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Stat3 up-regulates expression of nicotinamide N-methyltransferase in human cancer cells

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Abstract

Purpose

To discover new molecular targets for cancer therapy and diagnosis, we surveyed signal transducers and activators of transcription 3 (Stat3)-regulated genes, because constitutive activation of Stat3 is associated with a wide variety of human malignancies.

Methods

We investigated the Stat3-regulated genes in 293 cells with cDNA microarray analysis and found that Nicotinamide N-methyltransferase (NNMT) was induced on stimulation of the cells with leukemia inhibitory factor. We examined the expression of NNMT in several types of cancer cells by real-time quantitative RT-PCR. To examine the role of Stat3, Hep-G2 hepatocellular carcinoma cells were transfected with NNMT promoter-luciferase reporter construct together with conditionally active Stat3 (Stat3ER) or dominant-negative Stat3 expression vector and NNMT promoter activity was determined. The expression of NNMT and activated Stat3 in 88 colon cancer tissues and 17 normal colon tissues was examined with immunohistochemical analysis.

Results

In Hep-G2 cells and SW480 colon cancer cells, NNMT expression increased on stimulation of the cells with interleukin 6. NNMT promoter activity in Hep-G2 cells was dependent on the activation of Stat3. MDA-MB-468 breast cancer cells and HT29 colon cancer cells expressed constitutively a high level of NNMT. Treatment of these cells with Stat3 siRNA or curcumin, which inhibited Stat3 phosphorylation, resulted in reduction of the NNMT level. We found a correlation between the expression of NNMT and activated Stat3 (P < 0.001) in the colon cancer tissues.

Conclusion

NNMT is a novel Stat3-regulated gene. Its expression is enhanced with the activation of Stat3 in colon cancer tissues. NNMT may be a potential candidate for a tumor marker of various kinds of cancers.

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References

  • Abbud RA, Kelleher R, Melmed S (2004) Cell-specific pituitary gene expression profiles after treatment with leukemia inhibitory factor reveal novel modulators for proopiomelanocortin expression. Endocrinology 145:867–880

    Article  PubMed  CAS  Google Scholar 

  • Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T (1994) Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77:63–71

    Article  PubMed  CAS  Google Scholar 

  • Aksoy S, Brandriff BF, Ward A, Little PF, Weinshilboum RM (1995) Human nicotinamide N-methyltransferase gene: molecular cloning, structural characterization and chromosomal localization. Genomics 29:555–561

    Article  PubMed  CAS  Google Scholar 

  • Aksoy S, Szumlanski CL, Weinshilboum RM (1994) Human liver nicotinamide N-methyltransferase. cDNA cloning, expression, and biochemical characterization. J Biol Chem 269:14835–14840

    PubMed  CAS  Google Scholar 

  • Azare J, Leslie K, Al-Ahmadie H, Gerald W, Weinreb PH, Violette SM, Bromberg J (2007) Constitutively activated Stat3 induces tumorigenesis and enhances cell motility of prostate epithelial cells through integrin β6. Mol Cell Biol 27:4444–4453

    Article  PubMed  CAS  Google Scholar 

  • Bankfalvi AA, Piffko J, Ofner D, Dreier R, Bocker W, Werner K (1996) Significance of wet autoclave pretreatment in immunohistochemistry. Pathol Oncol Res 2:71–77

    Article  CAS  Google Scholar 

  • Bharti AC, Donato N, Aggarwal BB (2003) Curcumin (diferuloylmethane) inhibits constitutive and IL-6-inducible STAT3 phosphorylation in human multiple myeloma cells. J Immunol 171:3863–3871

    PubMed  CAS  Google Scholar 

  • Brocke-Heidrich K, Kretzschmar AK, Pfeifer G, Henze C, Loffler D, Koczan D, Thiesen HJ, Burger R, Gramatzki M, Horn F (2004) Interleukin-6-dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family independent survival pathway closely associated with Stat3 activation. Blood 103:242–251

    Article  PubMed  CAS  Google Scholar 

  • Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE Jr (1999) Stat3 as an oncogene. Cell 98:295–303

    Article  PubMed  CAS  Google Scholar 

  • Corvinus FM, Orth C, Moriggl R, Tsareva SA, Wagner S, Pfitzner EB, Baus D, Kaufmann R, Huber LA, Zatloukal K, Beug H, Ohlschlager P, Schutz A, Halbhuber KJ, Friedrich K (2005) Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia 7:545–555

    Article  PubMed  CAS  Google Scholar 

  • DeArmond D, Brattain MG, Jessup JM, Kreisberg J, Malik S, Zhao S, Freeman JW (2003) Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines. Oncogene 22:7781–7795

    Article  PubMed  CAS  Google Scholar 

  • Fernandes A, Hamburger AW, Gerwin BI (1999) ErbB-2 kinase is required for constitutive stat 3 activation in malignant human lung epithelial cells. Int J Cancer 83:564–570

    Article  PubMed  CAS  Google Scholar 

  • Iacobuzio-Donahue CA, Maitra A, Shen-Ong GL, van Heek T, Ashfaq R, Meyer R, Walter K, Berg K, Hollingsworth MA, Cameron JL, Yeo CJ, Kern SE, Goggins M, Hruban RH (2002) Discovery of novel tumor markers of pancreatic cancer using global gene expression technology. Am J Pathol 160:1239–1249

    PubMed  CAS  Google Scholar 

  • Jang JS, Cho HY, Lee YJ, Ha WS, Kim HW (2004) The differential proteome profile of stomach cancer: identification of the biomarker candidates. Oncol Res 14:491–499

    PubMed  CAS  Google Scholar 

  • Jiang WG, Martin TA, Parr C, Davies G, Matsumoto K, Nakamura T (2005) Hepatocyte growth factor, its receptor, and their potential value in cancer therapies. Crit Rev Oncol Hematol 53:35–69

    Article  PubMed  Google Scholar 

  • Kanda N, Seno H, Konda Y, Marusawa H, Kanai M, Nakajima T, Kawashima T, Nanakin A, Sawabu T, Uenoyama Y, Sekikawa A, Kawada M, Suzuki K, Kayahara T, Fukui H, Sawada M, Chiba T (2004) STAT3 is constitutively activated and supports cell survival in association with survivin expression in gastric cancer cells. Oncogene 23:4921–4929

    Article  PubMed  CAS  Google Scholar 

  • Kawada M, Seno H, Uenoyama Y, Sawabu T, Kanda N, Fukui H, Shimahara Y, Chiba T (2006) Signal transducers and activators of transcription 3 activation is involved in nuclear accumulation of β-catenin in colorectal cancer. Cancer Res 66:2913–2917

    Article  PubMed  CAS  Google Scholar 

  • Kobayashi Y, Tokuchi Y, Hashimoto T, Hayashi M, Nishimura H, Ishikawa Y, Nakagawa K, Sato Y, Takahashi A, Tsuchiya E (2004) Molecular markers for reinforcement of histological subclassification of neuroendocrine lung tumors. Cancer Sci 95:334–341

    Article  PubMed  CAS  Google Scholar 

  • Konnikova L, Kotecki M, Kruger MM, Cochran BH (2003) Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells. BMC Cancer 3:23–31

    Article  PubMed  Google Scholar 

  • Kusaba T, Nakayama T, Yamazumi K, Yakata Y, Yoshizaki A, Nagayasu T, Sekine I (2005) Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors. J Clin Pathol 58:833–838

    Article  PubMed  CAS  Google Scholar 

  • Lim BH, Cho BI, Kim YN, Kim JW, Park ST, Lee CW (2006) Overexpression of nicotinamide N-methyltransferase in gastric cancer tissues and its potential post-translational modification. Exp Mol Med 38:455–465

    PubMed  CAS  Google Scholar 

  • Lin Q, Lai R, Chirieac LR, Li C, Thomazy VA, Grammatikakis I, Rassidakis GZ, Zhang W, Fujio Y, Kunisada K, Hamilton SR, Amin HM (2005) Constitutive activation of JAK3/STAT3 in colon carcinoma tumors and cell lines: inhibition of JAK3/STAT3 signaling induces apoptosis and cell cycle arrest of colon carcinoma cells. Am J Pathol 167:969–980

    PubMed  CAS  Google Scholar 

  • Lowe DG, Nunes W, Bombara M, McCabe S, Rangea GE, Henzel W, Tomida M, Yamamoto-Yamaguchi Y, Hozumi M, Goeddel DV (1989) Genomic cloning and heterologous expression of human differentiation-stimulating factor. DNA 8:351–359

    PubMed  CAS  Google Scholar 

  • Ma XT, Wang S, Ye YJ, Du RY, Cui ZR, Somsouk M (2004) Constitutive activation of Stat3 signaling pathway in human colorectal carcinoma. World J Gastroenterol 10:1569–1573

    PubMed  CAS  Google Scholar 

  • Matsuda T, Nakamura T, Nakao K, Arai T, Katsuki M, Heike T, Yokota T (1999) STAT3 activation is sufficient to maintain an undifferentiated state of mouse embryonic stem cells. EMBO J 18:4261–4269

    Article  PubMed  CAS  Google Scholar 

  • O’Farrell AM, Liu Y, Moore KW, Mui AL (1998) IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat3-dependent and -independent pathways. EMBO J 17:1006–1018

    Article  PubMed  CAS  Google Scholar 

  • Paz K, Socci ND, van Nimwegen E, Viale A, Darnell JE (2004) Transformation fingerprint: induced STAT3-C, v-Src and Ha-Ras cause small initial changes but similar established profiles in mRNA. Oncogene 23:8455–8463

    Article  PubMed  CAS  Google Scholar 

  • Roessler M, Rollinger W, Palme S, Hagmann ML, Berndt P, Engel AM, Schneidinger B, Pfeffer M, Andres H, Karl J, Bodenmüller H, Rüschoff J, Henkel T, Rohr G, Rossol S, Rösch W, Langen H, Zolg W, Tacke M (2005) Identification of nicotinamide N-methyltransferase as a novel serum tumor marker for colorectal cancer. Clin Cancer Res 11:6550–6557

    Article  PubMed  CAS  Google Scholar 

  • Rogers CD, Fukushima N, Sato N, Shi C, Prasad N, Hustinx SR, Matsubayashi H, Canto M, Eshleman JR, Hruban RH, Goggins M (2006) Differentiating pancreatic lesions by microarray and QPCR analysis of pancreatic juice RNAs. Cancer Biol Ther 5:1383–1389

    Article  PubMed  CAS  Google Scholar 

  • Saito T, Tomida M (2005) Generation of inhibitory DNA aptamers against human hepatocyte growth factor. DNA Cell Biol 24:624–633

    Article  PubMed  CAS  Google Scholar 

  • Song L, Turkson J, Karras JG, Jove R, Haura EB (2003) Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene 22:4150–4165

    Article  PubMed  CAS  Google Scholar 

  • Tomida M, Heike T, Yokota T (1999) Cytoplasmic domains of the leukemia inhibitory factor receptor required for STAT3 activation, differentiation, and growth arrest of myeloid leukemic cells. Blood 93:1934–1941

    PubMed  CAS  Google Scholar 

  • Tomida M, Saito T (2004a) The human hepatocyte growth factor (HGF) gene is transcriptionally activated by leukemia inhibitory factor through the Stat binding element. Oncogene 23:679–686

    Article  PubMed  CAS  Google Scholar 

  • Tomida M, Saito T (2004b) Stat3 activity stimulates HGF expression. In: Fenton MJ (ed) 5th Joint meeting of the international cytokine society and the international society for interferon and cytokine research. MEDIMOND, Bologna, pp 113–116

    Google Scholar 

  • Turkson J, Jove R (2000) STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 19:6613–6626

    Article  PubMed  CAS  Google Scholar 

  • Watson CJ, Miller WR (1995) Elevated levels of members of the STAT family of transcription factors in breast carcinoma nuclear extracts. Br J Cancer 71:840–844

    PubMed  CAS  Google Scholar 

  • Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL, Xie K (2003) Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 22:319–329

    Article  PubMed  CAS  Google Scholar 

  • Xu J, Capezzone M, Xu X, Hershman JM (2005) Activation of nicotinamide N-methyltransferase gene promoter by hepatocyte nuclear factor-1β in human papillary thyroid cancer cells. Mol Endocrinol 19:527–539

    Article  PubMed  CAS  Google Scholar 

  • Xu J, Moatamed F, Caldwell JS, Walker JR, Kraiem Z, Taki K, Brent GA, Hershman JM (2003) Enhanced expression of nicotinamide N-methyltransferase in human papillary thyroid carcinoma cells. J Clin Endocrinol Metab 88:4990–4996

    Article  PubMed  CAS  Google Scholar 

  • Yan L, Otterness DM, Weinshilboum RM (1999) Human nicotinamide N-methyltransferase pharmacogenetics: gene sequence analysis and promoter characterization. Pharmacogenetics 9:307–316

    Article  PubMed  CAS  Google Scholar 

  • Yao M, Tabuchi H, Nagashima Y, Baba M, Nakaigawa N, Ishiguro H, Hamada K, Inayama Y, Kishida T, Hattori K, Yamada-Okabe H, Kubota Y (2005) Gene expression analysis of renal carcinoma: adipose differentiation-related protein as a potential diagnostic and prognostic biomarker for clear-cell renal carcinoma. J Pathol 205:377–387

    Article  PubMed  CAS  Google Scholar 

  • Yeh HH, Lai WW, Chen HH, Liu HS, Su WC (2006) Autocrine IL-6-induced Stat3 activation contributes to the pathogenesis of lung adenocarcinoma and malignant pleural effusion. Oncogene 25:4300–4309

    Article  PubMed  CAS  Google Scholar 

  • Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J, Jove R (1995) Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 269:81–83

    Article  PubMed  CAS  Google Scholar 

  • Yu H, Jove R (2004) The STATs of cancer–new molecular targets come of age. Nat Rev Cancer 4:97–105

    Article  PubMed  CAS  Google Scholar 

  • Yuan ZL, Guan YJ, Wang L, Wei W, Kane AB, Chin YE (2004) Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells. Mol Cell Biol 24:9390–9400

    Article  PubMed  CAS  Google Scholar 

  • Zhong Z, Wen Z, Darnell JE Jr (1994) Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264:95–98

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by the Project, Saitama Prefecture Collaboration of Regional Entities for the Advancement of Technological Excellence, JST. We thank A. Kodaka and T. Tanaka for their technical assistance.

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Authors and Affiliations

  1. Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina, Saitama, 362-0806, Japan

    Mikio Tomida & Hideki Ohtake

  2. REDS Group (Saitama Prefecture Collaboration of Regional Entities for the Advancement of Technological Excellence, JST), Saitama Small Enterprise Promotion Corporation, SKIP City, Kawaguchi, 333-0844, Japan

    Hideki Ohtake

  3. Department of Stem Cell Biology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8640, Japan

    Takashi Yokota

  4. Department of Pathology, Saitama Cancer Center, 818 Komuro, Ina, Saitama, 362-0806, Japan

    Yasuhito Kobayashi & Masafumi Kurosumi

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  1. Mikio Tomida
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  2. Hideki Ohtake
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  3. Takashi Yokota
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  4. Yasuhito Kobayashi
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Correspondence to Mikio Tomida.

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Tomida, M., Ohtake, H., Yokota, T. et al. Stat3 up-regulates expression of nicotinamide N-methyltransferase in human cancer cells. J Cancer Res Clin Oncol 134, 551–559 (2008). https://doi.org/10.1007/s00432-007-0318-6

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  • DOI: https://doi.org/10.1007/s00432-007-0318-6

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