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The Expanding Role of Sp1 in Pancreatic Cancer: Tumorigenic and Clinical Perspectives

  • Abdul Rauf
  • Saeed Ali
  • Muhammad Talha Khan
  • Asad-ur-Rahman
  • Sarfraz Ahmad
Chapter

Abstract

It is increasingly being recognized that in gastrointestinal malignancies, including pancreatic cancer, transcription factors get activated and alter the gene expression in the tumor cells to metastasize and develop. Pancreatic cancer is associated with a relatively very poor prognosis and survival outcomes. Currently, there are significant barriers to effective therapeutic interventions for this disease; hence timely diagnosis and clinical decision-making leading to appropriate treatment strategies for patients with metastatic pancreatic cancer are essential. This chapter summarizes some of the selected peer-reviewed translational and clinical research findings in the area of a transcription factor [specificity protein 1 (Sp1)] as it relates to the tumorigenesis and mechanistic role(s) for the potential of improving therapeutic targets/responses in pancreatic cancer. Particular emphasis has been given on the mechanistic roles of Sp1 in the cell cycle, metastasis (cellular adhesion, invasion, migration, angiogenesis), and apoptosis. Based on the available information and several ongoing clinical studies, it is implicated that Sp1 can well serve as an important prognostic marker for pancreatic tumor. Several drugs targeting Sp1 for pancreatic tumor therapy have also been studied and discussed in this chapter. These drugs work by downregulating the expression and activity of Sp1 in tumor cells in pancreatic cancer. Taken together, these molecular and cellular mechanisms/targets can have a very significant impact on the prognosis and overall quality-of-life and clinical outcomes for patients with pancreatic tumor.

Keywords

Pancreatic cancer Specificity proteins Sp1 Transcription factors Cellular and molecular mechanisms Tumorigenesis Anticancer drugs Clinical outcomes 

References

  1. 1.
    Abdelrahim M, Baker CH, Abbruzzese JL, Safe S (2006) Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation. J Natl Cancer Inst 98:855–868CrossRefPubMedGoogle Scholar
  2. 2.
    Abdelrahim M, Smith R, Burghardt R, Safe S (2004) Role of Sp proteins in regulation of vascular endothelial growth factor expression and proliferation of pancreatic cancer cells. Cancer Res 64:6740–6749CrossRefPubMedGoogle Scholar
  3. 3.
    Aghdassi A, Phillips P, Dudeja V, Dhaulakhandi D, Sharif R, Dawra R et al (2007) Heat shock protein 70 increases tumorigenicity and inhibits apoptosis in pancreatic adenocarcinoma. Cancer Res 67:616–625CrossRefPubMedGoogle Scholar
  4. 4.
    Banerjee S, Sangwan V, McGinn O, Chugh R, Dudeja V, Vickers SM et al (2013) Triptolide-induced cell death in pancreatic cancer is mediated by O-GlcNAc modification of transcription factor Sp1. J Biol Chem 288:33927–33938CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Basha R, Ingersoll SB, Sankpal UT, Ahmad S, Baker CH, Edwards JR et al (2011) Tolfenamic acid inhibits ovarian cancer cell growth and decreases the expression of c-Met and survivin through suppressing specificity protein transcription factors. Gynecol Oncol 122:163–170CrossRefPubMedGoogle Scholar
  6. 6.
    Bünger S, Laubert T, Roblick UJ, Habermann JK (2011) Serum biomarkers for improved diagnostic of pancreatic cancer: a current overview. J Cancer Res Clin Oncol 137:375–389CrossRefPubMedGoogle Scholar
  7. 7.
    Colon J, Basha MR, Madero-Visbal R, Konduri S, Baker CH, Herrera LJ et al (2011) Tolfenamic acid decreases c-Met expression through Sp proteins degradation and inhibits lung cancer cells growth and tumor formation in orthotopic mice. Investig New Drugs 29:41–51CrossRefGoogle Scholar
  8. 8.
    Hang J, Hu H, Huang J, Han T, Zhuo M, Zhou Y et al (2016) Sp1 and COX-2 expression is positively correlated with a poor prognosis in pancreatic ductal adenocarcinoma. Oncotarget 7:28207–28217PubMedPubMedCentralGoogle Scholar
  9. 9.
    Hedrick E, Cheng Y, Jin U-H, Kim K, Safe S (2016) Specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 are non-oncogene addiction genes in cancer cells. Oncotarget 7:22245–22256CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Higgins KJ, Abdelrahim M, Liu S, Yoon K, Safe S (2006) Regulation of vascular endothelial growth factor receptor-2 expression in pancreatic cancer cells by Sp proteins. Biochem Biophys Res Commun 345:292–301CrossRefPubMedGoogle Scholar
  11. 11.
    Hu H, Han T, Zhuo M, Wu L-L, Yuan C, Wu L et al (2017) Elevated COX-2 expression promotes angiogenesis through EGFR/p38-MAPK/Sp1-dependent signalling in pancreatic cancer. Sci Rep 7(1):470.  https://doi.org/10.1038/s41598-017-00288-4 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hu J, Hu H, J-j H, Yang H-y, Wang Z-y, Wang L et al (2016) Simultaneous high expression of PLD1 and Sp1 predicts a poor prognosis for pancreatic ductal adenocarcinoma patients. Oncotarget 7:78557–78565PubMedPubMedCentralGoogle Scholar
  13. 13.
    Huang C, Xie K (2012) Crosstalk of Sp1 and Stat3 signaling in pancreatic cancer pathogenesis. Cytokine Growth Factor Rev 23:25–35CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Jiang NY, Woda BA, Banner BF, Whalen GF, Dresser KA, Lu D (2008) Sp1, a new biomarker that identifies a subset of aggressive pancreatic ductal adenocarcinoma. Cancer Epidemiol Preven Biomark 17:1648–1652CrossRefGoogle Scholar
  15. 15.
    Jungert K, Buck A, von Wichert G, Adler G, König A, Buchholz M et al (2007) Sp1 is required for transforming growth factor-β–induced mesenchymal transition and migration in pancreatic cancer cells. Cancer Res 67:1563–1570CrossRefPubMedGoogle Scholar
  16. 16.
    Khorana AA, Mangu PB, Berlin J, Engebretson A, Hong TS, Maitra A et al (2017) Potentially curable pancreatic cancer: American Society of Clinical Oncology Clinical Practice Guideline update. J Clin Oncol 35:2324–2328CrossRefPubMedGoogle Scholar
  17. 17.
    Papineni S, Chintharlapalli S, Abdelrahim M, Lee SO, Burghardt R, Abudayyeh A et al (2009) Tolfenamic acid inhibits esophageal cancer through repression of specificity proteins and c-Met. Carcinogenesis 30:1193–1201CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Pietrasz D, Pécuchet N, Garlan F, Didelot A, Dubreuil O, Doat S et al (2017) Plasma circulating tumor DNA in pancreatic cancer patients is a prognostic marker. Clin Cancer Res 23:116–123CrossRefPubMedGoogle Scholar
  19. 19.
    Pishvaian MJ, Brody JR (2017) Therapeutic implications of molecular subtyping for pancreatic cancer. Oncology (Williston Park) 31:159–168Google Scholar
  20. 20.
    Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74:2913–2921CrossRefGoogle Scholar
  21. 21.
    Safe S, Abdelrahim M (2005) Sp transcription factor family and its role in cancer. Eur J Cancer 41:2438–2448CrossRefPubMedGoogle Scholar
  22. 22.
    Sankpal UT, Ingersoll SB, Ahmad S, Holloway RW, Bhat VB, Simecka JW et al (2016) Association of Sp1 and survivin in epithelial ovarian cancer: Sp1 inhibitor and cisplatin a novel combination for inhibiting epithelial ovarian cancer cell proliferation. Tumor Biol 37:14259–14269CrossRefGoogle Scholar
  23. 23.
    Sankpal UT, Goodison S, Jones-Pauley M, Hurtado M, Zhang F, Basha R (2017) Tolfenamic acid-induced alterations in genes and pathways in pancreatic cancer cells. Oncotarget 8:14593–14603CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Shi Q, Le X, Abbruzzese JL, Peng Z, Qian C-N, Tang H et al (2001) Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res 61:4143–4154PubMedGoogle Scholar
  25. 25.
    Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7–30CrossRefGoogle Scholar
  26. 26.
    Wei D, Wang L, He Y, Xiong HQ, Abbruzzese JL, Xie K (2004) Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity. Cancer Res 64:2030–2038CrossRefPubMedGoogle Scholar
  27. 27.
    Weinberg BA, Philip PA, Salem ME (2017) Evolving standards of care for resected pancreatic cancer. Clin Adv Hematol Oncol 15:141–150PubMedGoogle Scholar
  28. 28.
    Yuan P, Wang L, Wei D, Zhang J, Jia Z, Li Q et al (2007) Therapeutic inhibition of Sp1 expression in growing tumors by mithramycin a correlates directly with potent antiangiogenic effects on human pancreatic cancer. Cancer 110:2682–2690CrossRefPubMedGoogle Scholar
  29. 29.
    Zhang X, Li Y, Dai C, Yang J, Mundel P, Liu Y (2003) Sp1 and Sp3 transcription factors synergistically regulate HGF receptor gene expression in kidney. Am J Physiol 284:F82–F94CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd 2017

Authors and Affiliations

  • Abdul Rauf
    • 1
  • Saeed Ali
    • 2
  • Muhammad Talha Khan
    • 3
  • Asad-ur-Rahman
    • 2
  • Sarfraz Ahmad
    • 4
  1. 1.Khyber Teaching HospitalPeshawarPakistan
  2. 2.Department of Internal MedicineFlorida HospitalOrlandoUSA
  3. 3.Lady Reading HospitalPeshawarPakistan
  4. 4.UCF and FSU Colleges of Medicine, FH Gynecologic OncologyFlorida HospitalOrlandoUSA

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