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STAT3 in Pancreatic Cancer Metastasis

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Book cover Role of Transcription Factors in Gastrointestinal Malignancies

Abstract

Pancreatic cancer is one of the leading causes of mortality associated with cancer. Signal transducer and activator of transcription (STAT)3 is implicated in metastasis of pancreatic cancer. Various cytokines, growth factors and environmental stimuli have been identified to activate STAT3. Attenuation of malignant transformation susceptibility of different cell types was noted on inhibition of STAT3 activation; thus, STAT3 has been put forward as a possible drug target for pancreatic cancer therapy. Several inhibitors have been proposed to regulate the upstream positive or negative control elements of STAT3 activation and target STAT3 directly. However, it is imperative to explore further for the effective STAT3 inhibitors that could improve the clinical outcome in patients with pancreatic cancer.

The original version of this chapter was revised. The book was inadvertently published without Abstracts and Keywords, which are now included in all the chapters. An erratum to this chapter can be found at https://doi.org/10.1007/978-981-10-6728-0_39

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References

  1. Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T,…, 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(1): 63–71

    Article  CAS  PubMed  Google Scholar 

  2. Andersen JN, Mortensen OH, Peters GH, Drake PG, Iversen LF, Olsen OH, …, Moller NP (2001) Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol Cell Biol 21(21): 7117–7136. doi: https://doi.org/10.1128/MCB.21.21.7117-7136.2001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE Jr (1999) Stat3 as an oncogene. Cell 98(3):295–303

    Article  CAS  PubMed  Google Scholar 

  4. Chapman RS, Lourenco PC, Tonner E, Flint DJ, Selbert S, Takeda K,…, Watson CJ (1999) Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. Genes Dev 13(19): 2604–2616

    Article  CAS  Google Scholar 

  5. Chen W, Daines MO, Khurana Hershey GK (2004) Turning off signal transducer and activator of transcription (STAT): the negative regulation of STAT signaling. J Allergy Clin Immunol 114(3):476–489.; quiz 490. https://doi.org/10.1016/j.jaci.2004.06.042

    Article  PubMed  CAS  Google Scholar 

  6. Croker BA, Kiu H, Nicholson SE (2008) SOCS regulation of the JAK/STAT signalling pathway. Semin Cell Dev Biol 19(4):414–422. https://doi.org/10.1016/j.semcdb.2008.07.010

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Dang CV (1999) c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 19(1):1–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Darnell JE Jr (1997) STATs and gene regulation. Science 277(5332):1630–1635

    Article  CAS  PubMed  Google Scholar 

  9. Dechow TN, Pedranzini L, Leitch A, Leslie K, Gerald WL, Linkov I, Bromberg JF (2004) Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C. Proc Natl Acad Sci USA 101(29):10602–10607. https://doi.org/10.1073/pnas.0404100101

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Edderkaoui M, Eibl G (2014) Risk factors for pancreatic cancer: underlying mechanisms and potential targets. Front Physiol 5:490. https://doi.org/10.3389/fphys.2014.00490

    Article  PubMed  PubMed Central  Google Scholar 

  11. Feng Z (2010) p53 regulation of the IGF-1/AKT/mTOR pathways and the endosomal compartment. Cold Spring Harb Perspect Biol 2(2):a001057. https://doi.org/10.1101/cshperspect.a001057

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Frank DA (2007) STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett 251(2):199–210. https://doi.org/10.1016/j.canlet.2006.10.017

    Article  CAS  PubMed  Google Scholar 

  13. Furqan M, Mukhi N, Lee B, Liu D (2013) Dysregulation of JAK-STAT pathway in hematological malignancies and JAK inhibitors for clinical application. Biomark Res 1(1):5. https://doi.org/10.1186/2050-7771-1-5

    Article  PubMed  PubMed Central  Google Scholar 

  14. Gassmann P, Haier J (2008) The tumor cell-host organ interface in the early onset of metastatic organ colonisation. Clin Exp Metastasis 25(2):171–181. https://doi.org/10.1007/s10585-007-9130-6

    Article  PubMed  CAS  Google Scholar 

  15. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140(6):883–899. https://doi.org/10.1016/j.cell.2010.01.025

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Groner B, Lucks P, Borghouts C (2008) The function of Stat3 in tumor cells and their microenvironment. Semin Cell Dev Biol 19(4):341–350. https://doi.org/10.1016/j.semcdb.2008.06.005

    Article  PubMed  CAS  Google Scholar 

  17. Grunstein J, Roberts WG, Mathieu-Costello O, Hanahan D, Johnson RS (1999) Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. Cancer Res 59(7):1592–1598

    CAS  PubMed  Google Scholar 

  18. Huang S (2007) Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: clinical implications. Clin Cancer Res: Off J Am Assoc Cancer Res 13(5):1362–1366. https://doi.org/10.1158/1078-0432.CCR-06-2313

    Article  CAS  Google Scholar 

  19. Ihle JN (2001) The stat family in cytokine signaling. Curr Opin Cell Biol 13(2):211–217

    Article  CAS  PubMed  Google Scholar 

  20. Itoh M, Murata T, Suzuki T, Shindoh M, Nakajima K, Imai K, Yoshida K (2006) Requirement of STAT3 activation for maximal collagenase-1 (MMP-1) induction by epidermal growth factor and malignant characteristics in T24 bladder cancer cells. Oncogene 25(8):1195–1204. https://doi.org/10.1038/sj.onc.1209149

    Article  CAS  PubMed  Google Scholar 

  21. Kamran MZ, Patil P, Gude RP (2013) Role of STAT3 in cancer metastasis and translational advances. Biomed Res Int 2013:421821. https://doi.org/10.1155/2013/421821

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Kojima H, Sasaki T, Ishitani T, Iemura S, Zhao H, Kaneko S, …, Nakajima K (2005) STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFbeta-activated kinase 1 for STAT3 Ser-727 phosphorylation. Proc Natl Acad Sci USA 102(12): 4524–4529. doi: https://doi.org/10.1073/pnas.0500679102

    Article  CAS  Google Scholar 

  23. Kolodecik T, Shugrue C, Ashat M, Thrower EC (2013) Risk factors for pancreatic cancer: underlying mechanisms and potential targets. Front Physiol 4:415. https://doi.org/10.3389/fphys.2013.00415

    Article  PubMed  Google Scholar 

  24. Konig J, Hartel M, Nies AT, Martignoni ME, Guo J, Buchler MW, …, Keppler D (2005) Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma. Int J Cancer 115(3): 359–367. doi: https://doi.org/10.1002/ijc.20831

    Article  PubMed  Google Scholar 

  25. Koskela HL, Eldfors S, Ellonen P, van Adrichem AJ, Kuusanmaki H, Andersson EI, …, Mustjoki S (2012) Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med 366(20): 1905–1913. doi: https://doi.org/10.1056/NEJMoa1114885

    Article  PubMed  CAS  Google Scholar 

  26. Leaman DW, Leung S, Li X, Stark GR (1996) Regulation of STAT-dependent pathways by growth factors and cytokines. FASEB J: Off Publ Fed Am Soc Exp Biol 10(14):1578–1588

    Article  CAS  Google Scholar 

  27. Lee JY, Hennighausen L (2005) The transcription factor Stat3 is dispensable for pancreatic beta-cell development and function. Biochem Biophys Res Commun 334(3):764–768. https://doi.org/10.1016/j.bbrc.2005.06.162

    Article  PubMed  CAS  Google Scholar 

  28. Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Kloppel G, …, Algul H (2011) Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19(4): 456–469. doi: https://doi.org/10.1016/j.ccr.2011.03.009

    Article  PubMed  CAS  Google Scholar 

  29. Lu Z, Kleeff J, Shrikhande S, Zimmermann T, Korc M, Friess H, Buchler MW (2000) Expression of the multidrug-resistance 1 (MDR1) gene and prognosis in human pancreatic cancer. Pancreas 21(3):240–247

    Article  CAS  PubMed  Google Scholar 

  30. Miyatsuka T, Kaneto H, Shiraiwa T, Matsuoka TA, Yamamoto K, Kato K, …, Fujitani Y (2006) Persistent expression of PDX-1 in the pancreas causes acinar-to-ductal metaplasia through Stat3 activation. Genes Dev 20(11): 1435–1440. doi: https://doi.org/10.1101/gad.1412806

    Article  CAS  Google Scholar 

  31. Neesse A, Krug S, Gress TM, Tuveson DA, Michl P (2013) Emerging concepts in pancreatic cancer medicine: targeting the tumor stroma. OncoTargets Ther 7:33–43. https://doi.org/10.2147/OTT.S38111

    Article  CAS  Google Scholar 

  32. Niu G, Wright KL, Ma Y, Wright GM, Huang M, Irby R,…, Yu H (2005) Role of Stat3 in regulating p53 expression and function. Mol Cell Biol 25(17): 7432–7440. doi: https://doi.org/10.1128/MCB.25.17.7432-7440.2005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Oh MK, Park HJ, Kim NH, Park SJ, Park IY, Kim IS (2011) Hypoxia-inducible factor-1alpha enhances haptoglobin gene expression by improving binding of STAT3 to the promoter. J Biol Chem 286(11):8857–8865. https://doi.org/10.1074/jbc.M110.150557

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Pilati C, Amessou M, Bihl MP, Balabaud C, Nhieu JT, Paradis V,…, Zucman-Rossi J (2011) Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. J Exp Med 208(7): 1359–1366. doi: https://doi.org/10.1084/jem.20110283

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Rakesh S, Narinder S, Sharmila S (2014) STAT3 as an emerging molecular target in pancreatic cancer. Gastrointest Cancer: Targets Ther 4:115. https://doi.org/10.2147/gictt.s48993

    Article  Google Scholar 

  36. Scholz A, Heinze S, Detjen KM, Peters M, Welzel M, Hauff P,…, Rosewicz S (2003) Activated signal transducer and activator of transcription 3 (STAT3) supports the malignant phenotype of human pancreatic cancer. Gastroenterology 125(3): 891–905

    Article  CAS  PubMed  Google Scholar 

  37. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721–732. https://doi.org/10.1038/nrc1187

    Article  CAS  PubMed  Google Scholar 

  38. Shirogane T, Fukada T, Muller JM, Shima DT, Hibi M, Hirano T (1999) Synergistic roles for Pim-1 and c-Myc in STAT3-mediated cell cycle progression and antiapoptosis. Immunity 11(6):709–719

    Article  CAS  PubMed  Google Scholar 

  39. Shuai K, Liu B (2005) Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol 5(8):593–605. https://doi.org/10.1038/nri1667

    Article  PubMed  CAS  Google Scholar 

  40. Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ,…, Hilton DJ (1997) A family of cytokine-inducible inhibitors of signalling. Nature 387(6636): 917–921. doi: https://doi.org/10.1038/43206

    Article  PubMed  CAS  Google Scholar 

  41. Steele CW, Jamieson NB, Evans TR, McKay CJ, Sansom OJ, Morton JP, Carter CR (2013) Exploiting inflammation for therapeutic gain in pancreatic cancer. Br J Cancer 108(5):997–1003. https://doi.org/10.1038/bjc.2013.24

    Article  PubMed  PubMed Central  Google Scholar 

  42. Thomas SJ, Snowden JA, Zeidler MP, Danson SJ (2015) The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br J Cancer 113(3):365–371. https://doi.org/10.1038/bjc.2015.233

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Vicari AP, Caux C, Trinchieri G (2002) Tumour escape from immune surveillance through dendritic cell inactivation. Semin Cancer Biol 12(1):33–42. https://doi.org/10.1006/scbi.2001.0400

    Article  PubMed  CAS  Google Scholar 

  44. Vitale G, Zappavigna S, Marra M, Dicitore A, Meschini S, Condello M,…, Caraglia M (2012) The PPAR-gamma agonist troglitazone antagonizes survival pathways induced by STAT-3 in recombinant interferon-beta treated pancreatic cancer cells. Biotechnol Adv 30(1): 169–184. doi: https://doi.org/10.1016/j.biotechadv.2011.08.001

    Article  PubMed  CAS  Google Scholar 

  45. Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S,…, Yu H (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10(1): 48–54. doi: https://doi.org/10.1038/nm976

    Article  PubMed  Google Scholar 

  46. Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC et al (2003) Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 22(3):319–329. https://doi.org/10.1038/sj.onc.1206122

    Article  PubMed  CAS  Google Scholar 

  47. Yadav D, Lowenfels AB (2013) The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology 144(6):1252–1261. https://doi.org/10.1053/j.gastro.2013.01.068

    Article  PubMed  Google Scholar 

  48. Yahata Y, Shirakata Y, Tokumaru S, Yamasaki K, Sayama K, Hanakawa Y,…, Hashimoto K (2003) Nuclear translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor-induced human dermal microvascular endothelial cell migration and tube formation. J Biol Chem 278(41): 40026–40031. doi: https://doi.org/10.1074/jbc.M301866200

    Article  PubMed  CAS  Google Scholar 

  49. Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7(1):41–51. https://doi.org/10.1038/nri1995

    Article  PubMed  CAS  Google Scholar 

  50. Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798–809. https://doi.org/10.1038/nrc2734

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Yuan ZL, Guan YJ, Chatterjee D, Chin YE (2005) Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307(5707):269–273. https://doi.org/10.1126/science.1105166

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors gratefully acknowledge the Science and engineering research board, Department of science and technology, Government of India and Indian Council of Medical Research, New Delhi, for the research fellowships.

Conflict of Interests

We declare that we do not have any conflict of interests.

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Authors and Affiliations

  1. N-PDF, SERB-DST, New Delhi, India

    Rongala Laxmivandana

  2. ICAR-IIAB, Ranchi, India

    Rongala Laxmivandana

  3. National Institute of Virology, Pune, India

    Prudhvi Lal Bhukya

  4. Department of Zoology, Nizam College, Osmania University, Hyderabad, India

    Maddala Madhavi

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  1. Rongala Laxmivandana
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  2. Prudhvi Lal Bhukya
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  3. Maddala Madhavi
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Correspondence to Rongala Laxmivandana .

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Editors and Affiliations

  1. Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia, USA

    Ganji Purnachandra Nagaraju

  2. Department of Biotechnology, Krishna University, Machilipatnam, Andhra Pradesh, India

    Pallaval Veera Bramhachari

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Laxmivandana, R., Bhukya, P.L., Madhavi, M. (2017). STAT3 in Pancreatic Cancer Metastasis. In: Nagaraju, G., Bramhachari, P. (eds) Role of Transcription Factors in Gastrointestinal Malignancies. Springer, Singapore. https://doi.org/10.1007/978-981-10-6728-0_25

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