Gene Summary

Gene:IL6; interleukin 6
Aliases: CDF, HGF, HSF, BSF2, IL-6, BSF-2, IFNB2, IFN-beta-2
Summary:This gene encodes a cytokine that functions in inflammation and the maturation of B cells. In addition, the encoded protein has been shown to be an endogenous pyrogen capable of inducing fever in people with autoimmune diseases or infections. The protein is primarily produced at sites of acute and chronic inflammation, where it is secreted into the serum and induces a transcriptional inflammatory response through interleukin 6 receptor, alpha. The functioning of this gene is implicated in a wide variety of inflammation-associated disease states, including suspectibility to diabetes mellitus and systemic juvenile rheumatoid arthritis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 15 March, 2017


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 (1992-2017)
Graph generated 15 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 15 March, 2017 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: IL6 (cancer-related)

Shen L, Zhang G, Lou Z, et al.
Cryptotanshinone enhances the effect of Arsenic trioxide in treating liver cancer cell by inducing apoptosis through downregulating phosphorylated- STAT3 in vitro and in vivo.
BMC Complement Altern Med. 2017; 17(1):106 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Arsenic trioxide (ATO) is approved for treating terminal-stage liver cancer in China. Cryptotanshinone (CT), a STAT3 inhibitor, has exhibited certain anti-tumor potency; however, the use of CT enhanced ATO for treating liver cancer has not been reported. Here we try to elucidate how CT could enhance the efficacy of ATO for treating liver cancer and its correlation to STAT3 in vitro and in vivo.
METHODS: Cell viability of ATO combined with CT was assessed by (1)MTT assay. Cell apoptosis induced by ATO combined with CT was detected by Annexin V/PI staining and apoptosis-related proteins were detected by western blotting. STAT3-related proteins were analysis by western blotting analysis and Immunofluorescence assays. Efficacy evaluation of ATO combined with CT on xenograft was carried in nude mice and related proteins were analysis by Immunohistochemistry assays.
RESULTS: First we evaluated cell vitality, and our data indicated that the ATO combined with CT showed obvious growth inhibition of Bel-7404 cells compared to ATO or CT alone. Next we found that ATO combined with CT induced cell apoptosis in Bel-7404 cells and upregulated the activation of apoptosis-related proteins cleaved-caspase-3, cleaved-caspase-9, and cleaved-poly(ADP-ribose) polymerase in a time-dependent manner. Next, we found that ATO combined with CT not only inhibited the constitutive levels of phosphorylated-JAK2 and phosphorylated-STAT3(Tyr705) but did so in a time-dependent manner. We also found that ATO combined with CT reversed the upregulated expression of phosphorylated-STAT3(Tyr705) stimulated by interleukin-6 and downregulated STAT3 direct target genes and the anti-apoptotic proteins Bcl-2, XIAP, and survivin but obviously upregulated the promoting apoptosis proteins Bak,.In vivo studies showed that ATO combined with CT decreased tumor growth. Tumors from ATO combined with CT-treated mice showed decreased levels of phosphorylated-STAT3(Tyr705) and the anti-apoptotic protein Bcl-2 but an increased level of pro-apoptotic protein Bax.
CONCLUSIONS: Our study provides strong evidence that CT could enhance the efficacy of ATO in treating liver cancer both in vitro and in vivo. Downregulation of phosphorylated-STAT3 expression may play an important role in inducing apoptosis of Bel-7404 cells.

Nass N, Streit S, Wybranski C, et al.
Validation of VX2 as a Hepatocellular Carcinoma Model: Comparison of the Molecular Reaction of VX2 and HepG2 Tumor Cells to Sorafenib In Vitro.
Anticancer Res. 2017; 37(1):87-93 [PubMed] Related Publications
As there is currently no superior hepatocellular carcinoma (HCC) model with percutaneous vascular access for transarterial treatments available, the VX2 rabbit model is frequently used for in vivo investigations on liver carcinoma. However, the VX2 cell line was derived from a virus-induced skin papilloma that can form carcinosarcoma in liver of rabbits and the transferability of obtained results to HCC treatment remains open. Here we compared the most frequently investigated human HCC model cell line, HepG2, with VX2 cells in vitro in terms of sensitivity towards the broad specificity kinase inhibitor sorafenib and responsiveness to the addition of platelet-derived growth factor AB (PDGF-AB), vascular endothelial growth factor (VEGF) and hepatic growth factor (HGF), as well as insulin and interleukin-1β (IL1β). Phosphorylation of protein kinase B (AKT) the mitogen-activated protein kinases (MAPKs) p38 and p42/44 (extracellular signal-regulated kinase, ERK1/2) and inhibitor of kappa light chain gene enhancer alpha (IĸBα) was determined by western blotting as these events are associated with early signaling cascades. Additionally, the inhibition of phosphorylation under sorafenib treatment was investigated. Sorafenib was equally toxic to both cell lines, but only in HepG2 was activation of caspase 3/7 activity, as a sign of apoptosis, observed. VX2 cells exhibited generally more intense phosphorylation signals in response to the growth factors and also serum. In contrast to VX2, HepG2 cells showed no response to PDGF-AB or VEGF as determined by kinase phosphorylation. In both cell lines, sorafenib inhibited growth factor-induced phosphorylation of ERK and p38-MAPK. AKT phosphorylation was only inhibited in VX2 cells and IĸBα phosphorylation was not influenced by this kinase inhibitor in either cell type. Taken together, the two cellular models for HCC share several features related to sorafenib application, but differed in their responsiveness towards growth factors. Therefore, results obtained with the VX2 model cannot be extended to human HCC without appropriate caution.

Chang H, Sung JH, Moon SU, et al.
EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells.
Yonsei Med J. 2017; 58(1):9-18 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Rearrangement of the proto-oncogene rearranged during transfection (RET) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with RET fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes.
MATERIALS AND METHODS: The effects of EGF and HGF on the susceptibility of a CCDC6-RET lung cancer cell line to RET inhibitors (sunitinib, E7080, vandetanib, and sorafenib) were examined.
RESULTS: CCDC6-RET lung cancer cells were highly sensitive to RET inhibitors. EGF activated epidermal growth factor receptor (EGFR) and triggered resistance to sunitinib, E7080, vandetanib, and sorafenib by transducing bypass survival signaling through ERK and AKT. Reversible EGFR-TKI (gefitinib) resensitized cancer cells to RET inhibitors, even in the presence of EGF. Endothelial cells, which are known to produce EGF, decreased the sensitivity of CCDC6-RET lung cancer cells to RET inhibitors, an effect that was inhibited by EGFR small interfering RNA (siRNA), anti-EGFR antibody (cetuximab), and EGFR-TKI (Iressa). HGF had relatively little effect on the sensitivity to RET inhibitors.
CONCLUSION: EGF could trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, and endothelial cells may confer resistance to RET inhibitors by EGF. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positive lung cancer patients.

Eiro N, Fernandez-Gomez J, Sacristán R, et al.
Stromal factors involved in human prostate cancer development, progression and castration resistance.
J Cancer Res Clin Oncol. 2017; 143(2):351-359 [PubMed] Related Publications
PURPOSE: To detect new predictive markers from the prostate cancer tissue, to study the expression by cultured cancer-associated fibroblasts (CAFs) of stromal factors implicated in prostate carcinogenesis, and to compare their expressions in localized, metastatic, castration-sensitive (CSCP), castration-resistant prostate tumors (CRCP) as well as in fibroblasts from benign prostatic hyperplasia (BPH).
MATERIALS AND METHODS: The genomic expression of 20 stroma-derived factors, including the androgen receptor (AR), growth factors (FGF2, FGF7, FGF10, HGF, TGFβ, PDGFB), protein implicated in invasion (MMP-2, MMP-9 and MMP-11), inflammation (IL-6, IL-17, STAT-3 and NFκB), stroma/epithelium interaction (CDH11, FAP, CXCL12 and CXCL14) and chaperones (HPA1A and HSF1), was evaluated in cultured fibroblasts both from BHP and prostate carcinomas (PCa). After isolation and culture of fibroblasts by biopsy specimens, RNA was isolated and genomic studies performed.
RESULTS: Finally, 5 BPH and 37 PCa specimens were selected: clinically localized (19), metastatic (5), CSCP (7) and CRPC (6). Interleukin-17 receptor (IL-17RB) was highly expressed in CAFs compared with fibroblasts from BPH. However, metalloproteinase-2 and chemokine ligand 14 (CXCL14) were expressed at higher levels by fibroblasts from BPH. The fibroblastic growth factor-7 was highly expressed by CAFs from localized tumors, but metalloproteinase-11 in metastatic tumors. MMP-11, androgen receptor (AR) and heat-shock-70kda-protein-1A (HSPA1A) expressions were significantly higher in CAFs from CRPC.
CONCLUSIONS: These results demonstrate a CAFs heterogeneity among prostate carcinomas with regard to some molecular profile expressions that may be relevant in tumor development (IL-17RB), progression (MMP-11) and castration resistance (AR, MMP-11 and HSPA1A).

Teixeira LN, de Castro Raucci LM, Alonso GC, et al.
Osteopontin expression in co-cultures of human squamous cell carcinoma-derived cells and osteoblastic cells and its effects on the neoplastic cell phenotype and osteoclastic activation.
Tumour Biol. 2016; 37(9):12371-12385 [PubMed] Related Publications
This study evaluated the temporal expression of osteopontin (OPN) in co-cultures of human osteoblastic cells (SAOS-2) and oral squamous cell carcinoma (OSCC)-derived cells (SCC9) and examined the effects of osteoblast-derived OPN on the neoplastic cell phenotype. Additionally, the effects of these co-cultures on subsequent osteoclastic activity were explored. SCC9 cells were plated on Transwell® membranes that were either coated or not coated with Matrigel and were then co-cultured with SAOS-2 cells during the peak of OPN expression. SCC9 cells exposed to OPN-silenced SAOS-2 cultures and SCC9 cells cultured alone served as controls. SCC9 cells were quantitatively evaluated for cell adhesion, proliferation, migration, and invasion into Matrigel. The impact of co-culturing SAOS-2 and SCC9 cells on the resorptive capacity of U-937-derived osteoclastic cells was also investigated. Furthermore, a reciprocal induction of SAOS-2 and SCC9 cells in terms of OPN expression over the co-culture interval was identified. SAOS-2-secreted OPN altered the SCC9 cell phenotype, leading to enhanced cell adhesion and proliferation and higher Matrigel invasion. This invasion was also enhanced, albeit to a lesser degree, by co-culture with OPN-silenced SAOS-2 cells. Cell migration was not affected. Co-culture with SAOS-2 cells-mainly during the period of peak OPN expression-promoted over-expression of IL-6 and IL-8 by SCC9 cells and enhanced the resorptive capacity of osteoclastic cells. Taken together, these results suggest that osteoblast-derived OPN affects the interactions among OSCC-derived epithelial cells, osteoblasts, and osteoclasts, which could contribute to the process of bone destruction during bone invasion by OSCC.

Imura Y, Nakai T, Yamada S, et al.
Functional and therapeutic relevance of hepatocyte growth factor/c-MET signaling in synovial sarcoma.
Cancer Sci. 2016; 107(12):1867-1876 [PubMed] Free Access to Full Article Related Publications
Synovial sarcoma (SS) is an aggressive soft tissue sarcoma with a poor prognosis and, thus, novel therapeutic strategies for SS are urgently required. In the present study, we investigated the functional and therapeutic relevance of hepatocyte growth factor (HGF)/c-MET signaling in SS. Both HGF and c-MET were highly expressed in Yamato-SS cells, resulting in activation of c-MET and its downstream AKT and extracellular signal-regulated kinase signaling pathways, whereas c-MET was expressed but not activated in SYO-1 or HS-SY-II cells. c-MET-activated Yamato-SS cells showed higher anchorage-independent growth ability and less sensitivity to chemotherapeutic agents than did c-MET-inactivated SYO-1 or HS-SY-II cells. INC280, a selective c-MET inhibitor, inhibited growth of Yamato-SS cells both in vitro and in vivo but not that of SYO-1 or HS-SY-II cells. INC280 induced cell cycle arrest and apoptosis, and blocked phosphorylation of c-MET and its downstream effectors in Yamato-SS cells. Co-expression of HGF and c-MET in SS clinical samples correlated with a poor prognosis in patients with SS. Taken together, activation of HGF/c-MET signaling in an autocrine fashion leads to an aggressive phenotype in SS and targeting of this signaling exerts superior antitumor effects on c-MET-activated SS. HGF/c-MET expression status is a potential biomarker for identification of SS patients with a worse prognosis who can benefit from c-MET inhibitors.

Li Y, Du Z, Wang X, et al.
Association of IL-6 Promoter and Receptor Polymorphisms with Multiple Myeloma Risk: A Systematic Review and Meta-Analysis.
Genet Test Mol Biomarkers. 2016; 20(10):587-596 [PubMed] Related Publications
BACKGROUND: A number of studies show that the pleiotropic cytokine interleukin-6 (IL-6) plays an important role in the pathogenesis of multiple myeloma (MM). However, whether MM risk is associated with IL-6 genetic variability remains uncertain.
OBJECTIVE: The aim of our study was to evaluate the association between two different IL-6 polymorphisms (located in the IL-6 promoter and receptor, respectively) and the risk of developing MM using a meta-analytic approach.
MATERIALS AND METHODS: A systematic search for studies on the association of IL-6/IL-6R single-nucleotide polymorphisms with susceptibility to MM was conducted in PubMed, Cochrane Library, Embase, CNKI (Chinese) and Wanfang (Chinese) Digital Dissertations Databases from inception through November 2014. A meta-analysis was performed and results were presented as odds ratios (ORs) with 95% confidence intervals (CIs).
RESULTS: A total of eight case-control studies on the IL-6 promoter polymorphism and three studies on the IL-6 receptor (IL-6R) polymorphism were included. No significant association was found between the IL-6 promoter rs1800795 (G>C) polymorphism and MM susceptibility. A significantly increased risk of MM was observed with the IL-6R rs8192284 (A>C) polymorphism. In subgroup analyses, grouped by ethnicity, region, quality of studies, and Hardy-Weinberg equilibrium of control group, similar results were found.
CONCLUSION: Unlike the IL-6 promoter rs1800795 (G>C) polymorphism, the IL-6R rs8192284 (A>C) polymorphism may be associated with MM risk. However, large-scale studies are needed to validate our findings since they are based on a relatively small number of studies.

Komatsu K, Sakai T, Kaburaki T, et al.
Atypical presentation of primary intraocular lymphoma.
BMC Ophthalmol. 2016; 16(1):171 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In 2014, Pang et al. reported three cases with vitelliform submaculopathy as a preceding lesion of primary intraocular lymphoma (PIOL). Here, we report a case with an atypical presentation of PIOL who initially presented with vitelliform submaculopathy, vitreous haze and preripheral retinal focus.
CASE PRESENTATION: A 73-year-old female initially visited another hospital with a chief complaint of acute reduced vision in the right eye. Funduscopic examination of the right eye showed a yellowish retinal lesion at the fovea with vitreous haze and retinal foci scattered in the peripheral region. Spectral-domain optic coherence tomography (SD-OCT) revealed a hyperreflective subretinal debris above the retinal pigment epithelium (RPE) at the fovea, suggesting vitelliform submaculopathy. Vitrectomy was performed to improve visualization of the retinal lesions and for examination of PIOL. Vitreous cytology was class III and cytokine analysis of vitreous fluid showed increased IL-10 and an IL-10/IL-6 ratio >1, suggesting PIOL. Thereafter, there was a sub-RPE infiltration of presumed lymphoma in the nasal retina, and PCR analysis of anterior chamber fluid indicated IgH gene rearrangement, leading to diagnosis of PIOL. Three months later, there was complete disappearance of the vitelliform submacular lesion, with resultant disruption and thinning of the outer retinal layers on SD-OCT images.
CONCLUSIONS: Clinicians should be aware of atypical manifestations of PIOL such as vitelliform submaculopathy and peripheral retinal foci with vitreous haze. The patient's unusual funduscopic changes are findings that have not reported in patients with PIOL.

Huang WJ, Wu LJ, Min ZC, et al.
Interleukin-6 -572G/C polymorphism and prostate cancer susceptibility.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
Strong evidence suggests that cancer-associated inflammation promotes tumor growth and progression, and interleukin-6 (IL6) is an important modulator of inflammation. However, the roles of IL6 and mutations of its corresponding gene in prostate cancer have not been clearly documented. We retrieved data from the Oncomine database concerning IL6 expression in prostate cancer and its role in prostate-specific antigen (PSA) recurrence. We also performed a case-control study of the IL6 -572G/C polymorphism (rs1800796) in 236 sporadic prostate cancer patients and 256 healthy controls from a southern Han Chinese population. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between rs1800796 and prostate cancer susceptibility. A dual-luciferase reporter assay was used to test the transcriptional activity of the IL6 promoter G and C alleles. IL6 was overexpressed in prostate cancer tissues compared to normal tissues, especially in those with higher Gleason scores. Moreover, elevated IL6 expression was associated with high PSA recurrence rate in Oncomine data. Our case-control study demonstrated that compared with the -572C allele, the -572G allele conferred a borderline increased risk of prostate cancer (OR = 1.31, 95%CI = 0.99-1.74, P = 0.061). This was more pronounced in the subgroup of individuals having never smoked (OR = 1.85, 95%CI = 1.07-3.22). Moreover, the G allele showed increased activity relative to the C allele in the dual-luciferase reporter assay. Our results suggest that the -572G/C polymorphism may be associated with IL6 expression, which in turn plays a role in prostate cancer development.

Kilic-Baygutalp N, Ozturk N, Orsal-Ibisoglu E, et al.
Evaluation of serum HGF and CK18 levels in patients with esophageal cancer.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
Cytokeratins are thought to play a role in apoptosis. Cytokeratin 18 (CK18) is involved in the formation of intracellular cytoskeleton, and has been considered a promising apoptosis marker in gastrointestinal carcinomas. Growth factors, including hepatocyte growth factor (HGF), may provide a microenvironment for malignant cells. In this study, we aimed to compare serum HGF and CK18 levels between esophageal squamous cell carcinoma patients and healthy controls. The study included 41 adult patients (20 male, 21 female) diagnosed with esophageal squamous cell carcinoma, with a mean age of 63.54 ± 10.88 years (range, 41-82 years). We also recruited 39 age and gender-matched healthy control subjects. Venous blood samples were taken; serum HGF and CK18 concentrations were determined via ELISA. Results indicated that serum HGF levels were higher in patients (1.37 ± 0.63 ng/mL) as compared to the healthy subjects (0.41 ± 0.29 ng/mL). Similarly, serum CK18 levels were higher in the patient group (2.53 ± 1.33 ng/mL) than in the control group (0.34 ± 0.23 ng/mL) (P < 0.001). In addition, serum HGF and CK18 levels were positively correlated with metastasis stage, tumor stage, and disease stage of esophageal squamous cell carcinoma. To our knowledge, this is the first study to evaluate serum HGF and CK18 levels in patients with esophageal squamous cell carcinoma. The results suggest that serum CK18 and HGF levels may be used as prognostic and disease monitoring biomarkers of esophageal squamous cell carcinoma.

Zuo HD, Wu Yao W
The role and the potential regulatory pathways of high expression of forkhead box C1 in promoting tumor growth and metastasis of basal-like breast cancer.
J BUON. 2016 Jul-Aug; 21(4):818-825 [PubMed] Related Publications
PURPOSE: To investigate the role of high forkhead box C1 (FOXC1) expression in basal-like breast cancer (BLBC) in vitro and vivo and the underlying regulatory mechanism.
METHODS: The lentivirus vector with green fluorescent protein (GFP) was used. MDA-MB-231 cells expressing consistently high levels of FOXC1 (FOXC1-MDA-MB-231) were established. The parental MDA-MB-231 cells served as controls. Western blot analysis was used to determine the FOXC1 expression. The invasion capability was tested using the Trans-well assay. The tumorigenicity and the pulmonary metastatic ability were determined in mice in vivo. Histopathology and microarray processing and analysis were performed, and the various pathways involved and the related genes were analyzed.
RESULTS: The invasion ability of FOXC1-MDA-MB-231 cells was enhanced significantly (p<0.01). Pulmonary metastases were observed in vivo in 3 of 5 mice administered FOXC1-MDA-MB-231 cells through tail vein injection. However, no pulmonary metastatic lesions were observed with MDA-MB-231 cells. The average tumor volume was larger in the mice injected with FOXC1-MDA-MB-231 than in the control mice (p<0.05). The expression of Ki-67 in the FOXC1-MDA-MB-231 injected mice was higher than in the control mice. Ten of the most gene-enriched pathways and the critical genes (IL-6 and SNAI2) were found to be related to BLBC.
CONCLUSION: Elevated expression of FOXC1 enhanced the invasion ability of BLCB cells in vitro and promoted tumor growth and metastatic ability in vivo. This function may be regulated by many gene-enriched pathways and some critical genes.

Heidarian E, Keloushadi M, Ghatreh-Samani K, Valipour P
The reduction of IL-6 gene expression, pAKT, pERK1/2, pSTAT3 signaling pathways and invasion activity by gallic acid in prostate cancer PC3 cells.
Biomed Pharmacother. 2016; 84:264-269 [PubMed] Related Publications
Prostate cancer (PC) is one of the most common cancers among men. Progression of prostate cancer is associated with an increase in cellular level of interleukin-6 (IL-6). Gallic acid (GA) is a polyhydroxy phenolic compound which can inhibit the growth of cancer cells. The aim of this study was to evaluate the effects of GA treatment on cell viability, proliferation, invasion, IL-6 gene expression, IL-6 secretion, cellular levels of pSTAT3, pERK1/2, and pAKT signaling proteins in human prostate cancer PC3 cells. PC3 cells viability after treatment with GA (0-120μM) was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of IL-6 was investigated using real-time polymerase chain reaction. Cellular concentration of pSTAT3, pERK1/2, and pAKT signaling proteins were determined by Western blotting technic. PC3 cells invasion was assessed by invasion assay test. Treatment with GA caused a significant decrease in cell viability, proliferation, invasion, cellular levels of pSTAT3, pERK1/2, and pAKT signaling proteins after 48h in a dose-dependent manner. The level of IL-6 and its gene expression decreased significantly in PC3 cells treated with GA. Our results show that IL-6 down-regulation and decreased IL-6 protein level in PC3 cells by GA resulted in diminishing of pSTAT3, pERK1/2, and pAKT signaling proteins which lead to the reduction of the cell survival, proliferation, and invasion in PC3 cells. Therefore, it seems that GA can be considered an anticancer agent in the treatment of prostate cancer.

Huang Y, Tao Y, Hu K, et al.
Hypoxia-induced NIPP1 activation enhances metastatic potential and predicts poor prognosis in hepatocellular carcinoma.
Tumour Biol. 2016; 37(11):14903-14914 [PubMed] Related Publications
Hypoxia is known to promote hepatocellular carcinoma (HCC) invasion and metastasis and nuclear inhibitor of protein phosphatase 1 (NIPP1) overexpression contributes to the malignant phenotype in HCC. The aim of this study was to investigate the role of NIPP1 in HCC development under hypoxia. We first conducted a study with 106 cases to explore the association of NIPP1 and/or enhancer of zeste homolog 2 (EZH2) expression with poor prognosis in HCC. Then additional 352 independent cases were recruited to validate the results in the first stage. Hypoxia was induced by culturing HCC cells in 1 % O2 or of the treatment with hypoxic agent. The expression levels of NIPP1/EZH2 in both HCC tissues and HCC cell lines were detected by RT-PCR, Western blot, or immunohistochemistry. We also studied the effects of the loss of function of NIPP1 and EZH2 on malignant phenotypes, downstream pathway, and inflammatory factors activities using gene silencing strategy. Overall, we found that NIPP1 and EZH2 were overexpressed in both HCC tissue samples and HCC cell lines. High expression of HIPP1 was associated with poor prognosis and clinicopathological features in patients with advanced HCC. HIPP1 expression positively correlated with the expression of hypoxia marker (carbonic anhydrase IX). Hypoxia induced high expression of NIPP1. NIPP1/EZH2 knockdown in HCC cell lines under hypoxia suppressed the malignant phenotypes, reduced the expression of hypoxia-inducible Factor 1α, downstream molecules of EZH2, and inhibit the activity of inflammatory factors. In conclusion, we found that NIPP1 could be activated by hypoxia and contributed to hypoxia-induced invasive and metastatic potential in HCC.

Shen W, Yuan Y, Zhao M, et al.
Novel long non-coding RNA GACAT3 promotes gastric cancer cell proliferation through the IL-6/STAT3 signaling pathway.
Tumour Biol. 2016; 37(11):14895-14902 [PubMed] Related Publications
Long non-coding RNAs (lncRNAs) play an important role in cancer occurrence and development. We previously demonstrated that lncRNA gastric cancer-associated transcript 3 (GACAT3) was positively correlated with TNM stages, tumor size, and distant metastasis of patients with gastric cancer. However, the role of GACAT3 in gastric cancer remains unclear. In this study, to investigate its function, we synthesized small interference RNAs (siRNAs) against GACTA3 and developed a GACAT3 overexpression vector (pcDNA3-GACAT3), respectively. The siRNA-mediated knockdown of GACAT3 significantly decreased cell proliferation of the gastric cancer HGC-27 cells, in which GACAT3 is overexpressed. Furthermore, GACAT3 overexpression in gastric cancer SGC-7901 cells promoted cell growth. Moreover, GACAT3 expression in HGC-27 cells was greatly upregulated by IL-6 treatment in a concentration-dependent manner. In contrast, siRNA-mediated knockdown of STAT3 decreased GACAT3 expression even in the presence of IL-6. These results demonstrated that as a downstream target of the IL6/STAT3 signaling, lncRNA GACAT3 promotes gastric cancer cell growth suggesting that GACAT3 is an inflammatory response gene and may be served as a valuable potential target for the treatment of gastric cancer.

Matsumura Y, Hiraoka K, Ishikawa K, et al.
CD40 Expression in Human Esophageal Squamous Cell Carcinoma Is Associated with Tumor Progression and Lymph Node Metastasis.
Anticancer Res. 2016; 36(9):4467-75 [PubMed] Related Publications
BACKGROUND: The co-stimulatory molecule cluster of differentiation 40 (CD40) is widely expressed in various types of malignant tumors, but its role remains unclear. The purpose of this study was to investigate the relationship between CD40 expression and clinicopathological variables in patients with esophageal squamous cell carcinoma (ESCC), as well as the function of CD40 expressed on ESCC tumor cells in vitro.
MATERIALS AND METHODS: Tumor specimens of patients who underwent surgical resection for ESCC were immunohistochemically analyzed for CD40 expression.
RESULTS: Of the 122 specimens, 45 (37%) were positive for CD40. Significant positive correlation was found between CD40 expression and p-stage (p=0.0011), histopathological grade (p=0.0143), pT-classification (p=0.0011), and pN-classification (p=0.0007). Survival of patients with stage III and IV disease with positive CD40 expression was significantly shorter than that of those with negative expression (log-rank test, p=0.0422). In in vitro analysis, while the addition of recombinant human CD154 did not inhibit growth, it did induce a significant increase in interleukin 6 production in ESCC cell lines.
CONCLUSION: These results suggest that functional expression of CD40 on tumor cells might play an important role in tumor progression and lymph node metastasis in ESCC.

Chen GY, Shu YC, Chuang DY, Wang YC
Inflammatory and Apoptotic Regulatory Activity of Tanshinone IIA in Helicobacter pylori-Infected Cells.
Am J Chin Med. 2016; 44(6):1187-1206 [PubMed] Related Publications
Helicobacter pylori infections induce host cell inflammation and apoptosis, however, they are conflicting. Tanshinone IIA is an active compound of Salvia miltiorrhiza Bge. In this study, we investigated the regulatory effects of tanshinone IIA on H. pylori-induced inflammation and apoptosis in vitro. Tanshinone IIA treatments (13.6-54.4[Formula: see text][Formula: see text]M) significantly decreased nuclear factor kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) [p-38 and C-terminal Jun-kinase 1/2 (JNK1/2)] protein expressions and inflammatory substance [cyclooxygenase-2 (COX-2), 5-lipooxygenase (5-LOX), intercellular adhesion molecule-1 (ICAM-1), reactive oxygen species (ROS), nitric oxide (NO), inducible nitric oxide synthase (iNOS), interleukin-1[Formula: see text] (IL-1[Formula: see text], IL-6, and IL-8] production in the H. pylori-infected cells. In contrast, tanshinone IIA treatments significantly increased apoptotic relevant protein [Bcl-2-associated X protein (Bax) and caspase 9] expressions and increased mitochondrial transmembrane potential ([Formula: see text] disruption, mitochondrial cytochrome [Formula: see text] (cyt [Formula: see text] release, and caspase cascades. Tanshinone IIA treatments effectively decreased H. pylori-induced inflammation and significantly promoted H. pylori-induced intrinsic apoptosis through NF-kB and MAPK (p-38 and JNK) pathways. Tanshinone IIA has great potential as a candidate to protect host cells from H. pylori-induced severe inflammation and gastric cancer.

Chen Y, Teng F, Wang G, Nie Z
Overexpression of CXCR7 induces angiogenic capacity of human hepatocellular carcinoma cells via the AKT signaling pathway.
Oncol Rep. 2016; 36(4):2275-81 [PubMed] Related Publications
Angiogenesis is essential for tumor growth, especially in hepatocellular carcinoma (HCC). The hypervascularity is associated with poor prognosis and highly invasive HCC. The C‑X‑C chemokine receptor type 7 (CXCR7) has been implied overexpressed in many tumor types. Our study aimed to investigate the CXCR7 function in HCC. The tube formation, Transwell migration assay of human umbilical vein endothelial cells (HUVECs) and chicken chorioallantoic membrane (CAM) assay were used. We confirmed that CXCR7 induces angiogenic capacity. Moreover, overexpressing CXCR7 increased the phosphorylated (but not total) AKT expression in HCC cells. Furthermore, overexpressing CXCR7 increased the expression of tumor necrosis factor (TNF)‑α, interleukin (IL)‑6 and IL‑8 in HCC cells. Additionally, inhibition of AKT by LY294002 abrogated CXCR7‑induced angiogenic capacity in HCC cells. Our study suggested that CXCR7 plays an important pro‑angiogenic role in HCC via activation of the AKT pathway. So CXCR7 may be a potential target for anti‑angiogenic therapy in HCC.

Chen L, Zhang F, Sheng XG, et al.
MicroRNA-106a regulates phosphatase and tensin homologue expression and promotes the proliferation and invasion of ovarian cancer cells.
Oncol Rep. 2016; 36(4):2135-41 [PubMed] Related Publications
Ovarian cancer is a leading cause of malignant gynecological tumor-related mortality among women. The treatment of ovarian cancer patients continues to be challenging. MicroRNA‑106a (miR‑106a) is widely expressed in diverse human tumors. In the present study, we investigated the biological and pathological roles of miR-106a in ovarian cancers. We found that miR-106a expression was significantly increased in primary ovarian cancer tissues and ovarian cancer cells compared with the level in normal tissues. Ectopic expression of an miR-106a inhibitor attenuated ovarian cancer cell proliferation and invasion. miR-106a promoted the growth and invasion of SKOV3 cells by targeting phosphatase and tensin homolog (PTEN). Furthermore, the present study revealed that IL-6 inhibited miR-106a expression by activating STAT3. Tocilizumab, a humanized anti-human IL-6R antibody, that competitively inhibits IL-6/IL-6R signaling, did not inhibit the proliferation and invasion of SKOV3 cells. In conclusion, our studies revealed that miR-106a was significantly increased in the ovarian cancer tissues and cell lines. Downregulation of the expression of miR-106a inhibited cell growth and metastasis of ovarian cancer cells. Together, the present study suggests that miR‑106a acts as an oncogene in ovarian cancers.

Ahmadvand M, Noruzinia M, Soleimani M, Abroun S
Comparison of Expression Signature of Histone Deacetylases (HDACs) in Mesenchymal Stem Cells from Multiple Myeloma and Normal Donors.
Asian Pac J Cancer Prev. 2016; 17(7):3605-10 [PubMed] Related Publications
BACKGROUND: Histone acetylation in chromatin structures plays a key role in regulation of gene transcription and is strictly controlled by histone acetyltransferase (HAT) and deacetylase (HDAC) activities. HDAC deregulation has been reported in several cancers.
MATERIALS AND METHODS: The expression of 10 HDACs (including HDAC class I and II) was studied by quantitative reverse transcriptionPCR (qRTPCR) in a cohort of mesenchymal stem cells (MMMSCs) from 10 multiple myeloma patients with a median age 60y. The results were compared with those obtained for normal donors. Then, a coculture system was performed between MMMSCs and u266 cell line, in the presence or absence of sodium butyrate (NaBT), to understand the effects of HDAC inhibitors (HDACi) in MMMSCs on multiple myeloma cases. Also, the interleukin6 (IL6) and vascular endothelial growth factor (VEGFA) gene expression level and apoptotic effects were investigated in MMMSCs patients and control group following NaBT treatment.
RESULTS: The results indicated that upregulated (HDACs) and downregulated (IL6 and VEGFA) genes were differentially expressed in the MMMSCs derived from patients with multiple myeloma and NDMSCs from normal donors. Comparison of the MMMSCs and NDMSCs also showed distinct HDACs expression patterns. For the first time to our knowledge, a significant increase of apoptosis was observed in coculture with MMMSCs treated with NaBT.
CONCLUSIONS: The obtained findings elucidate a complex set of actions in MSCs in response to HDAC inhibitors, which may be responsible for anticancer effects. Also, the data support the idea that MSCs are new therapeutic targets as a potential effective strategy for MM.

Lv X, Li J, Yang B
Clinical effects of miR-101 on prognosis of hepatocellular carcinoma and carcinogenic mechanism of anti-miR-101.
Oncol Rep. 2016; 36(4):2184-92 [PubMed] Related Publications
The aim of this study was to verify whether anti-miR-101 participates in the treatment of hepatocellular carcinoma (HCC) as a small-molecule antitumor agent, and to explore the effect on phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Patients who received consecutive hepatectomies were followed-up, and miR-101 expressions in their tumor and paracancerous tissues were detected. Correlation between miR-101 expression and clinical pathological factors and prognosis was studied. High‑throughput sequencing was used to detect the genetic and microRNA (miRNA) levels of tumor tissues. Expression of anti-miR-101 in different HCC cell lines was determined, and those of desired genes and proteins were detected by qRT-PCR and western blotting to obtain the target gene. miR-101 was significantly upregulated in HCC patients compared with that in paracancerous tissues. High miR-101 expression, vascular invasion, tumor size ≥7 cm and late pathological stage were the risk factors of recurrence-free survival rate. High miR-101 expression was the independent prognostic factor of total and recurrence-free survival rates. CXCL12, IL6R, FOXO3 and PTEN were screened as desired genes, and only PTEN was expressed significantly differently in three cell lines. miR-101 could bind 3'-UTR of WT-PTEN with reduced fluorescent intensity, suggesting that PTEN was the target gene. SMMC-7721, HepG2 and Huh7 were eligible cell lines for miR-101 studies. miR-101 was an applicable molecular marker of HCC. Anti-miR-101 regulated the transcription of PTEN and may promote cell proliferation, differentiation and apoptosis by regulating downstream genes with PTEN. The regulatory effects of anti-miR-101 on PTEN provide valuable evidence for finding novel miRNA drugs.

Kobayashi K, Koyama K, Suzukawa M, et al.
Epithelial-mesenchymal transition promotes reactivity of human lung adenocarcinoma A549 cells to CpG ODN.
Allergol Int. 2016; 65 Suppl:S45-52 [PubMed] Related Publications
BACKGROUND: Epithelial-mesenchymal transition (EMT) is reported to promote airway remodeling in asthmatics, which is the main histological change that causes complex and severe symptoms in asthmatics. However, little is known about whether EMT also plays a role in acute exacerbations of asthma evoked by respiratory tract infections.
METHODS: A human lung adenocarcinoma line, A549, was incubated with TGF-β1 at 10 ng/ml to induce EMT. Then the cells were stimulated with CpG ODN. Expression of surface and intracellular molecules was analyzed by flow cytometry. IL-6, IL-8 and MCP-1 in the culture supernatant were measured by Cytometric Bead Assay, and the expression of mRNA was quantitated by real-time PCR. CpG ODN uptake was analyzed by flow cytometry.
RESULTS: The culture supernatant levels of IL-6, IL-8 and MCP-1 and the expression of mRNA for these cytokines in CpG ODN-stimulated A549 cells that had undergone EMT was significantly higher compared to those that had not. Addition of ODN H154, a TLR9-inhibiting DNA, significantly suppressed the CpG ODN-induced production of those cytokines. However, flow cytometry found the level of TLR9 expression to be slightly lower in A549 cells that had undergone EMT compared to those that had not. On the other hand, CpG ODN uptake was increased in cells that had undergone EMT.
CONCLUSIONS: EMT induction of A549 cells enhanced CpG ODN uptake and CpG ODN-induced production of IL-6, IL-8 and MCP-1. These results suggest that EMT plays an important role in exacerbation in asthmatics with airway remodeling by enhancing sensitivity to extrinsic pathogens.

Lei K, Du W, Lin S, et al.
3B, a novel photosensitizer, inhibits glycolysis and inflammation via miR-155-5p and breaks the JAK/STAT3/SOCS1 feedback loop in human breast cancer cells.
Biomed Pharmacother. 2016; 82:141-50 [PubMed] Related Publications
Compared to normal cells, most cancer cells produce ATP by glycolysis under aerobic conditions rather than via the tricarboxylic acid cycle (TCA). This study is intended to determine whether 3B, a novel photosensitizer, can inhibit glycolysis and inflammation in breast cancer cells. We showed that 3B had the ability to repress glucose consumption as well as the generation of ATP, lactate and lactate dehydrogenase. 3B-PDT not only inhibited the expression of IL-1β and IL-6 but also affected the JAK-STAT3 inflammatory pathway in vitro. The present study showed that 3B featured a significant inhibitory effect on the expression of microRNA-155-5p and SOCS1 might serve as a target gene. In vivo studies revealed that 3B inhibited tumor growth and exhibited almost no side effects. Therefore, through the anti-glycolytic effect and breakage of the JAK/STAT3/SOCS1 feedback loop via miR-155-5p, 3B may potentially serve as a potential therapeutic agent against breast cancer.

Ciccarese C, Brunelli M, Montironi R, et al.
The prospect of precision therapy for renal cell carcinoma.
Cancer Treat Rev. 2016; 49:37-44 [PubMed] Related Publications
The therapeutic landscape of renal cell carcinoma (RCC) has greatly expanded in the last decade. From being a malignancy orphan of effective therapies, kidney cancer has become today a tumor with several treatment options. Renal cell carcinoma (RCC) is a metabolic disease, being characterized by the dysregulation of metabolic pathways involved in oxygen sensing (VHL/HIF pathway alterations and the subsequent up-regulation of HIF-responsive genes such as VEGF, PDGF, EGF, and glucose transporters GLUT1 and GLUT4, which justify the RCC reliance on aerobic glycolysis), energy sensing (fumarate hydratase-deficient, succinate dehydrogenase-deficient RCC, mutations of HGF/MET pathway resulting in the metabolic Warburg shift marked by RCC increased dependence on aerobic glycolysis and the pentose phosphate shunt, augmented lipogenesis, and reduced AMPK and Krebs cycle activity) and/or nutrient sensing cascade (deregulation of AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR pathways). In this complex scenario it is important to find prognostic and predictive factors that can help in decision making in the treatment of mRCC.

Chen D, Liu S, Chen S, et al.
Donor interleukin 6 gene polymorphisms predict the recurrence of hepatocellular carcinoma after liver transplantation.
Int J Clin Oncol. 2016; 21(6):1111-1119 [PubMed] Related Publications
BACKGROUND: Application of the Milan criteria is an effective strategy to select patients with hepatocellular carcinoma (HCC) for liver transplantation, but HCC recurrence is still a major concern. The aim of this study was to determine whether interleukin 6 (IL6) polymorphisms and clinical variables are potential predictors for HCC recurrence and prognosis after transplantation.
METHODS: A total of 110 consecutive patients with HCC undergoing liver transplantation were enrolled in the study. Six tag single nucleotide polymorphisms in IL6 were genotyped in both the donors and recipients. Demographic characteristics, HCC features, and IL6 polymorphisms were assessed against HCC recurrence.
RESULTS: Pretransplant hepatitis B virus DNA (P = 0.014), pretransplant serum alpha-fetoprotein (P = 0.035), number of nodules (P = 0.011), diameter of main nodule (P = 0.001), macrovascular invasion (P = 0.001), microvascular invasion (P = 0.001), HCC exceeding the Milan criteria (P < 0.001), and donor rs2069852 AA genotype (P = 0.010) were associated with HCC recurrence. Recurrence-free survival rate and overall survival rate were significantly lower (P = 0.011 and P = 0.026, respectively) in patients whose donor had the rs2069852 AA genotype than in those whose donor had the AG and GG genotypes. Independent risk factors for recurrence-free survival and overall survival were microvascular invasion (P = 0.003; P = 0.002), HCC exceeding the Milan criteria (P < 0.001; P = 0.001), and donor rs2069852 AA genotype (P = 0.002; P = 0.010).
CONCLUSIONS: Our data suggest that donor IL6 rs2069852 polymorphisms may be a potential genetic marker for HCC recurrence after liver transplantation in the Han Chinese population.

Andreasen S, Heegaard S, Grauslund M, Homøe P
The interleukin-6/Janus kinase/STAT3 pathway in pleomorphic adenoma and carcinoma ex pleomorphic adenoma of the lacrimal gland.
Acta Ophthalmol. 2016; 94(8):798-804 [PubMed] Related Publications
PURPOSE: Pleomorphic adenoma (PA) is the most common tumour of the lacrimal gland, but very little is known about its biology. It has a tendency to recur and an ability to transform into the high-grade malignancy carcinoma ex pleomorphic adenoma (ca-ex-PA), which is also largely unexplored. In this study, we examine the expression of the interleukin-6/Janus kinase/STAT3 (IL-6/JAK/STAT3) pathway components in PA and ca-ex-PA.
METHODS: Sixteen PAs and two ca-ex-PAs were examined with immunohistochemistry. Seven PAs were subjected to microdissection and subsequent qPCR.
RESULTS: The IL-6/JAK/STAT3 pathway was overexpressed in PA compared to normal lacrimal gland. Overexpression of phosphorylated JAK1 (p-JAK1) and cyclin D1 was significantly overexpressed in ductal cells compared with myoepithelial cells in PA. A shift from p-JAK1 to p-JAK2 and p-Tyk2 overexpression was seen between PA and ca-ex-PA, combined with a high p-STAT3 expression in the latter.
CONCLUSION: The IL-6/JAK/STAT3 pathway is overexpressed in PA, and this overexpression was even more pronounced in ca-ex-PA, with a shift in the JAKs mediating STAT3 phosphorylation. Future studies are needed to clarify whether PA and ca-ex-PA could be treated with targeted therapy directed against components of the IL-6/JAK/STAT3 pathway.

Attar M, Azar SS, Shahbazi M
Interleukin-6-174 Promoter Polymorphism and Susceptibility to Hepatitis B Virus Infection as a Risk Factor for Hepatocellular Carcinoma in Iran.
Asian Pac J Cancer Prev. 2016; 17(5):2395-9 [PubMed] Related Publications
BACKGROUND: Hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma (HCC). Cytokines play an important role in the regulation of immune responses and defense against viral infections. Human interleukin 6 (IL6) is a multifunctional cytokine that participates in these processes.
OBJECTIVE: The aim of this study was to assess the IL6-174 gene polymorphism in patients with chronic hepatitis B virus (HBV) infection as compared with healthy controls in an Iranian population.
MATERIALS AND METHODS: Totals of 297 HBV patients and 368 control individuals were evaluated. Genomic DNA was extracted from peripheral blood and the SSP-PCR (sequence specific primer-polymerase chain reaction) method was applied for genotyping.
RESULTS: The frequencies of genotypes C/C, G/G and C/G in HBV cases were 4.7%, 34.3%, 60.9% and in controls were 12.8%, 39.7% and 47.6%, respectively. The frequencies of G and C allele in patients and controls were 78.1%, 21.9% and 67.4%, 32.6 % respectively. There was a significant difference in the frequencies of G/G genotype (CI=1.8-7.1, OR=3.47, P=0.00001) and G allele (CI=1.34-2.23, OR=1.72, P=0.0001) between HBV patients and the control group.
CONCLUSIONS: These findings suggest that the IL6-174 C/G genotype and the G allele are strongly associated with susceptibility to HBV infection. Demographic information showed that most of the subjects were male (74.4%). According to high frequency of G/G genotype in male participants (63.1%) men probably are more susceptible to hepatitis than women.

Ge X, Cao Z, Gu Y, et al.
PFKFB3 potentially contributes to paclitaxel resistance in breast cancer cells through TLR4 activation by stimulating lactate production.
Cell Mol Biol (Noisy-le-grand). 2016; 62(6):119-25 [PubMed] Related Publications
Paclitaxel is a commonly used agent for breast cancer therapy, which comes across the obstacle "drug resistance", resulting in shortened overall survival of patients. Warburg effect has become one character of cancer cell and was reported to induce paclitaxel resistance, the mechanism of which is poorly understood. In this study, we sought to examine the role of 6-Phosphofructo-2-kinase (PFKFB3), a critical regulator of glycolysis, in paclitaxel resistance development. Two clones of paclitaxel resistant breast cancer cells, MCF-7RA and MCF-7RB, were established by a long term exposure of MCF-7 cells to paclitaxel. Consequently, PFKFB3 expression was found to be increased in MCF-7RA and MCF-7RB cells compared with MCF-7 cells. Silencing PFKFB3 expression markedly reduced the IC50 concentrations of MCF-7RA and MCF-7RB cells. Moreover, PFKFB3 modulated toll like receptor 4 (TLR4) and MyD88 expression as well as interleukin (IL)-6 and IL-8 release from breast cancer cells in response to paclitaxel exposure. In addition, PFKFB3 overexpression boosted up fructose-2,6-bisphosphate (F2,6BP) and lactate production. The enhanced lactate contributed to TLR4 signaling activation, IL-6 and IL-8 generation, and cell viability promotion in MCF-7 cells. In all, we characterized the novel role of PFKFB3 in induction of paclitaxel resistance by raising lactate production and activating TLR4 signaling.

Jiang S, Zhao C, Yang X, et al.
miR-1 suppresses the growth of esophageal squamous cell carcinoma in vivo and in vitro through the downregulation of MET, cyclin D1 and CDK4 expression.
Int J Mol Med. 2016; 38(1):113-22 [PubMed] Free Access to Full Article Related Publications
Several aberrant microRNAs (miRNAs or miRs) have been implicated in esophageal cancer (EC), which is widely prevalent in China. However, their role in EC tumorigenesis has not yet been fully elucidated. In the present study, we determined that miR‑1 was downregulated in esophageal squamous cell carcinoma (ESCC) tissues compared with adjacent non-neoplastic tissues using RT-qPCR, and confirmed this using an ESCC cell line. Using a nude mouse xenograft model, we confirmed that the re-expression of miR‑1 significantly inhibited ESCC tumor growth. A tetrazolium assay and a trypan blue exclusion assay revealed that miR‑1 suppressed ESCC cell proliferation and increased apoptosis, whereas the silencing of miR‑1 promoted cell proliferation and decreased apoptosis, suggesting that miR‑1 is a novel tumor suppressor. To elucidate the molecular mechanisms of action of miR‑1 in ESCC, we investigated putative targets using bioinformatics tools. MET, cyclin D1 and cyclin-dependent kinase 4 (CDK4), which are involved in the hepatocyte growth factor (HGF)/MET signaling pathway, were found to be targets of miR‑1. miR‑1 expression inversely correlated with MET, cyclin D1 and CDK4 expression in ESCC cells. miR‑1 directly targeted MET, cyclin D1 and CDK4, suppressing ESCC cell growth. The newly identified miR‑1/MET/cyclin D1/CDK4 axis provides new insight into the molecular mechanisms of ESCC pathogenesis and indicates a novel strategy for the diagnosis and treatment of ESCC.

Jin G, Yang Y, Liu H, et al.
Genome-wide analysis of the effect of esophageal squamous cell carcinoma on human umbilical vein endothelial cells.
Oncol Rep. 2016; 36(1):155-64 [PubMed] Related Publications
A large volume of data indicates that controlling tumor-associated angiogenesis is a promising therapy against cancer. However, angiogenesis is a complex process, little is known about the differential gene expression in the process of normal endothelial cell differentiation toward tumor vascular endothelial cells induced by tumor microenvironment. The aim of this study is to investigate the effect of tumor microenvironment simulated by the supernatant of esophageal squamous cancer cells (KYSE70) on normal endothelial cells (HUVECs) at the whole genome level. The gene expression profile was studied through gene ontology and signal pathway analysis. Compared with the normal HUVECs, a total of 3769 differentially expressed genes in induced HUVECs were detected, including 1609 upregulated genes and 2160 downregulated genes. Moreover, the microarray data analysis showed that 11 significant biological processes and 10 significant signaling pathways changed most, which are associated with angiogenesis and cell differentiation. According to the different expression levels in the microarrays and their functions, four differentially expressed genes involved in tumor angiogenesis and cell differentiation (IL6, VEGFA, S1PR1, TYMP) were selected and analyzed by qRT-PCR. The qRT-PCR results were consistent with the microarray data. Furthermore, we simulated the tumor microenvironment by human esophageal carcinoma tissue homogenate to investigate its effect on HUVECs, the qRT-PCR results indicated that the above genes were highly expressed in HUVECs after induction by esophageal carcinoma tissue homogenate. In conclusion, tumor microenvironment impact on normal endothelial cells differentiated toward tumor vascular endothelial cells, and the selected genes, which are associated with tumor angiogenesis, would be anti-angiogenesis targets against esophageal carcinoma.

Kivrak Salim D, Sahin M, Köksoy S, et al.
Local Immune Response in Helicobacter pylori Infection.
Medicine (Baltimore). 2016; 95(20):e3713 [PubMed] Free Access to Full Article Related Publications
There have been few studies concerning the cytokine profiles in gastric mucosa of Helicobacter pylori-infected patients with normal mucosa, chronic gastritis, and gastric carcinoma (GAC).In the present study, we aimed to elucidate the genomic expression levels and immune pathological roles of cytokines-interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-6, IL-10, transforming growth factor (TGF)-β, IL-17A, IL-32-in H pylori-infected patients with normal gastric mucosa (NGM; control), chronic active gastritis (CAG), and GAC. Genomic expression levels of these cytokines were assayed by real-time PCR analysis in gastric biopsy specimens obtained from 93 patients.We found that the genomic expression levels of IFN-γ, TNF-α, IL-6, IL-10, IL-17A mRNA were increased in the CAG group and those of TNF-α, IL-6, IL-10, IL-17A, TGF-β mRNA were increased in the GAC group with reference to H pylori-infected NGM group.This study is on the interest of cytokine profiles in gastric mucosa among individuals with normal, gastritis, or GAC. Our findings suggest that the immune response of gastric mucosa to infection of H pylori differs from patient to patient. For individual therapy, levels of genomic expression of IL-6 or other cytokines may be tracked in patients.

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