Skip to main content

Advertisement

SpringerLink
Log in

APOBEC3B and IL-6 form a positive feedback loop in hepatocellular carcinoma cells

  • Research Paper
  • Published:
Science China Life Sciences Aims and scope Submit manuscript

Abstract

APOBEC3 protein families, a DNA cytidine deaminase, were up-regulated in multiple tumors. However, the relationship between Hepatocellular carcinoma (HCC) and APOBEC3B (A3B) remains unknown. It has been confirmed that interleukin-6 (IL-6) has significant impacts on oncogenesis of HCC. Here, we reported that the expression of IL-6 was substantially up-regulated by A3B in HepG2 cells. A3B induced IL-6 expression through relocating HuR to enhance the IL-6 mRNA stability. Further analysis indicated that IL-6 also increased the expression of A3B through JAK1/STAT3 signaling pathway, which formed a positive feedback to maintain the continuous expression of A3B and IL-6, and thereby promoted the prolonged non-resolving inflammation. Collectively, these findings suggest that A3B is essential for oncogenesis of HCC, and is a potential target for preventive intervention.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Beck, B., and Blanpain, C. (2013). Unravelling cancer stem cell potential. Nat Rev Cancer 13, 727–738.

    Article  CAS  PubMed  Google Scholar 

  • Bishop, K.N., Holmes, R.K., Sheehy, A.M., Davidson, N.O., Cho, S.J., and Malim, M.H. (2004). Cytidine deamination of retroviral DNA by diverse APOBEC proteins. Curr Biol 14, 1392–1396.

    Article  CAS  PubMed  Google Scholar 

  • Bonvin, M., Achermann, F., Greeve, I., Stroka, D., Keogh, A., Inderbitzin, D., Candinas, D., Sommer, P., Wain-Hobson, S., Vartanian, J.P., and Greeve, J. (2006). Interferon-inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication. Hepatology 43, 1364–1374.

    Article  CAS  PubMed  Google Scholar 

  • Burns, M.B., Lackey, L., Carpenter, M.A., Rathore, A., Land, A.M., Leonard, B., Refsland, E.W., Kotandeniya, D., Tretyakova, N., Nikas, J.B., Yee, D., Temiz, N.A., Donohue, D.E., McDougle, R.M., Brown, W.L., Law, E.K., and Harris, R.S. (2013a). APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 494, 366–370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burns, M.B., Temiz, N.A., and Harris, R.S. (2013b). Evidence for APOBEC3B mutagenesis in multiple human cancers. Nat Genet 45, 977–983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang, P.E., Ong, W.C., Lui, H.F., and Tan, C.K. (2013). Epidemiology and prognosis of paraneoplastic syndromes in hepatocellular carcinoma. ISRN Oncol 2013, 684026.

    PubMed  PubMed Central  Google Scholar 

  • Chisari, F.V., Klopchin, K., Moriyama, T., Pasquinelli, C., Dunsford, H.A., Sell, S., Pinkert, C.A., Brinster, R.L., and Palmiter, R.D. (1989). Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell 59, 1145–1156.

    Article  CAS  PubMed  Google Scholar 

  • Dubois-Pot-Schneider, H., Fekir, K., Coulouarn, C., Glaise, D., Aninat, C., Jarnouen, K., Le Guével, R., Kubo, T., Ishida, S., Morel, F., and Corlu, A. (2014). Inflammatory cytokines promote the retrodifferentiation of tumor-derived hepatocyte-like cells to progenitor cells. Hepatology 60, 2077–2090.

    Article  CAS  PubMed  Google Scholar 

  • Edwards, B.K., Noone, A.M., Mariotto, A.B., Simard, E.P., Boscoe, F.P., Henley, S.J., Jemal, A., Cho, H., Anderson, R.N., Kohler, B.A., Eheman, C.R., and Ward, E.M. (2014). Annual Report to the Nation on the status of cancer, 1975-2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer. Cancer 120, 1290–1314.

    Article  PubMed  Google Scholar 

  • He, G., Dhar, D., Nakagawa, H., Font-Burgada, J., Ogata, H., Jiang, Y., Shalapour, S., Seki, E., Yost, S.E., Jepsen, K., Frazer, K.A., Harismendy, O., Hatziapostolou, M., Iliopoulos, D., Suetsugu, A., Hoffman, R.M., Tateishi, R., Koike, K., and Karin, M. (2013). Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 155, 384–396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He, G., Yu, G.Y., Temkin, V., Ogata, H., Kuntzen, C., Sakurai, T., Sieghart, W., Peck-Radosavljevic, M., Leffert, H.L., and Karin, M. (2010). Hepatocyte IKKß/NF-?B inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 17, 286–297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Henderson, S., Chakravarthy, A., Su, X., Boshoff, C., and Fenton, T.R. (2014). APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumor development. Cell Rep 7, 1833–1841.

    Article  CAS  PubMed  Google Scholar 

  • Hunter, C.A., and Jones, S.A. (2015). IL-6 as a keystone cytokine in health and disease. Nat Immunol 16, 448–457.

    Article  CAS  PubMed  Google Scholar 

  • Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E., and Forman, D. (2011). Global cancer statistics. CA Cancer J Clin 61, 69–90.

    Article  PubMed  Google Scholar 

  • Johnson, C., Han, Y., Hughart, N., McCarra, J., Alpini, G., and Meng, F. (2012). Interleukin-6 and its receptor, key players in hepatobiliary inflammation and cancer. Transl Gastrointest Cancer 1, 58–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Köck, J., and Blum, H.E. (2008). Hypermutation of hepatitis B virus genomes by APOBEC3G, APOBEC3C and APOBEC3H. J General Virology 89, 1184–1191.

    Article  Google Scholar 

  • Koning, F.A., Newman, E.N.C., Kim, E.Y., Kunstman, K.J., Wolinsky, S.M., and Malim, M.H. (2009). Defining APOBEC3 expression patterns in human tissues and hematopoietic cell subsets. J Virology 83, 9474–9485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lackey, L., Demorest, Z.L., Land, A.M., Hultquist, J.F., Brown, W.L., and Harris, R.S. (2012). APOBEC3B and AID have similar nuclear import mechanisms. J Mol Biol 419, 301–314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leonard, B., Hart, S.N., Burns, M.B., Carpenter, M.A., Temiz, N.A., Rathore, A., Vogel, R.I., Nikas, J.B., Law, E.K., Brown, W.L., Li, Y., Zhang, Y., Maurer, M.J., Oberg, A.L., Cunningham, J.M., Shridhar, V., Bell, D.A., April, C., Bentley, D., Bibikova, M., Cheetham, R.K., Fan, J.B., Grocock, R., Humphray, S., Kingsbury, Z., Peden, J., Chien, J., Swisher, E.M., Hartmann, L.C., Kalli, K.R., Goode, E.L., Sicotte, H., Kaufmann, S.H., and Harris, R.S. (2013). APOBEC3B upregulation and genomic mutation patterns in serous ovarian carcinoma. Cancer Res 73, 7222–7231.

    Article  CAS  PubMed  Google Scholar 

  • Liu, F., Zhang, W., Yang, F., Feng, T., Zhou, M., Yu, Y., Yu, X., Zhao, W., Yi, F., Tang, W., and Lu, Y. (2016). Interleukin-6-stimulated progranulin expression contributes to the malignancy of hepatocellular carcinoma cells by activating mTOR signaling. Sci Rep 6, 21260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mantovani, A., Allavena, P., Sica, A., and Balkwill, F. (2008). Cancer-related inflammation. Nature 454, 436–444.

    Article  CAS  PubMed  Google Scholar 

  • Mantovani, A., Garlanda, C., and Allavena, P. (2010). Molecular pathways and targets in cancer-related inflammation. Ann Med 42, 161–170.

    Article  CAS  PubMed  Google Scholar 

  • McMullen, M.R., Cocuzzi, E., Hatzoglou, M., and Nagy, L.E. (2003). Chronic ethanol exposure increases the binding of HuR to the TNFa 3’-untranslated region in macrophages. J Biol Chem 278, 38333–38341.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mehta, H.V., Jones, P.H., Weiss, J.P., and Okeoma, C.M. (2012). IFN-a and lipopolysaccharide upregulate APOBEC3 mRNA through different signaling pathways. J Immunol 189, 4088–4103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nathan, C., and Ding, A. (2010). Nonresolving inflammation. Cell 140, 871–882.

    Article  CAS  PubMed  Google Scholar 

  • Okeoma, C.M., Huegel, A.L., Lingappa, J., Feldman, M.D., and Ross, S.R. (2010). APOBEC3 proteins expressed in mammary epithelial cells are packaged into retroviruses and can restrict transmission of milk-borne virions. Cell Host Microbe 8, 534–543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okeoma, C.M., Lovsin, N., Peterlin, B.M., and Ross, S.R. (2007). APOBEC3 inhibits mouse mammary tumour virus replication in vivo. Nature 445, 927–930.

    Article  CAS  PubMed  Google Scholar 

  • Peng, G., Lei, K.J., Jin, W., Greenwell-Wild, T., and Wahl, S.M. (2006). Induction of APOBEC3 family proteins, a defensive maneuver underlying interferon-induced anti–HIV-1 activity. J Exp Med 203, 41–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shinohara, M., Io, K., Shindo, K., Matsui, M., Sakamoto, T., Tada, K., Kobayashi, M., Kadowaki, N., and Takaori-Kondo, A. (2012). APOBEC3B can impair genomic stability by inducing base substitutions in genomic DNA in human cells. Sci Rep 2, 806.

    Article  PubMed  PubMed Central  Google Scholar 

  • Suzuki, E., Tsutsumi, A., Sugihara, M., Mamura, M., Goto, D., Matsumoto, I., Ito, S., Ikeda, K., Ochiai, N., Sato, Y., and Sumida, T. (2006). Expression of TNF-alpha, tristetraprolin, T-cell intracellular antigen-1 and Hu antigen R genes in synovium of patients with rheumatoid arthritis. Int J Mol Med 18, 273–278.

    CAS  PubMed  Google Scholar 

  • Tanaka, Y., Marusawa, H., Seno, H., Matsumoto, Y., Ueda, Y., Kodama, Y., Endo, Y., Yamauchi, J., Matsumoto, T., Takaori-Kondo, A., Ikai, I., and Chiba, T. (2006). Anti-viral protein APOBEC3G is induced by interferon-a stimulation in human hepatocytes. Biochem Biophysical Res Commun 341, 314–319.

    Article  CAS  Google Scholar 

  • Turelli, P., Liagre-Quazzola, A., Mangeat, B., Verp, S., Jost, S., and Trono, D. (2008). APOBEC3-independent interferon-induced viral clearance in hepatitis B virus transgenic mice. J Virology 82, 6585–6590.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vartanian, J.P., Henry, M., Marchio, A., Suspène, R., Aynaud, M.M., Gué tard, D., Cervantes-Gonzalez, M., Battiston, C., Mazzaferro, V., Pineau, P., Dejean, A., and Wain-Hobson, S. (2010). Massive APOBEC3 editing of hepatitis B viral DNA in cirrhosis. PLoS Pathog 6, e1000928.

    Article  Google Scholar 

  • Wan, S., Zhao, E., Kryczek, I., Vatan, L., Sadovskaya, A., Ludema, G., Simeone, D.M., Zou, W., and Welling, T.H. (2014). Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147, 1393–1404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, H., Su, X., Yang, M., Chen, T., Hou, J., Li, N., and Cao, X. (2015). Reciprocal control of miR-197 and IL-6/STAT3 pathway reveals miR-197 as potential therapeutic target for hepatocellular carcinoma. OncoImmunology 4, e1031440.

    Article  Google Scholar 

  • Wang, W., Caldwell, M.C., Lin, S., Furneaux, H., and Gorospe, M. (2000). HuR regulates cyclin A and cyclin B1 mRNA stability during cell proliferation.

  • EMBO J 19, 2340–2350.

  • Williams, G.M., Iatropoulos, M.J., and Jeffrey, A.M. (2000). Mechanistic basis for nonlinearities and thresholds in rat liver carcinogenesis by the DNA-reactive carcinogens 2-acetylaminofluorene and diethylnitrosamine. Toxicologic Pathol 28, 388–395.

    Article  CAS  Google Scholar 

  • Xu, R., Zhang, X., Zhang, W., Fang, Y., Zheng, S., and Yu, X.F. (2007). Association of human APOBEC3 cytidine deaminases with the generation of hepatitis virus B x antigen mutants and hepatocellular carcinoma. Hepatology 46, 1810–1820.

    Article  CAS  PubMed  Google Scholar 

  • Yang, X., Wang, W., Fan, J., Lal, A., Yang, D., Cheng, H., and Gorospe, M. (2004). Prostaglandin A2-mediated Stabilization of p21 mRNA through an ERK-dependent Pathway Requiring the RNA-binding Protein HuR. J Biol Chem 279, 49298–49306.

    Article  CAS  PubMed  Google Scholar 

  • Ying, S., Zhang, X., Sarkis, P.T.N., Xu, R., and Yu, X. (2007). Cell-specific regulation of APOBEC3F by interferons. Acta Biochim Biophys Sin 39, 297–304.

    Article  CAS  PubMed  Google Scholar 

  • Zhou, H., Jarujaron, S., Gurley, E.C., Chen, L., Ding, H., Studer, E., Pandak Jr., W.M., Hu, W., Zou, T., Wang, J.Y., and Hylemon, P.B. (2007). HIV protease inhibitors increase TNF-α and IL-6 expression in macrophages: Involvement of the RNA-binding protein HuR. Atherosclerosis 195, e134–e143

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the National Natural Science Foundation of China (91529304, 81502407, 81473230, 81273547, 81403020 and 91129731), the Jiangsu Province Natural Science Foundation of China (BK2014666), and the Central College Fund (ZJ14020).

Author information

Author notes

  1. Contributed equally to this work

Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, 211198, China

    Shuran Li, Xueyang Bao, Duowei Wang, Linjun You, Xianjing Li, Hongbao Yang, Yun Wang & Yong Yang

  2. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore

    Jinsong Bian

Authors
  1. Shuran Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xueyang Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Duowei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Linjun You
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xianjing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hongbao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jinsong Bian
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yun Wang or Yong Yang.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, S., Bao, X., Wang, D. et al. APOBEC3B and IL-6 form a positive feedback loop in hepatocellular carcinoma cells. Sci. China Life Sci. 60, 617–626 (2017). https://doi.org/10.1007/s11427-016-9058-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11427-016-9058-6

Keywords

Search

Navigation