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Cited by 166Immune cells in cancerAngiogenesis and VEGF in CancerTGF-β signaling in diseases

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PKN2 in colon cancer cells inhibits M2 phenotype polarization of tumor-associated macrophages via regulating DUSP6-Erk1/2 pathway

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Cheng, Yang, Zhu, Yun, Xu, Jiajia, Yang, Min, Chen, Peiyu, Xu, Wanfu, Zhao, Junhong, Geng, Lanlan, Gong, Sitang·2018·Molecular Cancer
DOI 10.1186/s12943-017-0747-zPMC PMC5784528
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Abstract

BACKGROUND: Protein kinase N2 (PKN2) is a PKC-related serine/threonine-protein kinase. PKN2 is required for tumor cell migration, invasion and apoptosis. However, the functional role of PKN2 in regulating tumor associated macrophages (TAMs) polarization in colon cancer has never been reported. METHODS: PKN2 expression in human colon cancer tissues was examined with immunohistochemistry (IHC). M1/M2 macrophage signatures were evaluated by RT-PCR, IHC and flow cytometry. The effects of PKN2 on tumor growth and TAM polarization were investigated both in vitro and in vivo. PKN2 targeted cytokines/pathway were analyzed by gene expression analysis and further confirmed by PCR, luciferase assay or western blot. Correlations between PKN2 and transcriptional factors for IL4 and IL10 were confirmed by ChIP-qPCR. The catalytic activities of PKN2 and DUSP6 were determined by kinase activity assay. Interactions between PKN2 and DUSP6 were confirmed by Co-IP. RESULTS: The expression of PKN2 in colon cancer cells predicted a favorable prognosis and was associated with low M2 macrophage content in human colon cancer tissues. PKN2 inhibited tumor growth in mice xenograft model and inhibited M2 phenotype polarization both in vitro and in vivo. Mechanistically, PKN2 suppresses the expression of IL4 and IL10 from colon cancer cells by inhibiting Erk1/2 phosphorylation, which is required for phosphorylation and binding of CREB and Elk-1 to the promoters of IL4 and IL10. DUSP6, which is phosphorylated and activated through direct association with PKN2, suppresses Erk1/2 activation. CONCLUSIONS: The expression of PKN2 in colon cancer cells suppresses tumor associated M2 macrophage polarization and tumor growth. Targeting PKN2 signaling pathway may provide a potential therapeutic strategy for colon cancer.

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Fig. 1 Overexpression of PKN2 is associated with better clinical outcome and high M1 content in human colon cancer. aThe protein expression of PKN2, CD68, CD206, CD86, CD163 and iNOS in a human colon cancer tissue array was detected by immunohistochemistry staining. Representative photos are shown (100X and 400X). b Number of CD68+, CD206+, CD86+, CD163+ and iNOS+ cells per low field in tissues from colon cancer patients at different stages. c PKN2 expression in normal colon tissue, polyp, adenoma and metastatic adenocarcinoma was measured using IHC. PKN2 expression scores were shown in (d). *, P < 0.05;***, P < 0.001 versusnormal colon. e Comparison of the percent of survival of patients with high level PKN2 (PKN2-High) and low level PKN2 (PKN2-Low) expression using the Kaplan-Meier method. f Number of CD68+, CD206+, CD86+, CD163+ and iNOS+ cells in tissues from colon cancer patients with different levels of PKN2 expression. ***, P < 0.001 versus PKN2-High
Fig. 1 Overexpression of PKN2 is associated with better clinical outcome and high M1 content in human colon cancer. aThe protein expression of PKN2, CD68, CD206, CD86, CD163 and iNOS in a human colon cancer tissue array was detected by immunohistochemistry staining. Representative photos are shown (100X and 400X). b Number of CD68+, CD206+, CD86+, CD163+ and iNOS+ cells per low field in tissues from colon cancer patients at different stages. c PKN2 expression in normal colon tissue, polyp, adenoma and metastatic adenocarcinoma was measured using IHC. PKN2 expression scores were shown in (d). *, P < 0.05;***, P < 0.001 versusnormal colon. e Comparison of the percent of survival of patients with high level PKN2 (PKN2-High) and low level PKN2 (PKN2-Low) expression using the Kaplan-Meier method. f Number of CD68+, CD206+, CD86+, CD163+ and iNOS+ cells in tissues from colon cancer patients with different levels of PKN2 expression. ***, P < 0.001 versus PKN2-HighCC BY · PubMed Central
Fig. 2 PKN2expression inhibits tumorformationand decreased macrophages polarizing towards the M2 type in the xenograft tumor. a HCT116 cells were stably infected with vector (WT), PKN2-WT, PKN2-K686R lentivirus and cultured for 1-6 days. Cell proliferation was detected by CCK8 assay. b Tumorigenesis assay of Balb/c nude mice subcutaneously injected with PKN2-WT/PKN2-K686R transduced or wild-type HCT116cells (n = 10). ***, P < 0.001 versus WT. c Representative photos of tumors from mice of the various groups. d TUNEL assay &IHC staining of Ki67 in tumor tissues in mice xenograft model and positive cell numbers per high field were counted.*, P < 0.05 versus WT. e Schematic picture on the procedure for separation of Tumor cells &TAM. f CD11b+ macrophages were separated from murine tumor tissues using CD11b magnetic beads. Surface expression of CD16/32 and CD206 was detected in CD11b+ macrophages usingflow cytometry.The percent of CD16/32+ or CD206+ cells in CD11b+macrophages were assayed.***, P < 0.001 versus WT. g Relative gene expression of M1 marker (Il1b, Tnf,Cxcl9, Il23, Ros1,Il12a, and Il12b) and M2 marker(Tgfb1, Vegfa, Egf, Il6, Retnla, Il10, Arg1 and Ccl22) (h) in the tumor tissues of mice.*, P < 0.05; **, P < 0.01; ***, P < 0.001 versus WT
Fig. 2 PKN2expression inhibits tumorformationand decreased macrophages polarizing towards the M2 type in the xenograft tumor. a HCT116 cells were stably infected with vector (WT), PKN2-WT, PKN2-K686R lentivirus and cultured for 1-6 days. Cell proliferation was detected by CCK8 assay. b Tumorigenesis assay of Balb/c nude mice subcutaneously injected with PKN2-WT/PKN2-K686R transduced or wild-type HCT116cells (n = 10). ***, P < 0.001 versus WT. c Representative photos of tumors from mice of the various groups. d TUNEL assay &IHC staining of Ki67 in tumor tissues in mice xenograft model and positive cell numbers per high field were counted.*, P < 0.05 versus WT. e Schematic picture on the procedure for separation of Tumor cells &TAM. f CD11b+ macrophages were separated from murine tumor tissues using CD11b magnetic beads. Surface expression of CD16/32 and CD206 was detected in CD11b+ macrophages usingflow cytometry.The percent of CD16/32+ or CD206+ cells in CD11b+macrophages were assayed.***, P < 0.001 versus WT. g Relative gene expression of M1 marker (Il1b, Tnf,Cxcl9, Il23, Ros1,Il12a, and Il12b) and M2 marker(Tgfb1, Vegfa, Egf, Il6, Retnla, Il10, Arg1 and Ccl22) (h) in the tumor tissues of mice.*, P < 0.05; **, P < 0.01; ***, P < 0.001 versus WTCC BY · PubMed Central
Fig. 3 PKN2 in colon cancer cells induces the differentiation of monocytes into M2 polarized macrophages in vitro. a HCT116 cells were stably transfected with vector/PKN2-WT or shCTL/ shPKN2-1/ shPKN2-2. The protein expression of PKN2 was detected by western blotting in total protein extracts. Human CD14+ monocytes were separated from peripheral blood and co-cultured with vector/PKN2-WT (b) or shCTL/ shPKN2-1/ shPKN2-2 (c) transfected HCT116 for 4 days, respectively. E:T ratios for colon cancer cells to monocytes were 50:1. Flow cytometry was used to explore surface expression of CD206. *, P < 0.05 versus Vector. (d-f) SW480 cells were treated and co-cultured with CD14+ monocytes as indicated in (a-c). Western blotting was used to evaluate PKN2 expression in SW480 cells. Flow cytometry was used to explore surface expression of CD206 in differentiated macrophages. **, P < 0.01 versus Vector. (g)~(i) HT-29 cells were treated and co-cultured with CD14+ monocytes as indicated in (a)~(c). PKN2 and CD206 expression was analyzed. *, P < 0.05 versus shCTL. (j) CD14+ monocytes were treated as indicated in (b), gene expression of IL1B, TNF, CXCL9, IL6, IL10, ARG1 and CCL22 in monocytes was detected. (k) CD14+ monocytes were treated as indicated in (i), gene expression of IL1B, TNF, CXCL9, IL6, IL10, ARG1and CCL22 in monocytes was detected. *, P < 0.05;**, P < 0.01 versus Vector or shCTL
Fig. 3 PKN2 in colon cancer cells induces the differentiation of monocytes into M2 polarized macrophages in vitro. a HCT116 cells were stably transfected with vector/PKN2-WT or shCTL/ shPKN2-1/ shPKN2-2. The protein expression of PKN2 was detected by western blotting in total protein extracts. Human CD14+ monocytes were separated from peripheral blood and co-cultured with vector/PKN2-WT (b) or shCTL/ shPKN2-1/ shPKN2-2 (c) transfected HCT116 for 4 days, respectively. E:T ratios for colon cancer cells to monocytes were 50:1. Flow cytometry was used to explore surface expression of CD206. *, P < 0.05 versus Vector. (d-f) SW480 cells were treated and co-cultured with CD14+ monocytes as indicated in (a-c). Western blotting was used to evaluate PKN2 expression in SW480 cells. Flow cytometry was used to explore surface expression of CD206 in differentiated macrophages. **, P < 0.01 versus Vector. (g)~(i) HT-29 cells were treated and co-cultured with CD14+ monocytes as indicated in (a)~(c). PKN2 and CD206 expression was analyzed. *, P < 0.05 versus shCTL. (j) CD14+ monocytes were treated as indicated in (b), gene expression of IL1B, TNF, CXCL9, IL6, IL10, ARG1 and CCL22 in monocytes was detected. (k) CD14+ monocytes were treated as indicated in (i), gene expression of IL1B, TNF, CXCL9, IL6, IL10, ARG1and CCL22 in monocytes was detected. *, P < 0.05;**, P < 0.01 versus Vector or shCTLCC BY · PubMed Central
Fig. 4 PKN2 negatively regulates IL4 and IL10 productionin colon cancer cells. a Gene expression profiles analysis was done in PKN2-K686R, PKN2-WT stably overexpressed or wild-type HCT116 cells. Genes in KEGG ‘chemokine signaling pathway’ and ‘cytokine-cytokine receptor interaction’ clusters showing 2-fold or higher differential expression were selected. b The clustered heatmap of two cytokine genes IL4 and IL10 were identified from PKN2-WT and PKN2-K686R HCT116 cells. The color-coding applies to gene expression level (log2) with 0 as a median. c The mRNA level of IL4 and IL10 in WT, PKN2-K686R and PKN2-WT HCT116 cells was assessed using RT-PCR.*, P < 0.05; ***, P < 0.001 versus WT. d Stable clone of SW480, HCT116 and HT-29 cells (as indicated in Fig. 3) were cultured for 48 h. The level of IL10 and IL4 in the culture supernatants was assessed using ELISA.*, P < 0.05; **, P < 0.01 versus Vector or shCTL. e SW480 cells were stably infected with shPKN2-1, shPKN2-2, PKN2-WT or vector lentivirus. Luciferase assays were performed to detect transcription factor binding activity of IL4 and IL10. Relative fold-change in luciferase activity was shown. *, P < 0.05; **, P < 0.01 versus WT. f Human CD14+ monocytes were cocultured with stably shCTL or shPKN2 transfected HT-29 with/without neutralizing antibody of IL10 (2 μg/ml) or IL4 (0.5 μg/ml) for 4 days. Surface expression of CD206 in differentiated macrophages was detected using flow cytometry. ***, P < 0.001 versus shCTL. #, P < 0.05; ##, P < 0.01 versus shPKN2. g Human CD14+ monocytes were cocultured with HCT116 stably preinfected with vector or PKN2-WT with/without neutralizing antibody of IL10 (2 μg/ml) or IL4 (0.5 μg/ml) for 4 days. Surface expression of CD86 was detected using flow cytometry.***, P < 0.001 versus Vector. #, P < 0.05 versus PKN2-WT
Fig. 4 PKN2 negatively regulates IL4 and IL10 productionin colon cancer cells. a Gene expression profiles analysis was done in PKN2-K686R, PKN2-WT stably overexpressed or wild-type HCT116 cells. Genes in KEGG ‘chemokine signaling pathway’ and ‘cytokine-cytokine receptor interaction’ clusters showing 2-fold or higher differential expression were selected. b The clustered heatmap of two cytokine genes IL4 and IL10 were identified from PKN2-WT and PKN2-K686R HCT116 cells. The color-coding applies to gene expression level (log2) with 0 as a median. c The mRNA level of IL4 and IL10 in WT, PKN2-K686R and PKN2-WT HCT116 cells was assessed using RT-PCR.*, P < 0.05; ***, P < 0.001 versus WT. d Stable clone of SW480, HCT116 and HT-29 cells (as indicated in Fig. 3) were cultured for 48 h. The level of IL10 and IL4 in the culture supernatants was assessed using ELISA.*, P < 0.05; **, P < 0.01 versus Vector or shCTL. e SW480 cells were stably infected with shPKN2-1, shPKN2-2, PKN2-WT or vector lentivirus. Luciferase assays were performed to detect transcription factor binding activity of IL4 and IL10. Relative fold-change in luciferase activity was shown. *, P < 0.05; **, P < 0.01 versus WT. f Human CD14+ monocytes were cocultured with stably shCTL or shPKN2 transfected HT-29 with/without neutralizing antibody of IL10 (2 μg/ml) or IL4 (0.5 μg/ml) for 4 days. Surface expression of CD206 in differentiated macrophages was detected using flow cytometry. ***, P < 0.001 versus shCTL. #, P < 0.05; ##, P < 0.01 versus shPKN2. g Human CD14+ monocytes were cocultured with HCT116 stably preinfected with vector or PKN2-WT with/without neutralizing antibody of IL10 (2 μg/ml) or IL4 (0.5 μg/ml) for 4 days. Surface expression of CD86 was detected using flow cytometry.***, P < 0.001 versus Vector. #, P < 0.05 versus PKN2-WTCC BY · PubMed Central
Fig. 5 PKN2 negatively regulates Erk1/2. a RKO cells were transfected with 0, 3 or 6 μg PKN2-WT-HA.Western blotting was used to detect the indicated proteins. b Stable clones of SW480, HCT116 and HT-29 cells (as indicated in Fig. 3) were detected for the expression of p-Erk1/2, Erk1/2 and GAPDH using western blotting. c IHC staining of PKN2 and p-ERK1/2 in the tumor tissues of mice xenograftmodels. The correlation between p-Erk1/2 positive number per high field and the PKN2 expression score was explored. d HT-29cells were stably transfected with shCTL or shPKN2 and treated with solvent, SCH772984 (1 μM) or U0126 (1 μM) for 1 h. Western blotting was used to detect the indicated proteins. e HT-29 cells were treated as indicated in (d). IL4 and IL10 gene expression was detected by RT-PCR.***, P < 0.001 versus lane 1. #, P < 0.05; ##, P < 0.01; ###, P < 0.001 versus lane 1. △△, P < 0.01; △△△, P < 0.001 versus lane4. f Human CD14+ monocytes were cocultured with stably transfected shCTL or shPKN2 HT-29 cells treated with SCH772984 (50 nM) or solvent for 4 days. Surface expression of CD206 and CD86 in differentiated macrophages was detected using flow cytometry.**, P < 0.01; ***, P < 0.001 versus shCTL
Fig. 5 PKN2 negatively regulates Erk1/2. a RKO cells were transfected with 0, 3 or 6 μg PKN2-WT-HA.Western blotting was used to detect the indicated proteins. b Stable clones of SW480, HCT116 and HT-29 cells (as indicated in Fig. 3) were detected for the expression of p-Erk1/2, Erk1/2 and GAPDH using western blotting. c IHC staining of PKN2 and p-ERK1/2 in the tumor tissues of mice xenograftmodels. The correlation between p-Erk1/2 positive number per high field and the PKN2 expression score was explored. d HT-29cells were stably transfected with shCTL or shPKN2 and treated with solvent, SCH772984 (1 μM) or U0126 (1 μM) for 1 h. Western blotting was used to detect the indicated proteins. e HT-29 cells were treated as indicated in (d). IL4 and IL10 gene expression was detected by RT-PCR.***, P < 0.001 versus lane 1. #, P < 0.05; ##, P < 0.01; ###, P < 0.001 versus lane 1. △△, P < 0.01; △△△, P < 0.001 versus lane4. f Human CD14+ monocytes were cocultured with stably transfected shCTL or shPKN2 HT-29 cells treated with SCH772984 (50 nM) or solvent for 4 days. Surface expression of CD206 and CD86 in differentiated macrophages was detected using flow cytometry.**, P < 0.01; ***, P < 0.001 versus shCTLCC BY · PubMed Central
Fig. 6 PKN2 inhibits the transcriptional activities of CREB and Elk-1. a HT-29cells were stably transfected with shCTL, shPKN2-1 or shPKN2-2 and treated with solvent or U0126 (1 μM) for 1 h. Western blotting was used to detect the indicated proteins. b Stable clones of SW480, HCT116 were detected for indicated proteins using western blotting. c RKO cells were transfected with PKN2-WT-HA, CREB-WT-flag, Elk-1-WT-flag or control vectors. IL4 and IL10 gene expression was detected. ***,P < 0.001 versus lane 1. ###, P < 0.001 versus lane 2. d Diagram shows the predicted binding sites of Elk-1 and CREB on the -1000 bp ~ + 1 bp promoter regions of IL4 and IL10. e ChIP assays of Elk-1 or CREB on the chemokine promoters in SW480 stably transduced with PKN2-WT or vector, and HT-29 cells transduced with shCTL or depletion of PKN2. These assays were repeated three times, and representative photos are shown
Fig. 6 PKN2 inhibits the transcriptional activities of CREB and Elk-1. a HT-29cells were stably transfected with shCTL, shPKN2-1 or shPKN2-2 and treated with solvent or U0126 (1 μM) for 1 h. Western blotting was used to detect the indicated proteins. b Stable clones of SW480, HCT116 were detected for indicated proteins using western blotting. c RKO cells were transfected with PKN2-WT-HA, CREB-WT-flag, Elk-1-WT-flag or control vectors. IL4 and IL10 gene expression was detected. ***,P < 0.001 versus lane 1. ###, P < 0.001 versus lane 2. d Diagram shows the predicted binding sites of Elk-1 and CREB on the -1000 bp ~ + 1 bp promoter regions of IL4 and IL10. e ChIP assays of Elk-1 or CREB on the chemokine promoters in SW480 stably transduced with PKN2-WT or vector, and HT-29 cells transduced with shCTL or depletion of PKN2. These assays were repeated three times, and representative photos are shownCC BY · PubMed Central
Fig. 7 PKN2 suppressesErk1/2 by directly binding to and activating DUSP6. a Protein expression of DUSP6 in human colon cancer tissue array was detected by immunohistochemistry staining. The correlation between DUSP6 expression score and PKN2 expression score was explored. b Comparison of the progression free survival (PFS) of patients with different levels of PKN2/DUSP6 expression using the Kaplan-Meier method. c RKO cells were transfected with PKN2-WT-HA, siCTL, siDUSP6-1 and siDUSP6-2, separately.Western blotting was used to detect the indicated proteins. d The DUSP6 activity was detected in stable clones of SW480, HCT116 and HT-29 cells as indicated in Fig. 3. **, P < 0.01; ***, P < 0.001 versus shCTL. *, P < 0.05 versus Vector. e The 293 T cells were transfected with PKN2-WT-HA, PKN2-K686R-HA, DUSP6-WT-flag or control vector as indicated and treated with/without cardiolipin (50 μg/mL). Whole lysates pulled down with anti-flag or anti-HA antibodies were assayed for DUSP6 and PKN2 activity, respectively. For PKN2 activity assay, *, P < 0.05 versus lane 5; #, P < 0.05 versus lane 6. For DUSP6 activity assay, ***, P < 0.001 versus lane 3; ###, P < 0.001 versus lane 4. f Co-IP of DUSP6 and PKN2 in HCT116, SW480 and HT-29 cells. g Co-expression of flag-tagged DUSP6 with or without different amounts (0, 3 and 6 μg) of HA-tagged PKN2-WT in 293 T cells. h, i Flag-tagged full-length DUSP6 and its truncation mutant vector were co-expressed with HA-tagged PKN2 in 293 T cells and immunoprecipitated by anti-flag antibody. j Schematic overview on the mechanisms by which PKN2 modulates TAMs polarization and inhibits colon cancer growth
Fig. 7 PKN2 suppressesErk1/2 by directly binding to and activating DUSP6. a Protein expression of DUSP6 in human colon cancer tissue array was detected by immunohistochemistry staining. The correlation between DUSP6 expression score and PKN2 expression score was explored. b Comparison of the progression free survival (PFS) of patients with different levels of PKN2/DUSP6 expression using the Kaplan-Meier method. c RKO cells were transfected with PKN2-WT-HA, siCTL, siDUSP6-1 and siDUSP6-2, separately.Western blotting was used to detect the indicated proteins. d The DUSP6 activity was detected in stable clones of SW480, HCT116 and HT-29 cells as indicated in Fig. 3. **, P < 0.01; ***, P < 0.001 versus shCTL. *, P < 0.05 versus Vector. e The 293 T cells were transfected with PKN2-WT-HA, PKN2-K686R-HA, DUSP6-WT-flag or control vector as indicated and treated with/without cardiolipin (50 μg/mL). Whole lysates pulled down with anti-flag or anti-HA antibodies were assayed for DUSP6 and PKN2 activity, respectively. For PKN2 activity assay, *, P < 0.05 versus lane 5; #, P < 0.05 versus lane 6. For DUSP6 activity assay, ***, P < 0.001 versus lane 3; ###, P < 0.001 versus lane 4. f Co-IP of DUSP6 and PKN2 in HCT116, SW480 and HT-29 cells. g Co-expression of flag-tagged DUSP6 with or without different amounts (0, 3 and 6 μg) of HA-tagged PKN2-WT in 293 T cells. h, i Flag-tagged full-length DUSP6 and its truncation mutant vector were co-expressed with HA-tagged PKN2 in 293 T cells and immunoprecipitated by anti-flag antibody. j Schematic overview on the mechanisms by which PKN2 modulates TAMs polarization and inhibits colon cancer growthCC BY · PubMed Central

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Metadata

Authors
Cheng, Y., Zhu, Y., Xu, J., Yang, M., Chen, P., Xu, W., Zhao, J., Geng, L., & Gong, S.
Affiliations
  • Guangzhou Women and Children Medical Center (CN)
  • Nanfang Hospital (CN)
Corresponding author
Gong, Sitang
ORCID
Venue
Molecular Cancer
Publisher
Springer Science and Business Media LLC
Published
2018-01-24
Volume
17
Issue
1
Pages
13-13
ISSN
1476-4598 (ISSN-L)
DOI
10.1186/s12943-017-0747-z
PMC
PMC5784528
OpenAlex
W2790033844
Cited by
161
References
54
Citations by year
2026: 11 · 2025: 22 · 2024: 25 · 2023: 22 · 2022: 28 · 2021: 37 · 2020: 8 · 2019: 7
FWCI
5.80
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81301758, 81602646)
  • Natural Science Foundation of Guangdong Province (2016A030310254)
  • China Postdoctoral Science Foundation (2016M600648)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
PKN2, colon cancer, tumor-associated macrophages, M2 macrophage polarization, DUSP6, ERK1/2 phosphorylation, IL-4, IL-10, CREB, Elk-1, tumor growth, prognostic factors, kinase signaling pathways
MeSH terms
Colonic Neoplasms, Humans, Immunohistochemistry, Macrophage Activation, Macrophages, Neoplasm Staging, Prognosis, Promoter Regions, Genetic, Protein Binding, Protein Kinase C, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Cytokines, MAP Kinase Signaling System, Cell Line, Tumor, ets-Domain Protein Elk-1, CREB-Binding Protein, Dual Specificity Phosphatase 6

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