Gene Summary

Gene:LIFR; leukemia inhibitory factor receptor alpha
Aliases: SWS, SJS2, STWS, CD118, LIF-R
Summary:This gene encodes a protein that belongs to the type I cytokine receptor family. This protein combines with a high-affinity converter subunit, gp130, to form a receptor complex that mediates the action of the leukemia inhibitory factor, a polyfunctional cytokine that is involved in cellular differentiation, proliferation and survival in the adult and the embryo. Mutations in this gene cause Schwartz-Jampel syndrome type 2, a disease belonging to the group of the bent-bone dysplasias. A translocation that involves the promoter of this gene, t(5;8)(p13;q12) with the pleiomorphic adenoma gene 1, is associated with salivary gland pleiomorphic adenoma, a common type of benign epithelial tumor of the salivary gland. Multiple splice variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:leukemia inhibitory factor receptor
Source:NCBIAccessed: 27 February, 2015


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 (1990-2015)
Graph generated 28 February 2015 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.

  • Chromosome 5
  • Transcription Factors
  • Single Nucleotide Polymorphism
  • Soft Tissue Cancers
  • Oligonucleotide Array Sequence Analysis
  • Signal Transduction
  • Antineoplastic Agents
  • Messenger RNA
  • Interleukin-6
  • CD Antigens
  • Receptors, OSM-LIF
  • Neoplasm Proteins
  • Tumor Markers
  • DNA-Binding Proteins
  • Molecular Sequence Data
  • Cell Division
  • Western Blotting
  • Receptors, Cytokine
  • Cytokines
  • Cancer Gene Expression Regulation
  • Tumor Suppressor Gene
  • Transcription
  • Gene Expression Profiling
  • Leukemia Inhibitory Factor Receptor alpha Subunit
  • Growth Inhibitors
  • Lymphokines
  • Leukemia Inhibitory Factor
  • Receptors, Oncostatin M
  • Colorectal Cancer
  • Neoplasm Metastasis
  • Base Sequence
  • STAT3 Transcription Factor
  • p53 Protein
  • Breast Cancer
  • Osteochondrodysplasias
  • beta Catenin
  • Promoter Regions
  • ras Proteins
  • Up-Regulation
  • Oncostatin M
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Latest Publications: LIFR (cancer-related)

Sun L, Sui L, Cong X, et al.
Low incidence of IL6ST (gp130) mutations in exon 6 in lung cancer of a Chinese cohort.
Cancer Genet. 2014 Jul-Aug; 207(7-8):291-8 [PubMed] Related Publications
Lung cancer is an inflammation-associated epithelial carcinoma. A highly active interleukin 6 (IL-6)/glycoprotein 130 (gp130)/signal transducer and activator of transcription 3 (STAT3) pathway has been identified in a subset of primary lung cancer and closely correlated with tumor progression and poor prognosis. In a previous study, the frequent occurrence of somatic gain-of-function mutations was observed in the gp130-encoding IL6ST gene in exon 6 in 60% of inflammatory hepatocellular adenomas. Prompted by this finding, we assessed 110 Chinese lung carcinomas using PCR and direct DNA sequencing but found no somatic mutation of IL6ST in exon 6. However, one new potential germline missense mutation c.599C>G was identified in one adenocarcinoma that harbors wild-type epidermal growth factor receptor and KRAS. Protein modeling analysis showed that this mutation might not affect the gp130 protein conformation. Moreover, activated STAT3 was observed in most of the lung tumor tissues at a higher level than that in matched normal lung tissues. In conclusion, the c.599C>G mutation may be a new single nucleotide polymorphism of IL6ST, but mutations in exon 6 of this gene are not apparently common genetic variations occurring and leading to constitutive activation of STAT3 in lung cancer.

Xu S, Xu Z, Liu B, et al.
LIFRα-CT3 induces differentiation of a human acute myelogenous leukemia cell line HL-60 by suppressing miR-155 expression through the JAK/STAT pathway.
Leuk Res. 2014; 38(10):1237-44 [PubMed] Related Publications
The distal cytoplasmic motifs of the leukemia inhibitory factor receptor α-chain (LIFRα-CT3) and its TAT fusion protein (TAT-CT3) can independently suppress cell viability and induce myeloid differentiation in human leukemia HL-60 cells in our previous studies. But its underlying mechanism remains undefined. Herein, we show that a prokaryotic expressed TAT-CT3 induced a rapid elevation of STAT3 phosphorylation (pSTAT3), and then suppress the transcription of miR-155 and induce the elevation of SOCS-1, which further inhibited STAT3 phosphorylation for a long-term period. Our result indicated a novel mechanism of TAT-CT3 to promote HL60 cells differentiation, which provides some potential therapeutic targets for future acute myelogenous leukemia therapy.

Zhang X, Blaskovich MA, Forinash KD, Sebti SM
Withacnistin inhibits recruitment of STAT3 and STAT5 to growth factor and cytokine receptors and induces regression of breast tumours.
Br J Cancer. 2014; 111(5):894-902 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
BACKGROUND: The binding of STAT3 and STAT5 to growth factor and cytokine receptors such as EGFR and IL-6 receptor gp130 is critical to their activation and ability to contribute to malignant transformation. Therefore, interfering with these biochemical processes could lead to the discovery of novel anticancer agents.
METHODS: Co-immunoprecipitation, western blotting, microscopy, DNA binding, invasion, and soft agar assays as well as a mouse model were used to investigate the mechanism by which the natural product Withacnistin (Wit) inhibits STAT 3/5 tyrosine phosphoryaltion and activation.
RESULTS: Wit blocks EGF- and IL-6-stimulated binding of STAT3 and STAT5 to EGFR and gp130. Wit inhibits EGF-, PDGF-, IL-6-, IFNβ-, and GM-CSF-stimulation of tyrosine phosphorylation of STAT3 and STAT5 but not of EGFR or PDGFR. The inhibition of P-STAT3 and P-STAT5 occurred rapidly, within minutes of Wit treatment and growth factor stimulation. Wit also inhibits STAT3 nuclear translocation, DNA binding, promoter transcriptional activation, and it suppresses the expression levels of STAT3 target genes such as Bcl-xL and Mcl-1. Finally, Wit induces apoptosis, inhibits anchorage-dependent and -independent growth and invasion, and causes breast tumour regression in an ErbB2-driven transgenic mouse model.
CONCLUSIONS: These data warrant further development of Wit as a novel anticancer drug for targeting tumours that harbour hyperactivated STAT3 and STAT5.

Liao YT, Jeng YM, Lee YH, et al.
The occurrence of primary hepatic adenoma in deceased donor renal transplant recipient.
Int Braz J Urol. 2014 Jan-Feb; 40(1):118-22 [PubMed] Related Publications
MAIN FINDINGS: We reported a case of new-onset, multi-focal hepatic adenoma in an 18 year-old man with no classic risk factors occurring forty months after a renal transplant from a cadaver donor. Histopathology of the adenoma was examined and genotype and phenotype were also analyzed. Histopathologic examination of the adenoma showed no malignancy. Genotype and phenotype analysis revealed no HNF1α or β-catenin gene mutations and no inflammatory infiltration. The patient was well and disease-free postoperatively. CASE HYPOTHESIS: Hepatic adenoma occurs mostly in those taking oral contraceptives or androgenic-anabolic steroids or in those with hereditary diseases. Hepatic adenoma in a renal transplant recipient is rare and has only been reported in one case with glycogen storage disease type Ia. Immunosuppressive treatment might have contributed to the development of the neoplasm.
PROMISING FUTURE IMPLICATIONS: Although malignant change occurs most often in β-catenin gene mutation hepatic adenoma, surgical resection of the adenoma in a patient under immunosuppressive therapy should be considered in order to avoid the possibility of malignant transformation or hemorrhagic rupture.

Mikelonis D, Jorcyk CL, Tawara K, Oxford JT
Stüve-Wiedemann syndrome: LIFR and associated cytokines in clinical course and etiology.
Orphanet J Rare Dis. 2014; 9:34 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
Stüve-Wiedemann syndrome (STWS; OMIM #610559) is a rare bent-bone dysplasia that includes radiologic bone anomalies, respiratory distress, feeding difficulties, and hyperthermic episodes. STWS usually results in infant mortality, yet some STWS patients survive into and, in some cases, beyond adolescence. STWS is caused by a mutation in the leukemia inhibitory factor receptor (LIFR) gene, which is inherited in an autosomally recessive pattern. Most LIFR mutations resulting in STWS are null mutations which cause instability of the mRNA and prevent the formation of LIFR, impairing the signaling pathway. LIFR signaling usually follows the JAK/STAT3 pathway, and is initiated by several interleukin-6-type cytokines. STWS is managed on a symptomatic basis since there is no treatment currently available.

Stuart E, Buchert M, Putoczki T, et al.
Therapeutic inhibition of Jak activity inhibits progression of gastrointestinal tumors in mice.
Mol Cancer Ther. 2014; 13(2):468-74 [PubMed] Related Publications
Aberrant activation of the latent transcription factor STAT3 and its downstream targets is a common feature of epithelial-derived human cancers, including those of the gastrointestinal tract. Mouse models of gastrointestinal malignancy implicate Stat3 as a key mediator of inflammatory-driven tumorigenesis, in which its cytokine/gp130/Janus kinase (Jak)-dependent activation provides a functional link through which the microenvironment sustains tumor promotion. Although therapeutic targeting of STAT3 is highly desirable, such molecules are not available for immediate clinical assessment. Here, we investigated whether the small-molecule Jak1/2 inhibitor AZD1480 confers therapeutic benefits in two mouse models of inflammation-associated gastrointestinal cancer, which are strictly dependent of excessive Stat3 activation. We confirm genetically that Cre-mediated, tumor cell-specific reduction of Stat3 expression arrests the growth of intestinal-type gastric tumors in gp130(F/F) mice. We find that systemic administration of AZD1480 readily replicates this effect, which is associated with reduced Stat3 activation and correlates with diminished tumor cell proliferation and increased apoptosis. Likewise, AZD1480 therapy also conferred a cytostatic effect on established tumors in a colitis-associated colon cancer model in wild-type mice. As predicted from our genetic observations in gp130(F/F) mice, the therapeutic effect of AZD1480 remains fully reversible upon cessation of compound administration. Collectively, our results provide the first evidence that pharmacologic targeting of excessively activated wild-type Jak kinases affords therapeutic suppression of inflammation-associated gastrointestinal cancers progression in vivo.

Przybyla BD, Shafirstein G, Vishal SJ, et al.
Molecular changes in bone marrow, tumor and serum after conductive ablation of murine 4T1 breast carcinoma.
Int J Oncol. 2014; 44(2):600-8 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
Thermal ablation of solid tumors using conductive interstitial thermal therapy (CITT) produces coagulative necrosis in the center of ablation. Local changes in homeostasis for surviving tumor and systemic changes in circulation and distant organs must be understood and monitored in order to prevent tumor re-growth and metastasis. The purpose of this study was to use a mouse carcinoma model to evaluate molecular changes in the bone marrow and surviving tumor after CITT treatment by quantification of transcripts associated with cancer progression and hyperthermia, serum cytokines, stress proteins and the marrow/tumor cross-talk regulator stromal-derived factor 1. Analysis of 27 genes and 22 proteins with quantitative PCR, ELISA, immunoblotting and multiplex antibody assays revealed that the gene and protein expression in tissue and serum was significantly different between ablated and control mice. The transcripts of four genes (Cxcl12, Sele, Fgf2, Lifr) were significantly higher in the bone marrow of treated mice. Tumors surviving ablation showed significantly lower levels of the Lifr and Sele transcripts. Similarly, the majority of transcripts measured in tumors decreased with treatment. Surviving tumors also contained lower levels of SDF-1α and HIF-1α proteins whereas HSP27 and HSP70 were higher. Of 16 serum chemokines, IFNγ and GM-CSF levels were lower with treatment. These results indicate that CITT ablation causes molecular changes which may slow cancer cell proliferation. However, inhibition of HSP27 may be necessary to control aggressiveness of surviving cancer stem cells. The changes in bone marrow are suggestive of possible increased recruitment of circulatory cancer cells. Therefore, the possibility of heightened bone metastasis after thermal ablation needs to be further investigated and inhibition strategies developed, if warranted.

Liu SC, Tsang NM, Chiang WC, et al.
Leukemia inhibitory factor promotes nasopharyngeal carcinoma progression and radioresistance.
J Clin Invest. 2013; 123(12):5269-83 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
Radioresistance of EBV-associated nasopharyngeal carcinoma (NPC) is associated with poor prognosis for patients with this form of cancer. Here, we found that NPC patients had increased serum levels of leukemia inhibitory factor (LIF) and that higher LIF levels correlated with local tumor recurrence. Furthermore, in vitro studies with NPC cells and in vivo xenograft mouse studies demonstrated that LIF critically contributes to NPC tumor growth and radioresistance. Using these model systems, we found that LIF treatment activated the mTORC1/p70S6K signaling pathway, enhanced tumor growth, inhibited DNA damage responses, and enhanced radioresistance. Treatment with either soluble LIF receptor (sLIFR), a LIF antagonist, or the mTOR inhibitor rapamycin reversed LIF-mediated effects, resulting in growth arrest and increased sensitivity to γ irradiation. Immunohistochemical (IHC) analyses of human NPC biopsies revealed that LIF and LIFR were overexpressed in tumor cells and that LIF expression correlated with the presence of the activated p-p70S6K. Finally, we found that the EBV-encoded protein latent membrane protein 1 (LMP1) enhances LIF production. Together, our findings indicate that LIF promotes NPC tumorigenesis and suggest that serum LIF levels may predict local recurrence and radiosensitivity in NPC patients.

Diao Y, Guo X, Jiang L, et al.
miR-203, a tumor suppressor frequently down-regulated by promoter hypermethylation in rhabdomyosarcoma.
J Biol Chem. 2014; 289(1):529-39 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma found in children and young adults. It is characterized by the expression of a number of skeletal muscle-specific proteins, including MyoD and muscle α-actin. However, unlike normal myoblasts, RMS cells differentiate poorly both in vivo and in culture. As microRNAs are known to regulate tumorigenesis, intensive efforts have been made to identify microRNAs that are involved in RMS development. In this work, we found that miR-203 was frequently down-regulated by promoter hypermethylation in both RMS cell lines and RMS biopsies and could be reactivated by DNA-demethylating agents. Re-expression of miR-203 in RMS cells inhibited their migration and proliferation and promoted terminal myogenic differentiation. Mechanistically, miR-203 exerts its tumor-suppressive effect by directly targeting p63 and leukemia inhibitory factor receptor in RMS cells, which promotes myogenic differentiation by inhibiting the Notch and the JAK1/STAT1/STAT3 pathways, respectively. Our work reveals that miR-203 functions as a tumor suppressor in RMS development.

Canaparo R, Varchi G, Ballestri M, et al.
Polymeric nanoparticles enhance the sonodynamic activity of meso-tetrakis (4-sulfonatophenyl) porphyrin in an in vitro neuroblastoma model.
Int J Nanomedicine. 2013; 8:4247-63 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
PURPOSE: Sonodynamic therapy is a developing noninvasive modality for cancer treatment, based on the selective activation of a sonosensitizer agent by acoustic cavitation. The activated sonosensitizer agent might generate reactive oxygen species leading to cancer cell death. We investigated the potential poly-methyl methacrylate core-shell nanoparticles (NPs) loaded with meso-tetrakis (4-sulfonatophenyl) porphyrin (TPPS) have to function as an innovative sonosensitizing system, ie, TPPS-NPs.
METHODS: Shockwaves (SWs) generated by a piezoelectric device were used to induce acoustic cavitation. The cytotoxic effect of the sonodynamic treatment with TPPS-NPs and SWs was investigated on the human neuroblastoma cell line, SH-SY5Y. Cells were exposed for 12 hours to TPPS-NPs (100 μg/mL) and then to SWs (0.43 mJ/mm(2) for 500 impulses, 4 impulses/second). Treatment with SWs, TPPS, and NPs alone or in combination was carried out as control.
RESULTS: There was a statistically significant decrease in SH-SY5Y cell proliferation after the sonodynamic treatment with TPPS-NPs and SWs. Indeed, there was a significant increase in necrotic (16.91% ± 3.89%) and apoptotic (27.45% ± 3.03%) cells at 48 hours. Moreover, a 15-fold increase in reactive oxygen species production for cells exposed to TPPS-NPs and SWs was observed at 1 hour compared with untreated cells. A statistically significant enhanced mRNA (messenger ribonucleic acid) expression of NRF2 (P<0.001) and a significant downregulation of TIGAR (P<0.05) and MAP3K5 (P<0.05) genes was observed in cells exposed to TPPS-NPs and SWs at 24 hours, along with a statistically significant release of cytochrome c (P<0.01) at 48 hours. Lastly, the sonosensitizing system was also investigated in an in vitro three-dimensional model, and the sonodynamic treatment significantly decreased the neuroblastoma spheroid growth.
CONCLUSION: The sonosensitizing properties of TPPS were significantly enhanced once loaded onto NPs, thus enhancing the sonodynamic treatment's efficacy in an in vitro neuroblastoma model.

Cross-Knorr S, Lu S, Perez K, et al.
RKIP phosphorylation and STAT3 activation is inhibited by oxaliplatin and camptothecin and are associated with poor prognosis in stage II colon cancer patients.
BMC Cancer. 2013; 13:463 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
BACKGROUND: A major obstacle in treating colorectal cancer (CRC) is the acquired resistance to chemotherapeutic agents. An important protein in the regulation of cancer cell death and clinical outcome is Raf kinase inhibitor protein (RKIP). In contrast, activated signal transducer and activator of transcription 3 (STAT3) is a protein that promotes tumor cell survival by inhibiting apoptosis and has an important role in cancer progression in many of cancer types. The aim of this study was to evaluate the regulation of RKIP and STAT3 after treatment with clinically relevant chemotherapeutic agents (camptothecin (CPT) and oxaliplatin (OXP)) and the cytokine interleukin-6 (IL-6) in HCT116 colon cancer cells as well as evaluate the association between RKIP and STAT3 with clinical outcome of Stage II colon cancer patients.
METHODS: HCT-116 colon cancer cells were treated with CPT, OXP, and IL-6 separately or in combination in a time and dose-dependent manner and examined for phosphorylated and non-phosphorylated RKIP and STAT3 via Western blot analysis. STAT3 transcriptional activity was measured via a luciferase reporter assay in HCT116 cells treated with CPT, IL-6 or transfected with JAK 1, 2 separately or in combination. We extended these observations and determined STAT3 and RKIP/ pRKIP in tumor microarrays (TMA) in stage II colon cancer patients.
RESULTS: We demonstrate IL-6-mediated activation of STAT3 occurs in conjunction with the phosphorylation of RKIP in vitro in human colon cancer cells. OXP and CPT block IL-6 mediated STAT3 activation and RKIP phosphorylation via the inhibition of the interaction of STAT3 with gp130. We determined that STAT3 and nuclear pRKIP are significantly associated with poor patient prognosis in stage II colon cancer patients.
CONCLUSIONS: In the analysis of tumor samples from stage II colon cancer patients and the human colon carcinoma cell line HCT116, pRKIP and STAT3, 2 proteins potentially involved in the resistance to conventional treatments were detected. The phosphorylation of pRKIP and STAT3 are induced by the cytokine IL-6 and suppressed by the chemotherapeutic drugs CPT and OXP. Therefore, these results suggest that STAT3 and pRKIP may serve as prognostic biomarkers in stage II colon cancer patients and may improve chemotherapy.

Wang Y, van Boxel-Dezaire AH, Cheon H, et al.
STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor.
Proc Natl Acad Sci U S A. 2013; 110(42):16975-80 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
The activation of STAT3 by tyrosine phosphorylation, essential for normal development and for a normal inflammatory response to invading pathogens, is kept in check by negative regulators. Abnormal constitutive activation of STAT3, which contributes to the pathology of cancer and to chronic inflammatory diseases such as rheumatoid arthritis, occurs when negative regulation is not fully effective. SOCS3, the major negative regulator of STAT3, is induced by tyrosine-phosphorylated STAT3 and terminates STAT3 phosphorylation about 2 h after initial exposure of cells to members of the IL-6 family of cytokines by binding cooperatively to the common receptor subunit gp130 and JAKs 1 and 2. We show here that when the epidermal growth factor receptor (EGFR) is present and active, STAT3 is rephosphorylated about 4 h after exposure of cells to IL-6 or oncostatin M and remains active for many hours. Newly synthesized IL-6 drives association of the IL-6 receptor and gp130 with EGFR, leading to EGFR-dependent rephosphorylation of STAT3, which is not inhibited by the continued presence of SOCS3. This second wave of STAT3 activation supports sustained expression of a subset of IL-6-induced proteins, several of which play important roles in inflammation and cancer, in which both IL-6 secretion and EGFR levels are often elevated.

Cheng Y, Cheung AK, Ko JM, et al.
Physiological β-catenin signaling controls self-renewal networks and generation of stem-like cells from nasopharyngeal carcinoma.
BMC Cell Biol. 2013; 14:44 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
BACKGROUND: A few reports suggested that low levels of Wnt signaling might drive cell reprogramming, but these studies could not establish a clear relationship between Wnt signaling and self-renewal networks. There are ongoing debates as to whether and how the Wnt/β-catenin signaling is involved in the control of pluripotency gene networks. Additionally, whether physiological β-catenin signaling generates stem-like cells through interactions with other pathways is as yet unclear. The nasopharyngeal carcinoma HONE1 cells have low expression of β-catenin and wild-type expression of p53, which provided a possibility to study regulatory mechanism of stemness networks induced by physiological levels of Wnt signaling in these cells.
RESULTS: Introduction of increased β-catenin signaling, haploid expression of β-catenin under control by its natural regulators in transferred chromosome 3, resulted in activation of Wnt/β-catenin networks and dedifferentiation in HONE1 hybrid cell lines, but not in esophageal carcinoma SLMT1 hybrid cells that had high levels of endogenous β-catenin expression. HONE1 hybrid cells displayed stem cell-like properties, including enhancement of CD24(+) and CD44(+) populations and generation of spheres that were not observed in parental HONE1 cells. Signaling cascades were detected in HONE1 hybrid cells, including activation of p53- and RB1-mediated tumor suppressor pathways, up-regulation of Nanog-, Oct4-, Sox2-, and Klf4-mediated pluripotency networks, and altered E-cadherin expression in both in vitro and in vivo assays. qPCR array analyses further revealed interactions of physiological Wnt/β-catenin signaling with other pathways such as epithelial-mesenchymal transition, TGF-β, Activin, BMPR, FGFR2, and LIFR- and IL6ST-mediated cell self-renewal networks. Using β-catenin shRNA inhibitory assays, a dominant role for β-catenin in these cellular network activities was observed. The expression of cell surface markers such as CD9, CD24, CD44, CD90, and CD133 in generated spheres was progressively up-regulated compared to HONE1 hybrid cells. Thirty-four up-regulated components of the Wnt pathway were identified in these spheres.
CONCLUSIONS: Wnt/β-catenin signaling regulates self-renewal networks and plays a central role in the control of pluripotency genes, tumor suppressive pathways and expression of cancer stem cell markers. This current study provides a novel platform to investigate the interaction of physiological Wnt/β-catenin signaling with stemness transition networks.

Looyenga BD, Resau J, MacKeigan JP
Cytokine receptor-like factor 1 (CRLF1) protects against 6-hydroxydopamine toxicity independent of the gp130/JAK signaling pathway.
PLoS One. 2013; 8(6):e66548 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
Oxidative stress is an important cause of cellular toxicity in the central nervous system and contributes to the pathology associated with neurodegenerative disorders including Parkinson's disease. As such, elucidation of cellular mechanisms that enhance neuronal resistance to oxidative stress may provide new avenues for therapy. In this study we employed a simple two-state cellular model to identify genes that are associated with resistance to oxidative stress induced by 6-hydroxydopamine (6-OHDA). In this model, undifferentiated neuroblastoma cells display higher sensitivity to 6-OHDA than differentiated cells. By comparing the gene expression between these two states, we identified several genes whose expression is altered concomitant with changes in 6-OHDA sensitivity. This gene set includes cytokine receptor-like factor 1 (CRLF1), which is up-regulated during the differentiation process and has been previously implicated in neuroprotection. We show that the product of this gene is both necessary and sufficient for increased resistance to 6-OHDA in differentiated neuroblastoma cells, and that CRLF1 serves its protective role by a cell autonomous mechanism that is independent from its known role as a co-ligand for the ciliary neurotrophic factor receptor. These data provide an additional role for CRLF1 that could potentially explain its broad expression pattern and effects on cells lacking expression of this receptor.

Antonescu CR, Zhang L, Shao SY, et al.
Frequent PLAG1 gene rearrangements in skin and soft tissue myoepithelioma with ductal differentiation.
Genes Chromosomes Cancer. 2013; 52(7):675-82 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
A subset of cutaneous and superficial soft tissue myoepithelial (ME) tumors displays a distinct ductal component and closely resembles mixed tumors/pleomorphic adenomas of salivary gland. As PLAG1 and HMGA2 rearrangements are the most common genetic events in pleomorphic adenomas, we sought to investigate if these abnormalities are also present in the skin/soft tissue ME lesions. In contrast, half of the deep-seated soft tissue ME tumors lacking ductal differentiation are known to be genetically unrelated, showing EWSR1 rearrangements. FISH analysis to detect PLAG1 and HMGA2 abnormalities was performed in 35 ME tumors, nine skin and 26 soft tissue, lacking EWSR1 and FUS rearrangements. For the PLAG1-rearranged tumors, FISH and RACE were performed to identify potential fusion partners, including CTNNB1 (beta-catenin) on 3p21 and LIFR (leukemia inhibitory factor receptor) on 5p13. Recurrent PLAG1 rearrangement by FISH was detected in 13 (37%) lesions, including three (33%) in the skin and 10 (38%) in the soft tissue. All were classified as benign and all except one showed abundant tubulo-ductal differentiation (comprising 12/24 [50%] of all tumors with ductal structures). A LIFR-PLAG1 fusion was detected by RACE and then confirmed by FISH in one soft tissue ME tumor with tubular formation. No CTNNB1 or LIFR abnormalities were detected in any of the remaining PLAG1-rearranged tumors. No structural HMGA2 abnormalities were detected in any of the 22 ME lesions tested. A subset of cutaneous and soft tissue ME tumors appears genetically linked to their salivary gland counterparts, displaying frequent PLAG1 gene rearrangements and occasionally LIFR-PLAG1 fusion.

Xu S, Grande F, Garofalo A, Neamati N
Discovery of a novel orally active small-molecule gp130 inhibitor for the treatment of ovarian cancer.
Mol Cancer Ther. 2013; 12(6):937-49 [PubMed] Related Publications
Interleukin (IL)-6 and Stat3 play key roles in ovarian cancer progression. However, the role of glycoprotein 130 (gp130), the signal transducer of this signaling axis, is not well-established. Currently, there are no small-molecule inhibitors of gp130 under clinical development. In this study, we show that gp130 is an attractive drug target in ovarian cancer due to its role in promoting cancer progression via the activation of its downstream Stat3 signaling. We also present preclinical studies of SC144, the first-in-class orally active small-molecule gp130 inhibitor. SC144 shows greater potency in human ovarian cancer cell lines than in normal epithelial cells. SC144 binds gp130, induces gp130 phosphorylation (S782) and deglycosylation, abrogates Stat3 phosphorylation and nuclear translocation, and further inhibits the expression of downstream target genes. In addition, SC144 shows potent inhibition of gp130 ligand-triggered signaling. Oral administration of SC144 delays tumor growth in a mouse xenograft model of human ovarian cancer without significant toxicity to normal tissues.

Kim MJ, Nam HJ, Kim HP, et al.
OPB-31121, a novel small molecular inhibitor, disrupts the JAK2/STAT3 pathway and exhibits an antitumor activity in gastric cancer cells.
Cancer Lett. 2013; 335(1):145-52 [PubMed] Related Publications
We investigated the mechanisms of action and antitumor effects of OPB-31121, a novel STAT3 inhibitor, in gastric cancer cells. OPB-31121 downregulated JAK2 and gp130 expression and inhibited JAK2 phosphorylation which leads to inhibition of STAT3 phosphorylation. OPB-31121 inhibited constitutively activated and IL-6-induced JAK/STAT signaling pathway. OPB-31121 decreased cell proliferation in both gastric cancer cells and in a xenograft model, induced the apoptosis of gastric cancer cells, inhibited the expression of antiapoptotic proteins, and showed synergism with 5-fluorouracil and cisplatin. Taken together, our study suggests that STAT3 inhibition with OPB-31121 can be tested in patients with gastric cancer.

Wang Z, Liu JQ, Liu Z, et al.
Tumor-derived IL-35 promotes tumor growth by enhancing myeloid cell accumulation and angiogenesis.
J Immunol. 2013; 190(5):2415-23 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
IL-35 is a member of the IL-12 family of cytokines that is comprised of an IL-12 p35 subunit and an IL-12 p40-related protein subunit, EBV-induced gene 3 (EBI3). IL-35 functions through IL-35R and has a potent immune-suppressive activity. Although IL-35 was demonstrated to be produced by regulatory T cells, gene-expression analysis revealed that it is likely to have a wider distribution, including expression in cancer cells. In this study, we demonstrated that IL-35 is produced in human cancer tissues, such as large B cell lymphoma, nasopharyngeal carcinoma, and melanoma. To determine the roles of tumor-derived IL-35 in tumorigenesis and tumor immunity, we generated IL-35-producing plasmacytoma J558 and B16 melanoma cells and observed that the expression of IL-35 in cancer cells does not affect their growth and survival in vitro, but it stimulates tumorigenesis in both immune-competent and Rag1/2-deficient mice. Tumor-derived IL-35 increases CD11b(+)Gr1(+) myeloid cell accumulation in the tumor microenvironment and, thereby, promotes tumor angiogenesis. In immune-competent mice, spontaneous CTL responses to tumors are diminished. IL-35 does not directly inhibit tumor Ag-specific CD8(+) T cell activation, differentiation, and effector functions. However, IL-35-treated cancer cells had increased expression of gp130 and reduced sensitivity to CTL destruction. Thus, our study indicates novel functions for IL-35 in promoting tumor growth via the enhancement of myeloid cell accumulation, tumor angiogenesis, and suppression of tumor immunity.

Thiem S, Pierce TP, Palmieri M, et al.
mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice.
J Clin Invest. 2013; 123(2):767-81 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
Gastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL-6 family cytokines, which promote tumorigenesis through persistent activation of the GP130/JAK/STAT3 pathway. Although tumor progression can be prevented by genetic ablation of Stat3 in mice, this transcription factor remains a challenging therapeutic target with a paucity of clinically approved inhibitors. Here, we uncovered parallel and excessive activation of mTOR complex 1 (mTORC1) alongside STAT3 in human intestinal-type gastric cancers (IGCs). Furthermore, in a preclinical mouse model of IGC, GP130 ligand administration simultaneously activated mTORC1/S6 kinase and STAT3 signaling. We therefore investigated whether mTORC1 activation was required for inflammation-associated gastrointestinal tumorigenesis. Strikingly, the mTORC1-specific inhibitor RAD001 potently suppressed initiation and progression of both murine IGC and colitis-associated colon cancer. The therapeutic effect of RAD001 was associated with reduced tumor vascularization and cell proliferation but occurred independently of STAT3 activity. We analyzed the mechanism of GP130-mediated mTORC1 activation in cells and mice and revealed a requirement for JAK and PI3K activity but not for GP130 tyrosine phosphorylation or STAT3. Our results suggest that GP130-dependent activation of the druggable PI3K/mTORC1 pathway is required for inflammation-associated gastrointestinal tumorigenesis. These findings advocate clinical application of PI3K/mTORC1 inhibitors for the treatment of corresponding human malignancies.

Hergovich A
YAP-Hippo signalling downstream of leukemia inhibitory factor receptor: implications for breast cancer.
Breast Cancer Res. 2012; 14(6):326 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
The proto-oncogenes YAP and TAZ have previously gained much attention as downstream effectors of Hippo tumour suppressor signalling. While the regulation of YAP/TAZ by MST/LATS kinases is reasonably well understood, the nature of factors functioning upstream of MST/LATS is yet to be elucidated in detail. A recent paper by Ma and co-workers defines a novel role for leukemia inhibitory factor receptor (LIFR) signalling upstream of the Hippo-YAP pathway in breast cancer metastasis. Moreover, a whole genome in vivo RNA interference screen by Lippmann and colleagues identified LIFR as a breast tumour suppressor. Here, we discuss the implications of these studies for breast cancer research and treatment.

Calderaro J, Labrune P, Morcrette G, et al.
Molecular characterization of hepatocellular adenomas developed in patients with glycogen storage disease type I.
J Hepatol. 2013; 58(2):350-7 [PubMed] Related Publications
BACKGROUND & AIMS: Hepatocellular adenomas (HCA) are benign liver tumors mainly related to oral contraception and classified into 4 molecular subgroups: inflammatory (IHCA), HNF1A-inactivated (H-HCA), β-catenin-activated (bHCA) or unclassified (UHCA). Glycogen storage disease type I (GSD) is a rare hereditary metabolic disease that predisposes to HCA development. The aim of our study was to characterize the molecular profile of GSD-associated HCA.
METHODS: We characterized a series of 25 HCAs developed in 15 patients with GSD by gene expression and DNA sequence of HNF1A, CTNNB1, IL6ST, GNAS, and STAT3 genes. Moreover, we searched for glycolysis, gluconeogenesis, and fatty acid synthesis alterations in GSD non-tumor livers and compared our results to those observed in a series of sporadic H-HCA and various non-GSD liver samples.
RESULTS: GSD adenomas were classified as IHCA (52%) mutated for IL6ST or GNAS, bHCA (28%) or UHCA (20%). In contrast, no HNF1A inactivation was observed, showing a different molecular subtype distribution in GSD-associated HCA from that observed in sporadic HCA (p = 0.0008). In non-tumor GSD liver samples, we identified glycolysis and fatty acid synthesis activation with gluconeogenesis repression. Interestingly, this gene expression profile was similar to that observed in sporadic H-HCA.
CONCLUSIONS: Our study showed a particular molecular profile in GSD-related HCA characterized by a lack of HNF1A inactivation. This exclusion could be explained by similar metabolic defects observed with HNF1A inactivation and glucose-6-phosphatase deficiency. Inversely, the high frequency of β-catenin mutations could be related to the increased frequency of malignant transformation in hepatocellular carcinoma.

Couto JP, Daly L, Almeida A, et al.
STAT3 negatively regulates thyroid tumorigenesis.
Proc Natl Acad Sci U S A. 2012; 109(35):E2361-70 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
Although tyrosine-phosphorylated or activated STAT3 (pY-STAT3) is a well-described mediator of tumorigenesis, its role in thyroid cancer has not been investigated. We observed that 63 of 110 (57%) human primary papillary thyroid carcinoma (PTC) cases expressed nuclear pY-STAT3 in tumor cells, preferentially in association with the tumor stroma. An inverse relationship between pY-STAT3 expression with tumor size and the presence of distant metastases was observed. Using human thyroid cancer-derived cell lines [harboring rearranged during transfection (RET)/PTC, v-RAF murine sarcoma viral oncogene homolog B (BRAF), or rat sarcoma virus oncogene (RAS) alterations], we determined that IL-6/gp130/JAK signaling is responsible for STAT3 activation. STAT3 knockdown by shRNA in representative thyroid cancer cell lines that express high levels of pY-STAT3 had no effect on in vitro growth. However, xenografted short hairpin STAT3 cells generated larger tumors than control cells. Similarly, STAT3 deficiency in a murine model of BRAFV600E-induced PTC led to thyroid tumors that were more proliferative and larger than those tumors expressing STAT3wt. Genome expression analysis revealed that STAT3 knockdown resulted in the down-regulation of multiple transcripts, including the tumor suppressor insulin-like growth factor binding protein 7. Furthermore, STAT3 knockdown led to an increase in glucose consumption, lactate production, and expression of Hypoxia-inducible factor 1 (HIF1α) target genes, suggesting that STAT3 is a negative regulator of aerobic glycolysis. Our studies show that, in the context of thyroid cancer, STAT3 is paradoxically a negative regulator of tumor growth. These findings suggest that targeting STAT3 in these cancers could enhance tumor size and highlight the complexities of the role of STAT3 in tumorigenesis.

Keshel SH, Soleimani M, Tavirani MR, et al.
Evaluation of unrestricted somatic stem cells as a feeder layer to support undifferentiated embryonic stem cells.
Mol Reprod Dev. 2012; 79(10):709-18 [PubMed] Related Publications
The use of unrestricted somatic stem cells (USSCs) holds great promise for future clinical applications. Conventionally, mouse embryonic fibroblasts (MEFs) or other animal-based feeder layers are used to support embryonic stem cell (ESC) growth; the use of such feeder cells increases the risk of retroviral and other pathogenic infection in clinical trials. Implementation of a human-based feeder layer, such as hUSSCs that are isolated from human sources, lowers such risks. Isolated cord blood USSCs derived from various donors were used as a novel, supportive feeder layer for growth of C4mES cells (Royan C4 ESCs). Complete cellular characterization using immunocytochemical and flow cytometric methods were performed on murine ESCs (mESCs) and hUSSCs. mESCs cultured on hUSSCs showed similar cellular morphology and presented the same cell markers of undifferentiated mESC as would have been observed in mESCs grown on MEFs. Our data revealed these cells had negative expression of Stat3, Sox2, and Fgf4 genes while showing positive expression for Pou5f1, Nanog, Rex1, Brachyury, Lif, Lifr, Tert, B2m, and Bmp4 genes. Moreover, mESCs cultured on hUSSCs exhibited proven differentiation potential to germ cell layers showing normal karyotype. The major advantage of hUSSCs is their ability to be continuously cultured for at least 50 passages. We have also found that hUSSCs have the potential to provide ESC support from the early moments of isolation. Further study of hUSSC as a novel human feeder layer may lead to their incorporation into clinical methods, making them a vital part of the application of human ESCs in clinical cell therapy.

Choi CH, Choi JJ, Park YA, et al.
Identification of differentially expressed genes according to chemosensitivity in advanced ovarian serous adenocarcinomas: expression of GRIA2 predicts better survival.
Br J Cancer. 2012; 107(1):91-9 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
BACKGROUND: The purpose of this study was to identify genes that are differentially expressed in chemosensitive serous papillary ovarian carcinomas relative to those expressed in chemoresistant tumours.
METHODS: To identify novel candidate biomarkers, differences in gene expression were analysed in 26 stage IIIC/IV serous ovarian adenocarcinomas (12 chemosensitive tumours and 14 chemoresistant tumours). We subsequently investigated the immunohistochemical expression of GRIA2 in 48 independent sets of advanced ovarian serous carcinomas.
RESULTS: Microarray analysis revealed a total of 57 genes that were differentially expressed in chemoresistant and chemosensitive tumours. Of the 57 genes, 39 genes were upregulated and 18 genes were downregulated in chemosensitive tumours. Five differentially expressed genes (CD36, LIFR, CHL1, GRIA2, and FCGBP) were validated by quantitative real-time PCR. The expression of GRIA2 was validated at the protein level by immunohistochemistry, and patients with GRIA2 expression showed a longer progression-free and overall survival (P=0.051 and P=0.031 respectively).
CONCLUSIONS: We found 57 differentially expressed genes to distinguish between chemosensitive and chemoresistant tumours. We also demonstrated that the expression of GRIA2 among the differentially expressed genes provides better prognosis of patients with advanced serous papillary ovarian adenocarcinoma.

Iorns E, Ward TM, Dean S, et al.
Whole genome in vivo RNAi screening identifies the leukemia inhibitory factor receptor as a novel breast tumor suppressor.
Breast Cancer Res Treat. 2012; 135(1):79-91 [PubMed] Related Publications
Cancer is caused by mutations in oncogenes and tumor suppressor genes, resulting in the deregulation of processes fundamental to the normal behavior of cells. The identification and characterization of oncogenes and tumor suppressors has led to new treatment strategies that have significantly improved cancer outcome. The advent of next generation sequencing has allowed the elucidation of the fine structure of cancer genomes, however, the identification of pathogenic changes is complicated by the inherent genomic instability of cancer cells. Therefore, functional approaches for the identification of novel genes involved in the initiation and development of tumors are critical. Here we report the first whole human genome in vivo RNA interference screen to identify functionally important tumor suppressor genes. Using our novel approach, we identify previously validated tumor suppressor genes including TP53 and MNT, as well as several novel candidate tumor suppressor genes including leukemia inhibitory factor receptor (LIFR). We show that LIFR is a key novel tumor suppressor, whose deregulation may drive the transformation of a significant proportion of human breast cancers. These results demonstrate the power of genome wide in vivo RNAi screens as a method for identifying novel genes regulating tumorigenesis.

Sommer J, Effenberger T, Volpi E, et al.
Constitutively active mutant gp130 receptor protein from inflammatory hepatocellular adenoma is inhibited by an anti-gp130 antibody that specifically neutralizes interleukin 11 signaling.
J Biol Chem. 2012; 287(17):13743-51 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
Ligand-independent constitutively active gp130 mutants were described to be responsible for the development of inflammatory hepatocellular adenomas (IHCAs). These variants had gain-of-function somatic mutations within the extracellular domain 2 (D2) of the gp130 receptor chain. Cytokine-dependent Ba/F3 cells were transduced with the constitutively active variant of gp130 featuring a deletion in the domain 2 from Tyr-186 to Tyr-190 (gp130ΔYY). These cells showed constitutive phosphorylation of signal transducer and activator of transcription-3 (STAT3) and cytokine-independent proliferation. Deletion of the Ig-like domain 1 (D1) of gp130, but not anti-gp130 mAbs directed against D1, abolished constitutive activation of gp130ΔYY, highlighting that this domain is involved in ligand-independent activation of gp130ΔYY. Moreover, soluble variants of gp130 were not able to inhibit the constitutive activation of gp130ΔYY. However, the inhibition of constitutive activation of gp130ΔYY was achieved by the anti-gp130 mAb B-P4, which specifically inhibits gp130 signaling by IL-11 but not by other IL-6 type cytokines. IL-11 but not IL-6 levels were found previously to be up-regulated in IHCAs, suggesting that mutations in gp130 are leading to IL-11-like signaling. The mAb B-P4 might be a valuable tool to inhibit the constitutive activation of naturally occurring gp130 mutants in IHCAs and rare cases of gp130-associated hepatocellular carcinoma.

Morris VA, Punjabi AS, Wells RC, et al.
The KSHV viral IL-6 homolog is sufficient to induce blood to lymphatic endothelial cell differentiation.
Virology. 2012; 428(2):112-20 [PubMed] Article available free on PMC after 26/08/2015 Related Publications
The predominant tumor cell of Kaposi's Sarcoma (KS) is the spindle cell, a cell of endothelial origin that expresses markers of lymphatic endothelium. In culture, Kaposi's Sarcoma-associated herpesvirus (KSHV) infection of blood endothelial cells drives expression of lymphatic endothelial cell specific markers, in a process that requires activation of the gp130 receptor and the JAK2/STAT3 and PI3K/AKT signaling pathways. While expression of each of the KSHV major latent genes in endothelial cells failed to increase expression of lymphatic markers, the viral homolog of human IL-6 (vIL-6) was sufficient for induction and requires the JAK2/STAT3 and PI3K/AKT pathways. Therefore, activation of gp130 and downstream signaling by vIL-6 is sufficient to drive blood to lymphatic endothelial cell differentiation. While sufficient, vIL-6 is not necessary for lymphatic reprogramming in the context of viral infection. This indicates that multiple viral genes are involved and suggests a central importance of this pathway to KSHV pathogenesis.

Kadam SD, Gucek M, Cole RN, et al.
Cell proliferation and oxidative stress pathways are modified in fibroblasts from Sturge-Weber syndrome patients.
Arch Dermatol Res. 2012; 304(3):229-35 [PubMed] Related Publications
Sturge-Weber syndrome (SWS) is defined by vascular malformations of the face, eye and brain and an underlying somatic mutation has been hypothesized. We employed isobaric tags for relative and absolute quantification (iTRAQ-8plex)-based liquid chromatography interfaced with tandem mass spectrometry (LC-MS/MS) approach to identify differentially expressed proteins between port-wine-derived and normal skin-derived fibroblasts of four individuals with SWS. Proteins were identified that were significantly up- or down-regulated (i.e., ratios >1.2 or <0.8) in two or three pairs of samples (n = 31/972 quantified proteins) and their associated p values reported. Ingenuity pathway analysis (IPA) tool showed that the up-regulated proteins were associated with pathways that enhance cell proliferation; down-regulated proteins were associated with suppression of cell proliferation. The significant toxicologic list pathway in all four observations was oxidative stress mediated by Nrf2. This proteomics study highlights oxidative stress also consistent with a possible mutation in the RASA1 gene or pathway in SWS.

Michaud-Levesque J, Bousquet-Gagnon N, Béliveau R
Quercetin abrogates IL-6/STAT3 signaling and inhibits glioblastoma cell line growth and migration.
Exp Cell Res. 2012; 318(8):925-35 [PubMed] Related Publications
Evidence has suggested that STAT3 functions as an oncogene in gliomagenesis. As a consequence, changes in the inflammatory microenvironment are thought to promote tumor development. Regardless of its origin, cancer-related inflammation has many tumor-promoting effects, such as the promotion of cell cycle progression, cell proliferation, cell migration and cell survival. Given that IL-6, a major cancer-related inflammatory cytokine, regulates STAT3 activation and is upregulated in glioblastoma, we sought to investigate the inhibitory effects of the chemopreventive flavonoid quercetin on glioblastoma cell proliferation and migration triggered by IL-6, and to determine the underlying mechanisms of action. In this study, we show that quercetin is a potent inhibitor of the IL-6-induced STAT3 signaling pathway in T98G and U87 glioblastoma cells. Exposure to quercetin resulted in the reduction of GP130, JAK1 and STAT3 activation by IL-6, as well as a marked decrease of the proliferative and migratory properties of glioblastoma cells induced by IL-6. Interestingly, quercetin also modulated the expression of two target genes regulated by STAT3, i.e. cyclin D1 and matrix metalloproteinase-2 (MMP-2). Moreover, quercetin reduced the recruitment of STAT3 at the cyclin D1 promoter and inhibited Rb phosphorylation in the presence of IL-6. Overall, these results provide new insight into the role of quercetin as a blocker of the STAT3 activation pathway stimulated by IL-6, with a potential role in the prevention and treatment of glioblastoma.

Ernst M, Putoczki TL
Stat3: linking inflammation to (gastrointestinal) tumourigenesis.
Clin Exp Pharmacol Physiol. 2012; 39(8):711-8 [PubMed] Related Publications
Tumourigenesis is a multistage process comprising initiation, promotion and progression that is governed by cumulative (epi-)genetic changes. However, tumour initiation, triggered by mutations in proto-oncogenes and/or tumour suppressor genes, is insufficient for the development of cancers. Tumour promotion often depends on the interaction between initiated cells and the microenvironment where an excessive abundance of inflammatory mediators, including those of the interleukin (IL-)6/glycoprotein 130 (gp130) family, promote their expansion. The activity of most soluble mediators ultimately converges on tumour cells through activation of the latent transcription factors nuclear factor (NF)-κB and signal transducer and activator of transcription (Stat) 3 to enhance survival of neoplastic cells. In addition, Stat3 promotes tumour cell proliferation, invasion and induction of an angiogenic switch. Persistent activation of STAT3 is a unifying hallmark of a majority of solid malignancies. However, persistent STAT3 activation usually occurs in the absence of activating mutations in, or amplification of, the STAT3 gene. Instead, it is associated with an oversupply of autocrine and/or paracrine activating cytokines secreted by tumour and stromal cells and comprising (among others) cytokines that use the gp130 receptor. Interleukin-6, IL-11 and other members of the gp130 cytokine family have been identified in preclinical mouse models as promising therapeutic targets for gastrointestinal, hepatic and breast cancers. Thus, pharmacological interference with specific cytokines and tyrosine kinases that trigger Stat3 activation affords opportunities to therapeutically target the non-redundant tumour-promoting signalling function of Stat3.

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