of caspase-7 in tumor tissue. Similarly, GQ combining with siIL-10 inhibited the growth of tumor, decreased the level of IL-10 and increased the level of TNF-α. These results revealed that GQ enhanced the pro-apoptosis effect of siSuvi on tumor cells and the modulating effect of siIL-10 on tumor microenvironment.
SIGNIFICANCES: Synergistic anti-tumor effect of GQ and siRNAs against breast cancer proved that chemical drugs combining with siRNAs is a promising antitumor strategy.

Yu B, Zhang M, Chen J, et al.
Abnormality of hepatic triglyceride metabolism in Apc
Life Sci. 2019; 227:201-211 [PubMed] Related Publications
AIMS: Colorectal cancer syndrome has been one of the greatest concerns in the world. Although several epidemiological studies have shown that hepatic low lipoprotein lipase (LPL) mRNA expression may be associated with dyslipidemia and tumor progression, it is still not known whether the liver plays an essential role in hyperlipidemia of Apc
MAIN METHODS: We measured the expression of metabolic enzymes that involved fatty acid uptake, de novo lipogenesis (DNL), β-oxidation and investigated hepatic triglyceride production in the liver of wild-type and Apc
KEY FINDINGS: We found that hepatic fatty acid uptake and DNL decreased, but there was no significant difference in fatty acid β-oxidation. Interestingly, the production of hepatic very low-density lipoprotein-triglyceride (VLDL-TG) decreased at 20 weeks of age, but marked steatosis was observed in the livers of the Apc
SIGNIFICANCE: Altogether, these findings highlighted a novel role of GPIHBP1 that might be responsible for hypertriglyceridemia in Apc

Møller T, James JP, Holmstrøm K, et al.
Co-Detection of miR-21 and TNF-α mRNA in Budding Cancer Cells in Colorectal Cancer.
Int J Mol Sci. 2019; 20(8) [PubMed] Free Access to Full Article Related Publications
MicroRNA-21 (miR-21) is upregulated in many cancers including colon cancers and is a prognostic indicator of recurrence and poor prognosis. In colon cancers, miR-21 is highly expressed in stromal fibroblastic cells and more weakly in a subset of cancer cells, particularly budding cancer cells. Exploration of the expression of inflammatory markers in colon cancers revealed tumor necrosis factor alpha (TNF-α) mRNA expression at the invasive front of colon cancers. Surprisingly, a majority of the TNF-α mRNA expressing cells were found to be cancer cells and not inflammatory cells. Because miR-21 is positively involved in cell survival and TNF-α promotes necrosis, we found it interesting to analyze the presence of miR-21 in areas of TNF-α mRNA expression at the invasive front of colon cancers. For this purpose, we developed an automated procedure for the co-staining of miR-21, TNF-α mRNA and the cancer cell marker cytokeratin based on analysis of frozen colon cancer tissue samples (

Ding X, Li F, Zhang L
Knockdown of Delta-like 3 restricts lipopolysaccharide-induced inflammation, migration and invasion of A2058 melanoma cells via blocking Twist1-mediated epithelial-mesenchymal transition.
Life Sci. 2019; 226:149-155 [PubMed] Related Publications
AIMS: To investigate the effects and mechanisms of DLL3 in inflammation-mediated A2058 melanoma cell invasion and metastasis.
MATERIALS AND METHODS: Melanoma A2058 cells was stimulated with lipopolysaccharide (LPS), with or without transfection of DLL3 siRNA, or DLL3 overexpression vector, or Twist1 siRNA. Cell migration and invasion were detected by wound healing and transwell invasion assay. The production of inflammatory factors TNF-α and IL-6 was measured by ELISA. The expression of Notch signaling-related molecules was detected by PCR and western blot. The protein expression of MMP1, MMP9, VEGF, DLL3, and EMT-related molecules was tested by western blot.
KEY FINDINGS: LPS treatment increased migration and invasion of A2058 cells, accompanied by increased expression of TNF-α and IL-6. DLL3 was both upregulated in the LPS- or TNF-α-stimulated A2058 cells, and DLL3 knockdown inhibited LPS-induced inflammation, migration and invasion of A2058 cells, accompanied by down-regulation of MMP1, MMP9 and VEGF. Besides, DLL3 knockdown inhibits the expression of Twist1, a key EMT regulating factor, as well as the EMT hallmarks slug, N-cadherin and vimentin. Moreover, Twist1 silence inhibited EMT, and limited LPS-induced migration and invasion of A2058 cells, with decreased expression of MMP1, MMP9 and VEGF and reduced production of TNF-α and IL-6 in LPS-stimulated A2058 cells.
SIGNIFICANCE: Knockdown of DLL3 restricts LPS-induced inflammation, migration and invasion of A2058 melanoma cells via blocking Twist1-mediated EMT. Therefore, targeting DLL3 may be a promising therapeutic strategy against inflammation-aggravated melanoma progression.

Germini DE, Franco MIF, Fonseca FLA, et al.
Association of expression of inflammatory response genes and DNA repair genes in colorectal carcinoma.
Tumour Biol. 2019; 42(4):1010428319843042 [PubMed] Related Publications
Inflammation is an important etiological factor of colorectal carcinoma and may be related to colorectal carcinoma growth and proliferation. This study aimed to verify whether the presence of chronic inflammation represented by tumor necrosis factor-α, interleukin-2, interleukin-6, and interleukin-10 gene expression is related to hMLH1, hMSH2, hMSH6, and PMS2 gene expression and the corresponding protein levels of these genes from the DNA repair system. A total of 83 patients were operated on for curative or palliative colorectal carcinoma. Expression of the inflammatory response genes tumor necrosis factor-α, interleukin-2, interleukin-6, and interleukin-10 as well as expression of the hMLH1, hMSH2, hMSH6, and PMS2 genes of the DNA repair system (mismatch repair) and the expression levels of the corresponding mismatch repair proteins were measured in neoplastic tissue by reverse transcription polymerase chain reaction and immunohistochemistry, respectively. Associations were observed between hMSH6 mRNA expression and interleukin-2 mRNA expression (p = 0.026) as well as between hMLH1 and hMSH2 gene expression and tumor necrosis factor-α gene expression (p = 0.042). Higher tissue levels of interleukin-2 and tumor necrosis factor-α gene expression were associated with lower hMSH6, hMLH1, and hMSH2 gene expression.

Buhrmann C, Yazdi M, Popper B, et al.
Induction of the Epithelial-to-Mesenchymal Transition of Human Colorectal Cancer by Human TNF-β (Lymphotoxin) and its Reversal by Resveratrol.
Nutrients. 2019; 11(3) [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Tumor necrosis factor-beta (TNF-β), as an inflammatory mediator that has been shown to promote tumorigenesis, induces NF-κB. Natural multi-targeted agent resveratrol in turn shows anti-inflammatory and anti-cancer properties. Epithelial-to-mesenchymal transition (EMT) allows cancer cells to turn into a motile state with invasive capacities and is associated with metastasis and development of cancer stem cells (CSC). However, TNF-β-induced EMT and the anti-invasion mechanism of resveratrol on CRC are not yet completely understood.
METHODS: We investigated the underlying molecular mechanisms of resveratrol on TNF-β/TNF-βR-induced EMT and migration of CRC cells (HCT116, RKO, SW480) in monolayer or 3D alginate cultures.
RESULTS: TNF-β, similar to TNF-α, induced significant cell proliferation, morphological change, from an epithelial to a spindle-like mesenchymal shape with the formation of filopodia and lamellipodia associated with the expression of EMT parameters (elevated vimentin and slug, reduced E-cadherin), increased migration/invasion, and formation of CSC in all CRC cells. Interestingly, these effects were dramatically decreased in the presence of resveratrol or anti-TNF-βR with TNF-β co-treatment, inducing biochemical changes to the mesenchymal-epithelial transition (MET), with a planar cell surface and suppressed formation of CSC cells. This was associated with a significant increase in apoptosis. Furthermore, we found that resveratrol suppressed TNF-β-induced NF-κB and NF-κB-regulated gene biomarkers associated with growth, proliferation, and invasion. Finally, TNF-βR interacts directly with focal adhesion kinase (FAK) and NF-κB.
CONCLUSION: These results suggest that resveratrol down-regulates TNF-β/TNF-βR-induced EMT, at least in part via specific suppression of NF-κΒ and FAK in CRC cells.

Li N, Fan X, Wang X, et al.
Autophagy-Related 5 Gene rs510432 Polymorphism Is Associated with Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Virus Infection.
Immunol Invest. 2019; 48(4):378-391 [PubMed] Related Publications
BACKGROUND: Despite the identification of autophagy-related protein 5 (ATG5) as a molecule involved in the activated autophagy machinery during hepatitis B virus (HBV) infection and hepatocarcinogenesis, the consequences of ATG5 mutation carriage for patients with chronic HBV infection remain unclear. This study examined the association of ATG5 polymorphisms with HBV-related diseases including hepatocellular carcinoma (HCC).
PATIENTS AND METHODS: Two functionally relevant polymorphisms ATG5 rs573775 and rs510432 were genotyped by ligase detection reaction-polymerase chain reaction in 403 patients with chronic HBV infection (171 chronic hepatitis, 119 cirrhosis and 113 HCC) and 196 healthy controls. Univariate and multivariate logistic regression was performed to evaluate factors associated with HCC.
RESULTS: The rs573775 genotype and allele frequencies had no significant differences between patients with different clinical diseases. However, HCC patients had significantly higher frequency of rs510432 genotype AA (odds ratio [OR] 2.185, 95% confidence interval [CI] 1.042-4.581, P = 0.037, P value by Bonferroni correction [P
CONCLUSION: These results indicate that rs510432 genotypes AA+GA are associated with disease progression and HCC risk in chronic HBV infection, providing novel evidence for a role of ATG5 in the pathogenesis of HBV-related HCC.
ABBREVIATIONS: HBV: hepatitis B virus; HCC hepatocellular carcinoma; TNFSF10: tumor necrosis factor superfamily member 10; ATG5: autophagy-related protein 5; DNA: deoxyribonucleic acid; LDR-PCR: ligase detection reactions-polymerase chain reaction; PCR: polymerase chain reaction; SLE: systemic lupus erythematosus; BD: Behçet's disease; IL-10: interlukin-10; LPS: lipopolysaccharide; PBMC: peripheral blood mononuclear cells; CWP: coal workers' pneumoconiosis; TNF-α: tumor necrosis factor-α.

Stojanovska V, Prakash M, McQuade R, et al.
Oxaliplatin Treatment Alters Systemic Immune Responses.
Biomed Res Int. 2019; 2019:4650695 [PubMed] Free Access to Full Article Related Publications
Purpose: Oxaliplatin is a platinum-based chemotherapeutic agent demonstrating significant antitumor efficacy. Unlike conventional anticancer agents which are immunosuppressive, oxaliplatin has the capacity to stimulate immunological effects in response to the presentation of damage associated molecular patterns (DAMPs) elicited upon cell death. However, the effects of oxaliplatin treatment on systemic immune responses remain largely unknown. Aims of this study were to investigate the effects of oxaliplatin treatment on the proportions of (1) splenic T cells, B cells, macrophages, pro-/anti-inflammatory cytokines, gene expression of splenic cytokines, chemokines, and mediators; (2) double-positive and single-positive CD4
Methods: Male BALB/c mice received intraperitoneal injections of oxaliplatin (3mg/kg/d) or sterile water tri-weekly for 2 weeks. Leukocyte populations within the spleen, thymus, and bone-marrow were assessed using flow cytometry. RT-PCR was performed to characterise changes in splenic inflammation-associated genes.
Results: Oxaliplatin treatment reduced spleen size and cellularity (CD45
Conclusion: Oxaliplatin does not cause systemic immunosuppression and, instead, has the capacity to induce beneficial antitumor immune responses.

Tuponchai P, Kukongviriyapan V, Prawan A, et al.
Myricetin ameliorates cytokine-induced migration and invasion of cholangiocarcinoma cells via suppression of STAT3 pathway.
J Cancer Res Ther. 2019 Jan-Mar; 15(1):157-163 [PubMed] Related Publications
Aim of Study: Cholangiocarcinoma (CCA) is an aggressive cancer with considerable metastatic potential. Various cytokines secreted by tumor cells or cells in the tumor environment can promote the metastasis of CCA. The aim of the present study was to investigate the effect of myricetin on the inhibition of cytokine-induced migration and invasion and the associated cellular mechanisms in human CCA cells.
Materials and Methods: CCA KKU-100 cells were treated with a pro-inflammatory cytokine mixture consisting of interleukin-6, interferon-γ, and tumor necrosis factor-α. The migratory and invasive ability of KKU-100 cells were determined using a wound-healing assay and transwell invasion assay. The effect of myricetin on cytokine-induced STAT3 activation in CCA cells was determined using Western blot analysis. The real-time polymerase chain reaction was performed to determine messenger RNA expression.
Results: Myricetin significantly inhibited cytokine-induced migration and invasion of KKU-100 cells. Detailed molecular analyses revealed that myricetin suppressed the activation of the STAT3 pathway, evidently by a decrease of the active phospho-STAT3 protein expression after myricetin treatment. The cytokine-mediated upregulation of metastasis- and inflammatory-associated genes, which are downstream genes of STAT3 including the intercellular adhesion molecule-1, matrix metalloproteinase-9, inducible nitric oxide synthase, and cyclo-oxygenase 2 (COX-2), were also significantly abolished by myricetin treatment. Moreover, the anti-migratory and anti-invasive activities of a widely prescribed COX inhibitor, indomethacin, were also revealed.
Conclusion: This finding reveals the anti-metastatic effect of myricetin against CCA cells which is mediated partly through suppression of the STAT3 pathway. This compound could be potentially useful as a therapeutic agent against CCA.

Moustaka K, Maleskou E, Lambrianidou A, et al.
Docosahexaenoic Acid Inhibits Proliferation of EoL-1 Leukemia Cells and Induces Cell Cycle Arrest and Cell Differentiation.
Nutrients. 2019; 11(3) [PubMed] Free Access to Full Article Related Publications
Τhe effect of docosahexaenoic acid (DHA, an omega-3 polyunsaturated fatty acid) upon the proliferation of EoL-1 (Eosinophilic leukemia) cell line was assessed, while additional cellular events during the antiproliferative action were recorded. DHA inhibited EoL-1 cells growth dose-dependently by inducing growth arrest at G0/1 phase of the cell cycle. After DHA addition to the cells, the expression of

Genov N, Basti A, Abreu M, Relógio A
Temporal Splicing Switches in Elements of the TNF-Pathway Identified by Computational Analysis of Transcriptome Data for Human Cell Lines.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
Alternative splicing plays an important role in numerous cellular processes and aberrant splice decisions are associated with cancer. Although some studies point to a regulation of alternative splicing and its effector mechanisms in a time-dependent manner, the extent and consequences of such a regulation remains poorly understood. In the present work, we investigated the time-dependent production of isoforms in two Hodgkin lymphoma cell lines of different progression stages (HD-MY-Z, stage IIIb and L-1236, stage IV) compared to a B lymphoblastoid cell line (LCL-HO) with a focus on tumour necrosis factor (TNF) pathway-related elements. For this, we used newly generated time-course RNA-sequencing data from the mentioned cell lines and applied a computational pipeline to identify genes with isoform-switching behaviour in time. We analysed the temporal profiles of the identified events and evaluated in detail the potential functional implications of alterations in isoform expression for the selected top-switching genes. Our data indicate that elements within the TNF pathway undergo a time-dependent variation in isoform production with a putative impact on cell migration, proliferation and apoptosis. These include the genes

Liu W, Chen X, He Y, et al.
TNF‑α inhibits xenograft tumor formation by A549 lung cancer cells in nude mice via the HIF‑1α/VASP signaling pathway.
Oncol Rep. 2019; 41(4):2418-2430 [PubMed] Related Publications
Lung cancer is the leading cause of cancer‑associated mortality worldwide. Tumor necrosis factor α (TNF‑α) is an important cytokine in the tumor microenvironment that serves a function in the balance of cell survival and cell death pathways. Our previous studies indicated that hypoxia‑inducible factor 1α (HIF‑1α) acts downstream of TNF‑α in MCF‑7 luminal breast cancer cells. However, whether vasodilator‑stimulated phosphoprotein (VASP) is implicated in the direct regulation of HIF‑1α in response to TNF‑α in lung cancer remains unknown. In vitro studies were performed using A549 and H226 lung carcinoma cells and in vivo studies of tumor xenograft models were performed to investigate the effects of TNF‑α. The results demonstrated that TNF‑α decreased VASP expression by upregulating the expression of HIF‑1α to inhibit A549 cell proliferation and adhesion. Inhibition of transplanted tumor growth was associated with downregulation of VASP expression in nude mice. Bioinformatics analysis indicated that expression levels of VASP or HIF‑1α lead to differential outcomes of overall survival in lung carcinoma. These results suggest that the HIF‑1α/VASP signaling pathway serves an important function in the regulation of TNF‑α‑induced suppression of A549 cell proliferation and xenograft growth. This may improve our understanding of the antitumor effect of TNF‑α.

Miyake S, Ogo A, Kubota H, et al.
β-Hydroxy-β-methylbutyrate Suppresses NF-ĸB Activation and IL-6 Production in TE-1 Cancer Cells.
In Vivo. 2019 Mar-Apr; 33(2):353-358 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIM: Stress reactions, especially those related to surgery, cause poor convalescence of cancer patients. β-Hydroxyβ-methylbutyrate (HMB) is known to regulate excessive inflammation in the body. The objective of this work was to investigate the capacity of HMB to suppress activation of nuclear factor-kappa B (NF-ĸB) and production of interleukin-6 (IL-6) in a human esophageal squamous cell carcinoma cell line (TE-1).
MATERIALS AND METHODS: Cell proliferation was measured using the water-soluble tetrazolium-1 method, while tumor necrosis factor alpha (TNFα)-induced IL-6 production was measured using an enzyme-linked immunosorbent assay (ELISA) assay. Nuclear translocation of NF-ĸB was detected by immunofluorescence staining.
RESULTS: HMB did not affect cell proliferation. However, HMB suppressed the TNFα-induced increase in IL-6 production in TE-1 cells by inhibiting NF-ĸB activation.
CONCLUSION: HMB did not influence TE-1 cell proliferation, but inhibited activation of NF-ĸB and IL-6 production. This result may be useful for improving excessive stress reactions during and after surgery.

Jiang Z, Li H, Qiao J, et al.
Potential Analysis and Preparation of Chitosan Oligosaccharides as Oral Nutritional Supplements of Cancer Adjuvant Therapy.
Int J Mol Sci. 2019; 20(4) [PubMed] Free Access to Full Article Related Publications
Cancer is considered to have an adverse influence on health around the world. Chitosan, a linear polysaccharide that contains copolymers of β -1-4 linked d-glucosamine and

Song G, Lu Y, Yu Z, et al.
The inhibitory effect of polysaccharide from Rhizopus nigricans on colitis-associated colorectal cancer.
Biomed Pharmacother. 2019; 112:108593 [PubMed] Related Publications
An extracellular polysaccharide (EPS1-1) of Rhizopus nigricans was found to enhance immunity and reduce colon cancer cell proliferation. Here, the effect of EPS1-1 on a mouse model of colitis-associated cancer (CAC) induced by azoxymethane (AOM)/dextran sodium sulfate (DSS) was investigated. Pathological symptoms, including weight loss, piloerection, hematochezia and insensitivity caused by AOM/DSS, were relieved by EPS1-1. Anatomical results showed a 100% tumor incidence, a series of neoplasms, disordered cell structure and hyperplastic glands in the model group, while the abnormal behaviors were relieved and the tumors decreased in the EPS1-1 group. Compared with the model group, the EPS1-1 group showed decreased oncogenic protein (COX-2, β-catenin, CyclinD1 and C-Myc) expression. TUNEL staining showed that EPS1-1 increased the apoptosis of colon cancer cells in mice. Furthermore, the expression of proliferative proteins (Ki-67 and PCNA) and an antiapoptotic gene transcript (Bcl-2) were significantly down regulated by EPS1-1, while apoptotic gene transcripts (p53 and Bax) were enhanced. In addition, EPS1-1 notably decreased the number of cells positive for CD68, F4/80 and NF-κB and reduced the concentrations of inflammatory factors (TNF-α and IL-6) in serum compared with those in the model group. Taken together, these results suggest that EPS1-1 may be a therapeutic option for the prevention and treatment of CAC.

Suh SS, Hong JM, Kim EJ, et al.
Antarctic freshwater microalga,
Int J Med Sci. 2019; 16(2):189-197 [PubMed] Free Access to Full Article Related Publications
Inflammation triggered by the innate immune system is a strategy to protect organisms from the risk of environmental infection. However, it has recently become clear that inflammation can cause a variety of human diseases, including cancer. In this study, we investigated the effects of an ethanol extract of the Antarctic freshwater microalgae,

Xu YX, Ma DS, Xu M, Yang J
[Correlation of EBV Infection with Expression of TNF-α-Inducing Protein 3 Gene and A20 Protein in Hodgkin's Lmphoma].
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2019; 27(1):91-95 [PubMed] Related Publications
OBJECTIVE: To analyze the correlation of EBV infection with expression of TNF-α-inducing protein 3 gene and A20 protein in Hodgkin lmphoma.
METHODS: The clinical data and pathological specimens of 65 cases of Hodgkin's lymphoma in our hospital were analyzed retrospectively, and the tissue chips were made for the rich area of the tumor cells. The latent membrane protein 1 encoded by EBV was measured by immunohistochemical staining, and the RNA encoded by EBV was measured by in situ hybridization to analyze the infection state. The gene expression of tumor necrosis factor.α-induced protein 3 was detected by fluorescence in situ hybridization, and the expression of A20 protein encoded by EBV was detected by immunohistochemical staining. The obtained data were processed by SPSS 23.0 version statistical software.
RESULTS: The positive rate of latent membrane protein 1 was 26.15% (17/65), the positive rate of EBV encoded RNA was 26.15% (17/65), and the coincidence rate was 100.00%. In 65 patients, A20 protein expression was lost in 18 cases (27.69%), and 14 cases (21.54%) showed homozygous or heterozygous deletion of tumor necrosis factorα protein 3 gene. Only 1 case showed A20 loss combined with homozygous deletion of TNFα inducible protein 3. Correlation analysis showed that EBV infection did not significantly relate with expression loss of A20 protein and the gene deletion of TNF-α inducing protein 3 (P>0.05).
CONCLUSION: The expression loss of A20 protein and gene detection of TNFα inducing protein 3 are found in both EBV negative and positive patients with Hodgkin's lymphoma, however the results of immunohistochemical staining and fluorescence in situ hybridization are not complete consistant, the reason may closely relate with the technical factors.

Zhang J, Wang L, Wang H, et al.
Neuroinflammation and central PI3K/Akt/mTOR signal pathway contribute to bone cancer pain.
Mol Pain. 2019 Jan-Dec; 15:1744806919830240 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Pain is one of the most common and distressing symptoms suffered by patients with progression of cancer; however, the mechanisms responsible for hyperalgesia are not well understood. Since the midbrain periaqueductal gray is an important component of the descending inhibitory pathway controlling on central pain transmission, in this study, we examined the role for pro-inflammatory cytokines of the periaqueductal gray in regulating mechanical and thermal hyperalgesia evoked by bone cancer via phosphatidylinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signals.
METHODS: Breast sarcocarcinoma Walker 256 cells were implanted into the tibia bone cavity of rats to induce mechanical and thermal hyperalgesia. Western blot analysis and ELISA were used to examine PI3K/protein kinase B (Akt)/mTOR and pro-inflammatory cytokine receptors and the levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α).
RESULTS: Protein expression levels of p-PI3K/p-Akt/p-mTOR were amplified in the periaqueductal gray of bone cancer rats, and blocking PI3K-mTOR pathways in the periaqueductal gray attenuated hyperalgesia responses. In addition, IL-1β, IL-6, and TNF-α were elevated in the periaqueductal gray of bone cancer rats, and expression of their respective receptors (namely, IL-1R, IL-6R, and tumor necrosis factor receptor (TNFR) subtype TNFR1) was upregulated. Inhibition of IL-1R, IL-6R, and TNFR1 alleviated mechanical and thermal hyperalgesia in bone cancer rats, accompanied with downregulated PI3K-mTOR.
CONCLUSIONS: Our data suggest that upregulation of pro-inflammatory cytokine signal in the periaqueductal gray of cancer rats amplifies PI3K-mTOR signal in this brain region and alters the descending pathways in regulating pain transmission, and this thereby contributes to the development of bone cancer-induced pain.

Jaleel JA, Ashraf SM, Rathinasamy K, Pramod K
Carbon dot festooned and surface passivated graphene-reinforced chitosan construct for tumor-targeted delivery of TNF-α gene.
Int J Biol Macromol. 2019; 127:628-636 [PubMed] Related Publications
Gene therapy is a promising alternative that ensures effective treatment and cure for cancer. Here, we report graphene-reinforced chitosan (CS) construct based non-viral vector for tumor-targeted gene therapy. The therapeutic gene, pDNA-TNF-α, was loaded on to chitosan-carboxylated graphene oxide (CS-CGO) construct via electrostatic interaction. The pDNA-TNF-α-CS-CGO thus obtained was further passivated with 4,7,10-trioxa-1,13-tridecanediamine for protecting the vector from the mononuclear phagocyte system that contributes to the prolongation of circulation half-life. The surface passivated carrier (PEG-pDNA-TNF-α-CS-CGO) then festooned with the folic acid derived carbon dots (C-dots) for targeting folate receptors that are overexpressed in most of the cancer cells. The results of TEM images and zeta potential values ensured the occurrence of desired changes in each stage of C-dot-PEG-pDNA-TNF-α-CS-CGO formulation. After 14 days of incubation, the anti-angiogenesis effect was observed for final formulation in the chorioallantoic membrane. The results of in vitro gene expression study in cancer cell line show a comparatively higher transfection efficacy of the developed system (C-dot-PEG-pDNA-TNF-α-CS-CGO) than pDNA-TNF-α. The efficiency of the developed gene delivery system was further confirmed using a developed and validated artificial tumor cell apparatus.

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