Research IndicatorsGraph generated 30 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (7)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: IL11 (cancer-related)
Yang SM, Li SY, Hao-Bin Y, et al.IL-11 activated by lnc-ATB promotes cell proliferation and invasion in esophageal squamous cell cancer.
Biomed Pharmacother. 2019; 114:108835 [PubMed
] Related Publications
IL-11 exerts important functions involved in tumorigenesis and cancer progression. However, the underlying functional role of IL-11 in esophageal squamous cell cancer (ESCC) is not well known. In this paper, we demonstrated that IL-11 expression was increased in esophageal cancer compared with normal tissues, whereas knockdown of IL-11 could inhibit the proliferation and invasion of Eca109 and KYSE410 ESCC cells. Besides, we found that the stability and expression of IL-11 was regulated by lnc-ATB in Eca109 and KYSE410 ESCC cells. More importantly, we found that knockdown of IL-11 partly abolished lnc-ATB-mediated the proliferation and invasion of Eca109 and KYSE410 ESCC cells. Collectively, these results indicated that IL-11 mediated by lnc-ATB increased the proliferation and invasion of ESCC cells, which may provide a promising therapeutic option for suppressing ESCC progression.
Poffenberger MC, Metcalfe-Roach A, Aguilar E, et al.LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis.
Science. 2018; 361(6400):406-411 [PubMed
] Related Publications
Germline mutations in
OBJECTIVE: Cell density in tumor cell three dimensional (3D) cultures affects secretome expression of components. A microenvironment characteristic shared by high-density 3D cell culture and in vivo tumor masses is poor oxygenation, with anoxia being a natural cell state in tumor centers. Until recently, the ability to study anoxia-adapted cell physiology was not possible. Using a newly-developed methodology, anoxic HeLa cell secretome expression was measured.
RESULTS: Anoxic HeLa cell cytokine levels after 3 days' (hypoxia inducible factor, HIF1 positive) and 10 days' growth (HIF1 negative; anaerobic respiration) were significantly (p < 0.01) higher than normoxic controls for: IL-8 (1.8- and 3.4-fold higher, respectively), GRO (1.3- and 1.1-fold higher, respectively), and IL-11 (1.4- and 1.1-fold higher, respectively). In contrast, G-CSF, IFNα2, and CXCL-10 levels decreased over time (day 3 vs. day 10). Thus, metabolically active HeLa cells respond to the lack of oxygen, in part, by regulating the levels of cytokines produced. Cytokines expressed at increased levels, in the absence of oxygen, correspond to a secretomic profile reported for paracrine signaling pathways associated with metastasis. Further studies defining physiologic changes that occur upon anoxic growth may lead to the discovery of novel chemotherapeutic drug targets.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer‑associated mortality in the 21st century. microRNA (miR)‑23b has been shown to be involved in the pathogenesis of many cancers, including breast and prostate cancer. However, the role of miR‑23b in HCC remains unclear. The present study revealed a negative correlation between miR‑23b expression in HCC tissues and progression of carcinomas. Compared to normal tissues, miR‑23b expression was significantly downregulated in HCC tissues, whereas the expression of interleukin (IL)‑11 and IL‑11 receptor α (IL‑11Rα) was significantly upregulated, indicating that miR‑23b expression is negatively correlated with IL‑11 and IL‑11Rα expression. In addition, miR‑23b inhibited proliferation and promoted apoptosis of SMMC‑7721 cells. This effect was mediated by IL‑11, which was found to be the direct target of miR‑23b in this study. These results indicated that miR‑23b regulates IL‑11 and IL‑11Rα expression, and might act as an anti‑oncogenic agent in the progression of HCC by directly downregulating IL‑11 expression.
Zhao M, Liu Y, Liu R, et al.Upregulation of IL-11, an IL-6 Family Cytokine, Promotes Tumor Progression and Correlates with Poor Prognosis in Non-Small Cell Lung Cancer.
Cell Physiol Biochem. 2018; 45(6):2213-2224 [PubMed
] Related Publications
BACKGROUND/AIMS: Cytokines are key players in tumorigenesis and are potential targets in cancer treatment. Although IL-6 has attracted considerable attention, interleukin 11 (IL-11), another member of the IL-6 family, has long been overlooked, and little is known regarding its specific function in non-small cell lung cancer (NSCLC). In this study, we explored IL-11's role in NSCLC and the detailed mechanism behind it.
METHODS: Cell proliferation in response to IL-11 was determined by colony formation, BrdU incorporation and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Cell motility was measured by Transwell and wound healing assays. NSCLC xenograft models were used to confirm oncogenic function of IL-11 in vivo. Immunohistochemical staining and western blot assay were performed to detect epithelial-mesenchymal transition (EMT) markers and cell signaling pathway alterations. Eighteen NSCLC patients and 5 normal lung samples were collected together with data from an online database to determine the link between IL-11 expression and malignant progression.
RESULTS: We observed that IL-11 was upregulated in NSCLC samples compared with normal tissue samples and correlated with poor prognosis. Data from in vitro and in vivo models indicated that IL-11 promotes cell proliferation and tumorigenesis. Cell migration and invasion were also enhanced by IL-11. Epithelial-mesenchymal transition (EMT) was also observed after IL-11 incubation. Furthermore, IL-11 activated AKT and STAT3 in our experimental models. In addition, we observed that hypoxia induced IL-11 expression in NSCLC cells. Deferoxamine (DFX) or dimethyloxalylglycine (DMOG) induced hypoxia-inducible factor 1-alpha (HIF1α) upregulation, which enhanced IL-11 expression in NSCLC cells.
CONCLUSIONS: Taken together, our results indicate that IL-11 is an oncogene in NSCLC, and elucidating the mechanism behind it may provide insights for NSCLC treatment.
BACKGROUND: Most patients with breast cancer in advanced stages of the disease suffer from bone metastases which lead to fractures and nerve compression syndromes. microRNA dysregulation is an important event in the metastases of breast cancer to bone. microRNA-124 (miR-124) has been proved to inhibit cancer progression, whereas its effect on bone metastases of breast cancer has not been reported. Therefore, this study aimed to investigate the role and underlying mechanism of miR-124 in bone metastases of breast cancer.
METHODS: In situ hybridization (ISH) was used to detect the expression of miR-124 in breast cancer tissues and bone metastatic tissues. Ventricle injection model was constructed to explore the effect of miR-124 on bone metastasis in vivo. The function of cancer cell derived miR-124 in the differentiation of osteoclast progenitor cells was verified in vitro. Dual-luciferase reporter assay was conducted to confirm Interleukin-11 (IL-11) as a miR-124 target. The involvement of miR-124/IL-11 in the prognosis of breast cancer patients with bone metastasis was determined by Kaplan-Meier analysis.
RESULTS: Herein, we found that miR-124 was significantly reduced in metastatic bone tissues from breast cancers. Down-regulation of miR-124 was associated with aggressive clinical characteristics and shorter bone metastasis-free survival and overall survival. Restoration of miR-124 suppressed, while inhibition of miR-124 promoted the bone metastasis of breast cancer cells in vivo. At the cellular level, gain of function and loss-of function assays indicated that cancer cell-derived miR-124 inhibited the survival and differentiation of osteoclast progenitor cells. At the molecular level, we demonstrated that IL-11 partially mediated osteoclastogenesis suppression by miR-124 using in vitro and in vivo assays. Furthermore, IL-11 levels were inversely correlated with miR-124, and up-regulation IL-11 in bone metastases was associated with a poor prognosis.
CONCLUSIONS: Thus, the identification of a dysregulated miR-124/IL-11 axis helps elucidate mechanisms of breast cancer metastases to bone, uncovers new prognostic markers, and facilitates the development of novel therapeutic targets to treat and even prevent bone metastases of breast cancer.
Li Y, Ye Y, Chen HAstragaloside IV inhibits cell migration and viability of hepatocellular carcinoma cells via suppressing long noncoding RNA ATB.
Biomed Pharmacother. 2018; 99:134-141 [PubMed
] Related Publications
Astragaloside IV (AS-IV), the major active component of Astragalus membranaceus, has shown attractive anticancer effects in certain cancers. However, the roles and action mechanisms of AS-IV in hepatocellular carcinoma (HCC) are largely unclear. Long noncoding RNAs (lncRNAs) are recently revealed to have crucial roles in HCC initiation and progression, but whether lncRNAs participate in the anticancer roles of AS-IV are unknown. In this study, we demonstrated that AS-IV significantly downregulated lncRNA-ATB expression in a dose- and time-dependent manner in HCC cells. Through downregulating lncRNA-ATB, AS-IV repressed epithelial-mesenchymal transition (EMT) and migration of HCC cells. Furthermore, through downregulating lncRNA-ATB, AS-IV inactivated IL-11/STAT3 signaling, induced HCC cell apoptosis, and decreased HCC cell viability. Overexpression of lncRNA-ATB reversed the effects of AS-IV on HCC cell migration, EMT, cell apoptosis, cell viability, and IL-11/STAT3 signaling. Taken together, our results showed that AS-IV inhibited migration and cell viability of HCC cells via downregulating lncRNA-ATB. Thus, our data provided a novel molecular basis for the applications of AS-IV in the therapy of HCC.
The vasohibin (VASH) family consists of two genes, VASH1 and VASH2. VASH1 is mainly expressed in vascular endothelial cells and suppresses angiogenesis in an autocrine manner, whereas VASH2 is mainly expressed in cancer cells and exhibits pro-angiogenic activity. Employing adenomatous polyposis coli gene mutant mice, we recently reported on the role of Vash2 in the spontaneous formation of intestinal tumors. In this study, we used K19-Wnt1/C2mE (Gan) mice and examined the role of Vash2 in spontaneous gastric cancer formation. Gan mice spontaneously develop gastric tumors by activation of Wnt and prostaglandin E2 signaling pathways in gastric mucosa after 30 weeks of age. Expression of Vash2 mRNA was significantly increased in gastric tumor tissues compared with normal stomach tissues. When Gan mice were crossed with the Vash2-deficient (Vash2
Wang Q, Du X, Yang M, et al.LncRNA ZEB1-AS1 contributes to STAT3 activation by associating with IL-11 in B-lymphoblastic leukemia.
Biotechnol Lett. 2017; 39(12):1801-1810 [PubMed
] Related Publications
OBJECTIVE: To investigate the role of lncRNA ZEB1-AS1 in B-lineage acute lymphoblastic leukemia (B-ALL).
RESULTS: ZEB1-AS1 levels were aberrantly up-regulated in B-ALL. All correlated with STAT3 activation and IL-11 production. Moreover, a high level of ZEB1-AS1 predicted poor prognosis of B-ALL patients. Mechanistically, ZEB1-AS1 could bind to IL-11 and promote IL-11 stability. Down-regulation of ZEB1-AS1 decreased IL-11 production of human bone marrow stromal cells (BMSCs), which led to suppressed proliferation and inhibited IL-11/STAT3 pathway in BALL-1 cells.
CONCLUSIONS: ZEB1-AS1 promotes the activation of IL-11/STAT3 signaling pathway by associating with IL-11 in B-ALL.
Kitamura H, Onodera Y, Murakami S, et al.IL-11 contribution to tumorigenesis in an NRF2 addiction cancer model.
Oncogene. 2017; 36(45):6315-6324 [PubMed
] Related Publications
The interaction between cancer cells and their microenvironment is an important determinant of the pathological nature of cancers, particularly their tumorigenic abilities. The KEAP1-NRF2 system, originally identified as a critical defense mechanism against oxidative stress, is often dysregulated in various human cancers forming solid tumors, resulting in the aberrant activation of NRF2. Increased accumulation of NRF2 in cancers is strongly associated with the poor prognoses of cancer patients, including those with lung and breast cancers. Multiple lines of evidence suggest that aberrantly activated NRF2 in cancer cells drives their malignant progression and that the cancer cells consequently develop 'NRF2 addiction.' Although the downstream effectors of NRF2 that are responsible for cancer malignancy have been extensively studied, mechanisms of how NRF2 activation contributes to the aggressive tumorigenesis remains to be elucidated. In this study, we found a significant correlation between NRF2 and IL-11 status in breast cancer patients. Based on a recent report demonstrating that IL-11 is induced downstream of NRF2, we examined the significance of IL-11 in NRF2-driven tumorigenesis with a newly established NRF2 addiction cancer model. Expression of Il11 was elevated during the tumorigenesis of the NRF2 addiction cancer model, but intriguingly, it was hardly detected when the cancer model cells were cultured in vitro. These results imply that a signal originating from the microenvironment cooperates with NRF2 to activate Il11. To the best of our knowledge, this is the first report showing the influence of the microenvironment on the NRF2 pathway in cancer cells and the contribution of NRF2 to the secretory phenotypes of cancers. Disruption of Il11 in the NRF2 addiction cancer model remarkably inhibited the tumorigenesis, suggesting an essential role of IL-11 in NRF2-driven tumorigenesis. Thus, this study suggests that IL-11 is a potential therapeutic target for NRF2-addicted breast cancers.
Patients with Ulcerative Colitis (UC) have an increased risk to develop colitis-associated colorectal cancer (CAC). Here, we found that protein expression of ABCB1 (ATP Binding Cassette Subfamily B Member 1) / MDR1 (multidrug resistance 1) was diminished in the intestinal mucosa of patients with active UC with or without CAC, but not in non-UC patients with sporadic colon cancer. We investigated the consequences of ABCB1/MDR1 loss-of-function in a common murine model for CAC (AOM/DSS). Mice deficient in MDR1A (MDR1A KO) showed enhanced intratumoral inflammation and cellular damage, which were associated with reduced colonic tumor size and decreased degree of dysplasia, when compared to wild-type (WT). Increased cell injury correlated with reduced capacity for growth of MDR1A KO tumor spheroids cultured ex-vivo. Gene expression analysis by microarray demonstrated that MDR1A deficiency shaped the inflammatory response towards an anti-tumorigenic microenvironment by downregulating genes known to be important mediators of cancer progression (PTGS2 (COX2), EREG, IL-11). MDR1A KO tumors showed increased gene expression of TNFSF10 (TRAIL), a known inducer of cancer cell death, and CCL12, a strong trigger of B cell chemotaxis. Abundant B220+ B lymphocyte infiltrates with interspersed CD138+ plasma cells were recruited to the MDR1A KO tumor microenvironment, concomitant with high levels of immunoglobulin light chain genes. In contrast, MDR1A deficiency in RAG2 KO mice that lack both B and T cells aggravated colonic tumor progression. MDR1A KO CD19+ B cells, but not WT CD19+ B cells, suppressed growth of colonic tumor-derived spheroids from AOM/DSS-WT mice in an ex-vivo co-culture system, implying that B-cell regulated immune responses contributed to delayed tumor development in MDR1A deficiency. In conclusion, we provide first evidence that loss of ABCB1/MDR1 function may represent an essential tumor-suppressive host defense mechanism in CAC.
Transforming growth factor-beta (TGF-β) signaling has gained extensive interest in hepatocellular carcinoma (HCC). The small molecule kinase inhibitor galunisertib, targeting the TGF-β receptor I (TGF-βRI), blocks HCC progression in preclinical models and shows promising effects in ongoing clinical trials. As the drug is not similarly effective in all patients, this study was aimed at identifying new companion diagnostics biomarkers for patient stratification. Next-generation sequencing-based massive analysis of cDNA ends was used to investigate the transcriptome of an invasive HCC cell line responses to TGF-β1 and galunisertib. These identified mRNA were validated in 78 frozen HCC samples and in 26 ex-vivo HCC tissues treated in culture with galunisertib. Respective protein levels in patients blood were measured by enzyme-linked immunosorbent assay. SKIL, PMEPA1 ANGPTL4, SNAI1, Il11 and c4orf26 were strongly upregulated by TGF-β1 and downregulated by galunisertib in different HCC cell lines. In the 78 HCC samples, only SKIL and PMEPA1 (P<0.001) were correlated with endogenous TGF-β1. In ex-vivo samples, SKIL and PMEPA1 were strongly downregulated (P<0.001), and correlated (P<0.001) with endogenous TGF-β1. SKIL and PMEPA1 mRNA expression in tumor tissues was significantly increased compared with controls and not correlated with protein levels in the blood of paired HCC patients. SKIL and PMEPA1 mRNA levels were positively correlated with TGF-β1 mRNA concentrations in HCC tissues and strongly downregulated by galunisertib. The target genes identified here may serve as biomarkers for the stratification of HCC patients undergoing treatment with galunisertib.
Winship A, Van Sinderen M, Heffernan-Marks A, Dimitriadis EChondroitin sulfate proteoglycan protein is stimulated by interleukin 11 and promotes endometrial epithelial cancer cell proliferation and migration.
Int J Oncol. 2017; 50(3):798-804 [PubMed
] Related Publications
Endometrial cancer is the most common gynecological cancer. We identified interleukin 11 (IL11) as a critical mediator of endometrial tumourigenesis and demonstrated that IL11 regulates chondroitin sulfate proteoglycan (CSPG4) in human placental trophoblasts. CSPG4 is a cell membrane protein overexpressed in numerous human cancers, although its role in endometrial cancer has not been investigated. We examined CSPG4 expression and localization in primary human type I endometrioid grade (G) 1-3 tumours by qPCR and immunohistochemistry and determined whether IL11 stimulated CSPG4. IL11 upregulated CSPG4 mRNA in HEC1A (G2-derived endometrial epithelial cancer cell line) cells. IL11 administration to BALB/c nude mice enhanced HEC1A xenograft tumour growth and increased CSPG4 protein in tumours. CSPG4 mRNA was unchanged between human G1-3 endometrial cancer and control tissues. CSPG4 protein levels were elevated in the epithelium of G2 and G3 endometrial cancer and in the tumour-associated stroma of G3 tumour tissues compared to proliferative phase or post-menopausal endometrium. CSPG4 knockdown by siRNA reduced HEC1A proliferation and migration in vitro and reduced gene expression of the key epithelial-to-mesenchymal transition (EMT) regulator SNAIL. Our data suggest that CSPG4 inhibition may impair endometrial cancer progression by reducing cancer cell proliferation, migration and potentially EMT.
Cancer-associated fibroblasts (CAF) are recognized as one of the key determinants in the malignant progression of lung adenocarcinoma. And its contributions to chemoresistance acquisition of lung cancer has raised more and more attention. In our study, cancer associated fibroblasts treated with cisplatin conferred chemoresistance to lung cancer cells. Meanwhile, Interleukin-11(IL-11) was significantly up-regulated in the CAF stimulated by cisplatin. As confirmed in lung adenocarcinoma cells in vivo and in vitro, IL-11 could protect cancer cells from cisplatin-induced apoptosis and thus promote their chemoresistance. Furthermore, it was also observed that IL-11 induced STAT3 phosphorylation and increased anti-apoptotic protein Bcl-2 and Survivin expression in cancer cells. The effect could be abrogated by suppressing STAT3 phosphorylation or silencing IL-11Rα expression in cancer cells. In conclusion, chemotherapy-induced IL-11 upregulation in CAF promotes lung adenocarcinoma cell chemoresistance by activating IL-11R/STAT3 anti-apoptotic signaling pathway.
AIM: To identify common copy number alterations on gastric cancer cell lines.
METHODS: Four gastric cancer cell lines (ACP02, ACP03, AGP01 and PG100) underwent chromosomal comparative genome hybridization and array comparative genome hybridization. We also confirmed the results by fluorescence
RESULTS: The amplification of 9p13.3 was detected in all cell lines by both methodologies. An increase in the copy number of 9p13.3 was also confirmed by fluorescence
CONCLUSION: The characterization of a small gain region at 9p13.3 in gastric cancer cell lines and primary gastric adenocarcinoma samples has revealed
Transmembrane p24 trafficking protein 3(TMED3) is a metastatic suppressor in colon cancer, but its function in the progression of hepatocellular carcinoma (HCC) is unknown. Here, we report that TMED3 was up-regulated in HCC and portal vein tumor thrombus. TMED3 up-regulation in HCC was significantly correlated with aggressive characteristics and predicted poor prognosis in HCC patients. TMED3 overexpression in HCC cell lines promoted cell migration and invasion. In contrast, TMED3 knockdown suppressed HCC metastasis both in vitro and in vivo. Gene microarray analysis revealed decreased IL-11 expression in TMED3-knockdown cells. We propose that TMED3 promotes HCC metastasis through IL-11/STAT3 signaling. Taken together, these findings demonstrate that TMED3 promotes HCC metastasis and is a potential prognostic biomarker in HCC.
Genome-wide association studies have identified multiple renal cell carcinoma (RCC) susceptibility loci. Here, we use regional imputation and bioinformatics analysis of the 12p12.1 locus to identify the single-nucleotide polymorphism (SNP) rs7132434 as a potential functional variant. Luciferase assays demonstrate allele-specific regulatory activity and, together with data from electromobility shift assays, suggest allele-specific differences at rs7132434 for AP-1 transcription factor binding. In an analysis of The Cancer Genome Atlas data, SNPs highly correlated with rs7132434 show allele-specific differences in BHLHE41 expression (trend P value=6.3 × 10(-7)). Cells overexpressing BHLHE41 produce larger mouse xenograft tumours, while RNA-seq analysis reveals that constitutively increased BHLHE41 induces expression of IL-11. We conclude that the RCC risk allele at 12p12.1 maps to rs7132434, a functional variant in an enhancer that upregulates BHLHE41 expression which, in turn, induces IL-11, a member of the IL-6 cytokine family.
UNLABELLED: Previously, we identified the transcriptional coactivator CITED2 as a potential facilitator of bone metastasis using a murine mammary cancer model. Extending these studies to human breast cancer, it was observed that CITED2 mRNA expression was significantly elevated in patient specimens of metastatic breast cancer relative to primary tumors, with highest levels in metastasis to bone relative to non-bone sites. To further evaluate CITED2 functions in breast cancer metastasis, CITED2 expression was stably reduced in the human breast cancer cell lines MDA-MB-231 and MDA-MB-468, which are metastatic in animal models. While CITED2 knockdown had no effect on cell proliferation, cell migration and invasion were significantly reduced, as was the establishment of metastasis following intracardiac administration in athymic nude mice. To explore the mechanism behind these effects, gene expression following CITED2 knockdown in MDA-MB-231 cells by cDNA microarray was performed. As confirmed at the mRNA and protein levels in both MDA-MB-231 and MDA-MB-468 cells, expression of the NF-κB regulator IKKα was significantly reduced, along with several NF-κB targets with known roles in metastasis (OPN, MMP9, uPA, SPARC, IL11, and IL1β). Furthermore, ChIP assay revealed recruitment of CITED2 to the promoter of IKKα, indicating a direct role in regulating its expression. Consistent with reduced IKKα expression, CITED2 knockdown inhibited both canonical and noncanonical NF-κB signaling. Finally, restoration of IKKα expression following CITED2 knockdown in MDA-MB-231 and MDA-MB-468 cells rescued their invasive ability. Collectively, these data demonstrate that CITED2 modulates metastatic ability in human breast cancer cells, at least in part, through the regulation of IKKα.
IMPLICATIONS: The current study highlights the role of CITED2 in facilitating breast cancer metastasis, partly via regulation of IKKα. Mol Cancer Res; 14(8); 730-9. ©2016 AACR.
Cyclooxygenase-2 (COX-2) and its downstream product prostaglandin E2 (PGE2 ) play a key role in generation of the inflammatory microenvironment in tumor tissues. Gastric cancer is closely associated with Helicobacter pylori infection, which stimulates innate immune responses through Toll-like receptors (TLRs), inducing COX-2/PGE2 pathway through nuclear factor-κB activation. A pathway analysis of human gastric cancer shows that both the COX-2 pathway and Wnt/β-catenin signaling are significantly activated in tubular-type gastric cancer, and basal levels of these pathways are also increased in other types of gastric cancer. Expression of interleukin-11, chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, and CXCL5, which play tumor-promoting roles through a variety of mechanisms, is induced in a COX-2/PGE2 pathway-dependent manner in both human and mouse gastric tumors. Moreover, the COX-2/PGE2 pathway plays an important role in the maintenance of stemness with expression of stem cell markers, including CD44, Prom1, and Sox9, which are induced in both gastritis and gastric tumors through a COX-2/PGE2 -dependent mechanism. In contrast, disruption of Myd88 results in suppression of the inflammatory microenvironment in gastric tumors even when the COX-2/PGE2 pathway is activated, indicating that the interplay of the COX-2/PGE2 and TLR/MyD88 pathways is needed for inflammatory response in tumor tissues. Furthermore, TLR2/MyD88 signaling plays a role in maintenance of stemness in normal stem cells as well as gastric tumor cells. Accordingly, these results suggest that targeting the COX-2/PGE2 pathway together with TLR/MyD88 signaling, which would suppress the inflammatory microenvironment and maintenance of stemness, could be an effective preventive or therapeutic strategy for gastric cancer.
Mechanisms of stromal-epithelial crosstalk are essential for Prostate cancer (PCa) tumorigenesis and progression. Peripheral zone of the prostate gland possesses a stronger inclination for PCa than transition zone. We previously found a variety of genes that differently expressed among different prostate stromal cells, including LIM domain only 2 (LMO2) which highly expressed in peripheral zone derived stromal cells (PZSCs) and PCa associated fibroblasts (CAFs) compared to transition zone derived stromal cells (TZSCs). Studies on its role in tumors have highlighted LMO2 as an oncogene. Herein, we aim to study the potential mechanisms of stromal LMO2 in promoting PCa progression. The in vitro cells co-culture and in vivo cells recombination revealed that LMO2 over-expressed prostate stromal cells could promote the proliferation and invasiveness of either prostate epithelial or cancer cells. Further protein array screening confirmed that stromal LMO2 stimulated the secretion of Interleukin-11 (IL-11), which could promote proliferation and invasiveness of PCa cells via IL-11 receptor α (IL11Rα) - STAT3 signaling. Moreover, stromal LMO2 over-expression could suppress miR-204-5p which was proven to be a negative regulator of IL-11 expression. Taken together, results of our study demonstrate that prostate stromal LMO2 is capable of stimulating IL-11 secretion and by which activates IL11Rα - STAT3 signaling in PCa cells and then facilitates PCa progression. These results may make stromal LMO2 responsible for zonal characteristic of PCa and as a target for PCa microenvironment-targeted therapy.
Wu J, Wang Y, Xu X, et al.Transcriptional activation of FN1 and IL11 by HMGA2 promotes the malignant behavior of colorectal cancer.
Carcinogenesis. 2016; 37(5):511-21 [PubMed
] Related Publications
Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide, and metastasis is the principle reason for its poor prognosis. Overexpression of high-mobility gene group A2 (HMGA2) contributes to the aggressiveness of CRC. However, the underlying molecular mechanism of its overexpression is still elusive. In this study, we showed that ectopic expression of HMGA2 significantly enhanced cell migration and invasion in vitro and promoted tumor growth and distant metastasis in vivo In contrast, the silencing of HMGA2 produced the opposite effects in vitro and in vivo Chromatin immunoprecipitation-PCR and luciferase assays revealed that HMGA2 bound directly to the promoters of FN1 and IL11 and significantly induced their transcriptional activities. Moreover, as the direct downstream target of HMGA2, IL11 modulated cell migration and invasion through a pSTAT3-dependent signaling pathway. Furthermore, a strong positive correlation between HMGA2 and IL11 expression was identified in 122 CRC tissues. High IL11 expression was associated with poor differentiation, a large tumor size, lymph node metastasis and low overall survival in CRC patients. Collectively, our data reveal novel insights into the molecular mechanisms underlying HMGA2-mediated CRC metastasis and highlight the possibility of targeting HMGA2 and IL11 for treating CRC patients with metastasis.
Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in numerous cancer types, including more than 40% of breast cancers. In contrast to tight regulation of STAT3 as a latent transcription factor in normal cells, its signaling in breast cancer oncogenesis is multifaceted. Signaling through the IL-6/JAK/STAT3 pathway initiated by the binding of IL-6 family of cytokines (i.e., IL-6 and IL-11) to their receptors have been implicated in breast cancer development. Receptors with intrinsic kinase activity such as EGFR and VEGFR directly or indirectly induce STAT3 activation in various breast cancer types. Aberrant STAT3 signaling promotes breast tumor progression through deregulation of the expression of downstream target genes which control proliferation (Bcl-2, Bcl-xL, Survivin, Cyclin D1, c-Myc and Mcl-1), angiogenesis (Hif1α and VEGF) and epithelial-mesenchymal transition (Vimentin, TWIST, MMP-9 and MMP-7). These multiple modes of STAT3 regulation therefore make it a central linking point for a multitude of signaling processes. Extensive efforts to target STAT3 activation in breast cancer had no remarkable success in the past because the highly interconnected nature of STAT3 signaling introduces lack of selectivity in pathway identification for STAT3 targeted molecular therapies or because its role in tumorigenesis may not be as critical as it was thought. This review provides a full spectrum of STAT3's involvement in breast cancer by consolidating the knowledge about its role in breast cancer development at multiple levels: its differential regulation by different receptor signaling pathways, its downstream target genes, and modification of its transcriptional activity by its coregulatory transcription factors.
Cancer stem cells (CSCs) are associated with cancer recurrence and metastasis. Prostate cancer cells often metastasize to the bone with a complex microenvironment of cytokines favoring cell survival. In this study, the cell stemness influence of a group of interleukins including IL-3, 6, 10, 11 and 24 on human prostate cancer cell lines LNCaP and PC-3 was explored in vitro. Sulforhodamine B(SRB) and 5-ethynyl-2'-deoxyuridine (EdU) assays were applied to examine the effect on cell proliferation, and wound healing and transwell assays were used for migration and invasion studies, in addition to colony formation, Western blotting and flowcytometry for the expression of stemness factors and chemotherapy sensitivity. We observed that ILs-3, 6 and 11 stimulated while ILs-10 and 24 inhibited the growth, invasion and migration of both cell lines. Interestingly, ILs-3, 6 and 11 significantly promoted colony formation and increased the expression of SOX2, CD44 and ABCG2 in both prostate cancer cell lines. However, ILs-10 and 24 showed the opposite effect on the expression of these factors. In line with the above findings, treatment with either IL-3 or IL-6 or IL-11 decreased the chemosensitivity to docetaxel while treatment with either IL-10 or IL-24 increased the sensitivity of docetaxel chemotherapy. In conclusion, our results suggest that ILs-3, 6 and 11 function as tumor promoters while ILs-10 and 24 function as tumor suppressors in the prostate cancer cell lines PC-3 and LNCaP in vitro, and such differences may attribute to their different effect on the stemness of PCa cells.
Ma J, Hou X, Li M, et al.Genome-wide methylation profiling reveals new biomarkers for prognosis prediction of glioblastoma.
J Cancer Res Ther. 2015; 11 Suppl 2:C212-5 [PubMed
] Related Publications
OBJECTIVE: To identify a specific hypermethylated molecular biomarker for human malignant glioblastoma prognosis.
MATERIALS AND METHODS: Genome-wide methylation profiling was performed on 33 tumors and 3 normal glioblastoma samples using the Infinium HumanMethylation450 microarray. Cluster analysis was carried out in these samples according to the differentiated methylated genes. DNA methylation of selected significant candidates was subsequently validated to analyze the association of methylation status of these genes with overall survival as well as gene expression.
RESULTS: We found 217 hypermethylated CpG sites located in 210 respective genes with significant differences in short- and long-term survival (STS and LTS) samples (P < 0.01). Cluster analysis revealed fine clustering of genes with LTS and STS. Of these, we selected 10 most hypermethylated genes, including IL11, RRAD, MS4A6A, SNAPC2, ALDH1A3, ADCY1, MMS19L, NDUFB8, POMC, and THSD4, to perform cluster analysis. It came out with the same fine classification and with survival time of these patients. The top ranking genes were further examined to compare their methylation status with the overall survival rate of patients, as well as with gene expression levels.
CONCLUSION: We obtained a featured global profiling of DNA methylation in glioblastoma. Our findings strongly indicate that epigenetic silencing of IL11, RRAD, MS4A6A, SNAPC2, and ALDH1A3 are common events in glioblastoma which could be used as novel biomarkers for the prognosis of glioblastoma.
Agajanian M, Runa F, Kelber JAIdentification of a PEAK1/ZEB1 signaling axis during TGFβ/fibronectin-induced EMT in breast cancer.
Biochem Biophys Res Commun. 2015; 465(3):606-12 [PubMed
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Transforming Growth Factor beta (TGFβ) is the archetypal member of the TGFβ superfamily of ligands and has pleiotropic functions during normal development, adult tissue homeostasis and pathophysiological processes such as cancer. In epithelial cancers TGFβ signaling can either suppress tumor growth or promote metastasis via the induction of a well-characterized epithelial-mesenchymal transition (EMT) program. We recently reported that PEAK1 kinase mediates signaling cross talk between TGFβ receptors and integrin/Src/MAPK pathways and functions as a critical molecular regulator of TGFβ-induced breast cancer cell proliferation, migration, EMT and metastasis. Here, we examined the breast cancer cell contexts in which TGFβ induces both EMT and PEAK1, and discovered this event to be unique to oncogene-transformed mammary epithelial cells and triple-negative breast cancer cells. Using the Cancer BioPortal database, we identified PEAK1 co-expressors across multiple malignancies that are also common to the TGFβ response gene signature (TBRS). We then used the ScanSite database to identify predicted protein-protein binding partners of PEAK1 and the PEAK1-TBRS co-expressors. Analysis of the Cytoscape interactome and Babelomics-derived gene ontologies for a novel gene set including PEAK1, CRK, ZEB1, IL11 and COL4A1 enabled us to hypothesize that PEAK1 may be regulating TGFβ-induced EMT via its interaction with or regulation of these other genes. In this regard, we have demonstrated that PEAK1 is necessary for TGFβ to induce ZEB1-mediated EMT in the context of fibronectin/ITGB3 activation. These studies and future mechanistic studies will pave the way toward identifying the context in which TGFβ blockade may significantly improve breast cancer patient outcomes.
Johnstone CN, Chand A, Putoczki TL, Ernst MEmerging roles for IL-11 signaling in cancer development and progression: Focus on breast cancer.
Cytokine Growth Factor Rev. 2015; 26(5):489-98 [PubMed
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Interleukin (IL)-11 is a member of the IL-6 family of cytokines that is defined by the shared use of the GP130 signal transducing receptor subunit. In addition of its long recognized activities as a hemopoietic growth factor, IL-11 has an emerging role in epithelial cancer biology. Through the activation of the GP130-Janus kinase signaling cascade and associated transcription factor STAT3, IL-11 can confer many of the tumor intrinsic 'hallmark' capabilities to neoplastic cells, if they express the ligand-specific IL-11Rα receptor subunit. Accordingly, IL-11 signaling has recently been identified as a rate-limiting step for the growth tumors arising from the mucosa of the gastrointestinal tract. However, there is less appreciation for a potential role of IL-11 to support breast cancer progression, apart from its well documented capacity to facilitate bone metastasis. Here we review evidence that IL-11 expression in breast cancer correlates with poor disease outcome and discuss some of the molecular mechanisms that are likely to underpin these observations. These include the capacity of IL-11 to stimulate survival and proliferation of cancer cells alongside angiogenesis of the primary tumor and of metastatic progenies at distant organs. We review current strategies to interfere with IL-11 signaling and advocate that inhibition of IL-11 signaling may represent an emerging therapeutic opportunity for numerous cancers.
Buchert M, Burns CJ, Ernst MTargeting JAK kinase in solid tumors: emerging opportunities and challenges.
Oncogene. 2016; 35(8):939-51 [PubMed
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Various human malignancies are characterized by excessive activation of the Janus family of cytoplasmic tyrosine kinases (JAK) and their associated transcription factors STAT3 and STAT5. In the majority of solid tumors, this occurs in response to increased abundance of inflammatory cytokines in the tumor microenvironment prominently produced by infiltrating innate immune cells. Many of these cytokines share common receptor subunits and belong to the interleukin (IL)-6/IL-11, IL-10/IL-22 and IL-12/IL-23 families. Therapeutic inhibition of the JAK/STAT3 pathway potentially offers considerable benefit owing to the capacity of JAK/STAT3 signaling to promote cancer hallmarks in the tumor and its environment, including proliferation, survival, angiogenesis, tumor metabolism while suppressing antitumor immunity. This is further emphasized by the current successful clinical applications of JAK-specific small molecule inhibitors for the treatment of inflammatory disorders and hematopoietic malignancies. Here we review current preclinical applications for JAK inhibitors for the treatment of solid cancers in mice, with a focus on the most common malignancies emanating from oncogenic transformation of the epithelial mucosa in the stomach and colon. Emerging data with small molecule JAK-specific adenosine triphosphate-binding analogs corroborate genetic findings and suggest that interference with the JAK/STAT3 pathway may suppress the growth of the most common forms of sporadic colon cancers that arise from mutations of the APC tumor suppressor gene. Likewise inhibition of cytokine-dependent activation of the JAK/STAT3 pathway may also afford orthogonal treatment opportunities for other oncogene-addicted cancer cells that have gained drug resistance.
BACKGROUND: We have preliminarily reported MTA2 expression in gastric cancer and its biological functions by using knockdown cell models, while the molecular mechanisms of MTA2 in regulating malignant behaviors are still unclear.
METHODS: MTA2 overexpression models were established by transfection assay in gastric cancer cells BGC-823 and MKN28. Cell proliferation assay, colony formation in soft agar, wound-healing assay and transwell migration assay were performed with MTA2 overexpression and negative control (NC) cells. Subcutaneous xenografts and pulmonary metastasis models by BGC-823/MTA2 and BGC-823/NC cells were used to observe the capacity of growth and metastasis in vivo. Differential gene expression in MTA2 knockdown and overexpression cells was analyzed by microarrays. IL-11, which demonstrated as differential expression in microarray, was detected by real-time PCR, western blot, ELISA and immunohistochemistry staining. Recombinant human IL-11 (rhIL-11) was administrated in cell proliferation and colony formation as rescue assay.
RESULTS: The numbers of colonies in soft agar were significantly more in BGC-823/MTA2 and MKN28/MTA2 cells, comparing with those in their NC cells. Capabilities of cell proliferation, wound-healing and cell migration were not significantly changed in MTA2 overexpression cells. The sizes of subcutaneous xenografts and pulmonary metastases of BGC-832/MTA2 cells were significantly larger than those in BGC-823/NC group. Differential expression of IL-11 was identified by genome expression microarray both in MTA2 knockdown and overexpression cells. IL-11 expression was elevated in BGC-823/MTA2 cells, whereas reduced in SGC-7901/shMTA2 cells. Administration of rhIL-11 recovered colony formation capacity of SGC-7901/shMTA2 cells.
CONCLUSIONS: MTA2 overexpression enhances colony formation and tumor growth of gastric cancer cells, but not plays important role in cancer cell migration and metastasis. IL-11 is one of the downstream effectors of MTA2 in regulating gastric cancer cells growth.
In tumor cells, two factors are abnormally increased that contribute to metastatic bone disease: Runx2, a transcription factor that promotes expression of metastasis related and osteolytic genes; and IL-11, a secreted osteolytic cytokine. Here, we addressed a compelling question: Does Runx2 regulate IL-11 gene expression? We find a positive correlation between Runx2, IL-11 and TGFβ1, a driver of the vicious cycle of metastatic bone disease, in prostate cancer (PC) cell lines representing early (LNCaP) and late (PC3) stage disease. Further, like Runx2 knockdown, IL-11 knockdown significantly reduced expression of several osteolytic factors. Modulation of Runx2 expression results in corresponding changes in IL-11 expression. The IL-11 gene has Runx2, AP-1 sites and Smad binding elements located on the IL-11 promoter. Here, we demonstrated that Runx2-c-Jun as well as Runx2-Smad complexes upregulate IL-11 expression. Functional studies identified a significant loss of IL-11 expression in PC3 cells in the presence of the Runx2-HTY mutant protein, a mutation that disrupts Runx2-Smad signaling. In response to TGFβ1 and in the presence of Runx2, we observed a 30-fold induction of IL-11 expression, accompanied by increased c-Jun binding to the IL-11 promoter. Immunoprecipitation and in situ co-localization studies demonstrated that Runx2 and c-Jun form nuclear complexes in PC3 cells. Thus, TGFβ1 signaling induces two independent transcriptional pathways - AP-1 and Runx2. These transcriptional activators converge on IL-11 as a result of Runx2-Smad and Runx2-c-Jun interactions to amplify IL-11 gene expression that, together with Runx2, supports the osteolytic pathology of cancer induced bone disease.