Display options
Share it on

Transl Gastrointest Cancer. 2012 Apr 01;1(1):58-70. doi: 10.3978/j.issn.2224-4778.2011.11.02.

Interleukin-6 and its receptor, key players in hepatobiliary inflammation and cancer.

Translational gastrointestinal cancer

Christopher Johnson, Yuyan Han, Nathan Hughart, Jennifer McCarra, Gianfranco Alpini, Fanyin Meng

PMID: 22724089 PMCID: PMC3378312 DOI: 10.3978/j.issn.2224-4778.2011.11.02

Abstract

In recent years, the relationship between interleukin-6 (IL-6), hepatobiliary inflammation, and cancer has been studied. It is becoming clear that this cytokine plays an important role in the pathogenesis of both cholangiocarcinoma (CCA, cancer of the bile ducts) and hepatocellular carcinoma (HCC, cancer arising from the liver parenchyma). Inflammation due to various chronic hepatobiliary diseases including hepatitis B, hepatitis C, alcoholic liver injury, and primary sclerosing cholangitis (PSC) has been associated with increased levels of IL-6 and with increased rates of malignancy. In this review, we will summarize the current knowledge linking inflammation to hepatobiliary cancer, and discuss the key role of IL-6 and its signaling pathways in mediating this link. We will first review the major signaling pathways that are triggered when IL-6 engages its receptor. These include PI3 kinase, JAK/STAT, p38 MAP kinase and others that ultimately lead to cell proliferation, protection from apoptosis and increased metastatic potential. We will then discuss data linking IL-6 and hepatobiliary cancer, namely HCC and CCA.

References

  1. J Biol Chem. 2002 Mar 8;277(10):7875-81 - PubMed
  2. Gynecol Oncol. 1993 Jul;50(1):15-9 - PubMed
  3. Ann Surg Oncol. 1998 Apr-May;5(3):279-86 - PubMed
  4. J Biol Chem. 2004 Sep 24;279(39):40412-8 - PubMed
  5. Curr Opin Gastroenterol. 2009 Sep;25(5):472-6 - PubMed
  6. J Hepatol. 2005 Nov;43(5):757-63 - PubMed
  7. Glia. 2000 May;30(3):253-70 - PubMed
  8. Hepatology. 2010 Mar;51(3):881-90 - PubMed
  9. Oncology. 2010 Jul;78 Suppl 1:172-9 - PubMed
  10. J Invest Dermatol. 2002 Nov;119(5):1121-7 - PubMed
  11. Oncogene. 2004 Apr 22;23(19):3368-75 - PubMed
  12. Mol Biol Cell. 1999 Dec;10(12):4231-46 - PubMed
  13. Arch Surg. 1996 Apr;131(4):360-5 - PubMed
  14. Endocrinology. 2004 Mar;145(3):1211-7 - PubMed
  15. Trends Biochem Sci. 2003 Nov;28(11):573-6 - PubMed
  16. Oncogene. 1999 Apr 15;18(15):2507-17 - PubMed
  17. Circulation. 2001 Jan 30;103(4):555-61 - PubMed
  18. Cancer Res. 2009 May 1;69(9):4018-26 - PubMed
  19. Curr Biol. 2002 Nov 19;12(22):R785-7 - PubMed
  20. Cancer Res. 1997 Jan 1;57(1):141-6 - PubMed
  21. Proc Natl Acad Sci U S A. 1987 Jan;84(1):265-9 - PubMed
  22. Oncogene. 2004 Apr 19;23(18):3172-9 - PubMed
  23. J Exp Med. 2008 Jan 21;205(1):91-103 - PubMed
  24. J Cell Biol. 2004 Nov 8;167(3):399-403 - PubMed
  25. Cancer Res. 1995 Oct 15;55(20):4633-9 - PubMed
  26. Oncogene. 2000 May 15;19(21):2548-56 - PubMed
  27. Hepatology. 2005 Dec;42(6):1329-38 - PubMed
  28. Prostate. 1999 Feb 15;38(3):199-207 - PubMed
  29. Eur J Clin Invest. 1999 Jun;29(6):536-45 - PubMed
  30. Gastroenterology. 2007 Jan;132(1):384-96 - PubMed
  31. Hepatology. 2010 Aug;52(2):480-92 - PubMed
  32. Int J Cancer. 1995 Feb 20;64(1):27-31 - PubMed
  33. Clin Cancer Res. 2003 Oct 15;9(13):4653-65 - PubMed
  34. Oncogene. 2008 Jan 10;27(3):378-86 - PubMed
  35. Science. 1992 Oct 23;258(5082):593-7 - PubMed
  36. Cancer Res. 2004 Feb 15;64(4):1293-8 - PubMed
  37. Cancer Cell. 2011 May 17;19(5):629-39 - PubMed
  38. J Cell Mol Med. 2012 Jan;16(1):160-73 - PubMed
  39. J Gastroenterol Hepatol. 1994 Sep-Oct;9(5):462-7 - PubMed
  40. Eur J Cancer. 2003 Sep;39(14):2093-8 - PubMed
  41. Gastroenterology. 2006 Jul;131(1):179-93 - PubMed
  42. J Clin Invest. 2011 Sep;121(9):3375-83 - PubMed
  43. Am J Pathol. 1999 Jul;155(1):247-55 - PubMed
  44. Carcinogenesis. 2008 Dec;29(12):2279-88 - PubMed
  45. Nat Cell Biol. 2002 Sep;4(9):658-65 - PubMed
  46. Science. 2002 Dec 6;298(5600):1911-2 - PubMed
  47. J Biol Chem. 1997 Sep 26;272(39):24183-90 - PubMed
  48. Clin Cancer Res. 2001 Nov;7(11):3504-9 - PubMed
  49. J Biol Chem. 2003 Dec 26;278(52):52231-9 - PubMed
  50. Cancer Res. 1991 May 15;51(10):2720-6 - PubMed
  51. J Biol Chem. 1996 Mar 15;271(11):5961-4 - PubMed
  52. J Biol Chem. 2003 Feb 14;278(7):5242-9 - PubMed
  53. Oncogene. 2004 Apr 12;23(16):2838-49 - PubMed
  54. Cytokine. 2002 Mar 7;17(5):234-42 - PubMed
  55. Cell. 1999 Aug 6;98(3):295-303 - PubMed
  56. Ann Surg. 2002 May;235(5):732-8; discussion 738-9 - PubMed
  57. Nat Rev Cancer. 2004 Aug;4(8):579-91 - PubMed
  58. Prostate. 1999 Oct 1;41(2):127-33 - PubMed
  59. J Biol Chem. 2000 Jul 14;275(28):21525-31 - PubMed
  60. Oncogene. 2002 Mar 27;21(13):2000-8 - PubMed
  61. Curr Opin Cell Biol. 1998 Apr;10(2):268-75 - PubMed
  62. J Biol Chem. 2002 May 3;277(18):15712-20 - PubMed
  63. Life Sci. 2006 Apr 18;78(21):2494-502 - PubMed
  64. Oncogene. 2001 Sep 20;20(42):5991-6000 - PubMed
  65. J Biol Chem. 1999 Aug 13;274(33):23013-9 - PubMed
  66. Genes Dev. 2011 Mar 15;25(6):634-45 - PubMed
  67. Mol Cell Biol. 1998 Jul;18(7):4109-17 - PubMed
  68. Gastroenterology. 1992 Jul;103(1):264-74 - PubMed
  69. Ann Hum Genet. 2003 Jan;67(Pt 1):87-96 - PubMed
  70. Eur J Cancer. 1996 Jun;32A(6):1082-8 - PubMed
  71. FEBS Lett. 1989 Jul 3;250(2):607-10 - PubMed
  72. Cancer Biol Ther. 2002 Nov-Dec;1(6):599-606 - PubMed
  73. Cancer Res. 2006 Nov 1;66(21):10517-24 - PubMed
  74. Cancer Res. 2002 Jun 1;62(11):3257-63 - PubMed
  75. Oncogene. 2004 Apr 29;23(20):3530-40 - PubMed
  76. Cancer Res. 2000 Dec 1;60(23):6763-70 - PubMed
  77. Eur J Cancer. 1996 Jun;32A(6):912-20 - PubMed
  78. Prostate. 2004 Jul 1;60(2):120-9 - PubMed
  79. Oncogene. 2003 Mar 13;22(10):1517-27 - PubMed
  80. Biochem J. 1998 Sep 1;334 ( Pt 2):297-314 - PubMed
  81. Nature. 2009 Jan 8;457(7226):200-4 - PubMed
  82. Int J Cancer. 2009 Jun 15;124(12):2766-70 - PubMed
  83. Lancet. 2001 Feb 17;357(9255):539-45 - PubMed
  84. Int J Cancer. 2009 Nov 15;125(10):2264-9 - PubMed
  85. Blood Cells Mol Dis. 2001 Sep-Oct;27(5):825-9 - PubMed
  86. J Intern Med. 2000 Sep;248(3):171-83 - PubMed
  87. Cell Res. 2011 Jan;21(1):159-68 - PubMed
  88. Biochem Soc Symp. 1999;64:1-12 - PubMed
  89. J Clin Oncol. 1999 Sep;17(9):2909-14 - PubMed
  90. Cell. 2010 Jan 22;140(2):197-208 - PubMed
  91. Mol Cell Biol. 1998 Mar;18(3):1379-87 - PubMed
  92. Nature. 2002 Dec 19-26;420(6917):860-7 - PubMed
  93. J Hepatol. 2006 Jun;44(6):1055-65 - PubMed
  94. Cancer Res. 2006 Apr 1;66(7):3737-46 - PubMed
  95. Nat Cell Biol. 2002 Sep;4(9):648-57 - PubMed
  96. Gastroenterology. 2005 Jun;128(7):2054-65 - PubMed
  97. Hematol Oncol Clin North Am. 1995 Apr;9(2):275-318 - PubMed
  98. Curr Opin Immunol. 2003 Dec;15(6):704-8 - PubMed
  99. Cancer Res. 2001 Dec 15;61(24):8851-8 - PubMed
  100. J Exp Med. 2011 Jul 4;208(7):1359-66 - PubMed
  101. Genes Dev. 2003 Aug 1;17(15):1829-34 - PubMed
  102. Am J Pathol. 2003 Sep;163(3):1101-7 - PubMed
  103. Trends Mol Med. 2004 Mar;10(3):125-9 - PubMed
  104. Hepatology. 2001 Jan;33(1):43-51 - PubMed
  105. Mol Med. 2008 Jul-Aug;14(7-8):485-92 - PubMed
  106. Hepatogastroenterology. 2004 Jan-Feb;51(55):15-9 - PubMed
  107. Neoplasma. 2004;51(3):181-7 - PubMed
  108. Ann Surg. 1998 Mar;227(3):398-404 - PubMed
  109. Am J Physiol Gastrointest Liver Physiol. 2003 Jun;284(6):G924-32 - PubMed
  110. Nat Rev Genet. 2009 Oct;10(10):704-14 - PubMed
  111. Int J Biochem Cell Biol. 1999 Jan;31(1):59-72 - PubMed
  112. Int J Cancer. 1996 Mar 15;65(6):858-63 - PubMed
  113. Cytokine. 2002 Nov 7;20(3):113-20 - PubMed
  114. Annu Rev Immunol. 2002;20:55-72 - PubMed
  115. N Engl J Med. 2003 Apr 24;348(17):1625-38 - PubMed
  116. Cell. 2000 Oct 13;103(2):239-52 - PubMed
  117. J Gastroenterol Hepatol. 2007 Jun;22 Suppl 1:S108-11 - PubMed
  118. N Engl J Med. 1999 Oct 28;341(18):1368-78 - PubMed
  119. Annu Rev Biochem. 1987;56:779-827 - PubMed
  120. Am J Gastroenterol. 2007 Oct;102(10):2164-70 - PubMed
  121. Cell. 2010 Mar 19;140(6):883-99 - PubMed
  122. OMICS. 2011 Mar;15(3):183-6 - PubMed
  123. Hepatology. 1999 Nov;30(5):1128-33 - PubMed
  124. Cancer Res. 1998 Jan 15;58(2):256-62 - PubMed
  125. J Natl Cancer Inst. 1989 Jun 7;81(11):844-9 - PubMed
  126. Hepatology. 2003 Jul;38(1):158-66 - PubMed
  127. Science. 2003 Mar 21;299(5614):1859-63 - PubMed
  128. Science. 2007 Jul 6;317(5834):121-4 - PubMed
  129. Bull Cancer. 1996 May;83(5):379-84 - PubMed
  130. J Clin Endocrinol Metab. 2000 Sep;85(9):3338-42 - PubMed
  131. Am J Physiol Cell Physiol. 2005 Oct;289(4):C971-81 - PubMed
  132. Oncogene. 2002 Feb 21;21(9):1391-400 - PubMed

Publication Types

Grant support