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Increased adiponectin associated with poor survival in hepatocellular carcinoma

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

Alterations of adiponectin (APN), one of the adipokines, have been associated with human cancers. However, the clinical significance and impacts of APN on hepatocellular carcinoma (HCC) remain undetermined.

Methods

Using immunohistochemistry, expression patterns of APN were semiquantitatively scored and further statistically correlated with clinicopathological characteristics and patient survival. Furthermore, the bioeffects and underlying mechanisms of ectopic APN overexpression were determined in Hep3B and HepG2 cells by XTT, immunoblotting, flowcytometry, and invasion assays with or without chemical inhibitors and neutralization antibody.

Results

We found that cytoplasmic APN staining in 85 cancerous lesions was increased and associated with a poor survival rate (P = 0.007), even when using the Cox regression model (OR = 3.590; 95 % CI = 1.240–10.394; P = 0.018). Ectopic overexpression of APN in Hep3B and HepG2 cells increased proliferation and invasion as well as the levels of p-AKT (Ser473), p-STAT3 (Tyr705), and those downstream, i.e., cyclin D1 and β-catenin. Similar results were also demonstrated in a stable APN-overexpressing clone, HepG2#136. APN neutralization antibody and LY294002 blocked the APN-mediated effects via inhibition of activated AKT.

Conclusions

Our results suggest that increased APN may contribute to HCC at least in part through its activation of AKT signalling and may serve as a prognostic factor in HCC.

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References

  1. Gil-Campos M, Canete RR, Gil A. Adiponectin, the missing link in insulin resistance and obesity. Clin Nutr. 2004;23(5):963–74.

    Article  CAS  PubMed  Google Scholar 

  2. Anania FA. Adiponectin and alcoholic fatty liver: is it, after all, about what you eat? Hepatology. 2005;42(3):530–2.

    Article  PubMed  Google Scholar 

  3. Neumeier M, Weigert J, Schcaffler A, Wehrwein G, Muller-Ladner U, Scholmerich J, et al. Different effects of adiponectin isoforms in human monocytic cells. J Leukoc Biol. 2006;79(4):803–8.

    Article  CAS  PubMed  Google Scholar 

  4. Haugen F, Drevon CA. Activation of nuclear factor-kappaB by high molecular weight and globular adiponectin. Endocrinology. 2007;148(11):5478–86.

    Article  CAS  PubMed  Google Scholar 

  5. Otero M, Lago R, Gomez R, Lago F, Dieguez C, Gomez-Reino JJ, et al. Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65(9):1198–201.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Haugen F, Ranheim T, Harsem NK, Lips E, Staff AC, Drevon CA. Increased plasma levels of adipokines in preeclampsia: relationship to placenta and adipose tissue gene expression. Am J Physiol Endocrinol Metab. 2006;290(2):E326–33.

    Article  CAS  PubMed  Google Scholar 

  7. Zoccali C, Mallamaci F, Tripepi G, Benedetto FA, Cutrupi S, Parlongo S, et al. Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease. J Am Soc Nephrol. 2002;13(1):134–41.

    CAS  PubMed  Google Scholar 

  8. Liu CJ, Chen PJ, Lai MY, Liu CH, Chen CL, Kao JH, et al. High serum adiponectin correlates with advanced liver disease in patients with chronic hepatitis B virus infection. Hep Intl. 2009;3(2):364–70.

    Article  Google Scholar 

  9. Arano T, Nakagawa H, Tateishi R, Ikeda H, Uchino K, Enooku K, et al. Serum level of adiponectin and the risk of liver cancer development in chronic hepatitis C patients. Int J Cancer. 2011;129(9):2226–35.

    Article  CAS  PubMed  Google Scholar 

  10. Chen MJ, Yeh YT, Lee KT, Tsai CJ, Lee HH, Wang SN. The promoting effect of adiponectin in hepatocellular carcinoma. J Surg Oncol. 2012;106(2):181–7.

    Article  CAS  PubMed  Google Scholar 

  11. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 2003;423(6941):762–9.

    Article  CAS  PubMed  Google Scholar 

  12. Ouchi N, Kobayashi H, Kihara S, Kumada M, Sato K, Inoue T, et al. Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells. J Biol Chem. 2004;279(2):1304–9.

    Article  CAS  PubMed  Google Scholar 

  13. Ogunwobi OO, Beales IL. Adiponectin stimulates proliferation and cytokine secretion in colonic epithelial cells. Regul Pept. 2006;134(2–3):105–13.

    Article  CAS  PubMed  Google Scholar 

  14. Barb D, Neuwirth A, Mantzoros CS, Balk SP. Adiponectin signals in prostate cancer cells through Akt to activate the mammalian target of rapamycin pathway. Endocr Relat Cancer. 2007;14(4):995–1005.

    Article  CAS  PubMed  Google Scholar 

  15. The general rules for the clinical and pathological study of primary liver cancer. Liver Cancer Study Group of Japan. Jpn J Surg. 1989; 19(1):98–129.

    Google Scholar 

  16. Yang SF, Wang SN, Wu CF, Yeh YT, Chai CY, Chunag SC, et al. Altered p-STAT3 (tyr705) expression is associated with histological grading and intratumour microvessel density in hepatocellular carcinoma. J Clin Pathol. 2007;60(6):642–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Wang SN, Yeh YT, Yang SF, Chai CY, Lee KT. Potential role of leptin expression in hepatocellular carcinoma. J Clin Pathol. 2006;59(9):930–4.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Yuan SS, Cox LA, Dasika GK, Lee EY. Cloning and functional studies of a novel gene aberrantly expressed in RB-deficient embryos. Dev Biol. 1999;207(1):62–75.

    Article  CAS  PubMed  Google Scholar 

  19. Chang HL, Su JH, Yeh YT, Lee YC, Chen HM, Wu YC, et al. Protoapigenone, a novel flavonoid, inhibits ovarian cancer cell growth in vitro and in vivo. Cancer Lett. 2008;267(1):85–95.

    Article  CAS  PubMed  Google Scholar 

  20. Lin SY, Liu JD, Chang HC, Yeh SD, Lin CH, Lee WS. Magnolol suppresses proliferation of cultured human colon and liver cancer cells by inhibiting DNA synthesis and activating apoptosis. J Cell Biochem. 2002;84(3):532–44.

    Article  PubMed  Google Scholar 

  21. Yang L, Chan CC, Kwon OS, Liu S, McGhee J, Stimpson SA, et al. Regulation of peroxisome proliferator-activated receptor-gamma in liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2006;291(5):G902–11.

    Article  CAS  PubMed  Google Scholar 

  22. Bogan JS, Lodish HF. Two compartments for insulin-stimulated exocytosis in 3T3-L1 adipocytes defined by endogenous ACRP30 and GLUT4. J Cell Biol. 1999;146(3):609–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Wang SN, Yeh YT, Yu ML, Wang CL, Lee KT. Serum adiponectin levels in cholesterol and pigment cholelithiasis. Br J Surg. 2006;93(8):981–6.

    Article  CAS  PubMed  Google Scholar 

  24. Yeh YT, Ou-Yang F, Chen IF, Yang SF, Su JH, Hou MF, et al. Altered p-JAK1 expression is associated with estrogen receptor status in breast infiltrating ductal carcinoma. Oncol Rep. 2007;17(1):35–9.

    CAS  PubMed  Google Scholar 

  25. Yang SF, Wang SN, Wu CF, Yeh YT, Chai CY, Chunag SC, et al. Altered p-STAT3 (tyr705) expression is associated with histological grading and intratumour microvessel density in hepatocellular carcinoma. J Clin Pathol. 2007;60(6):642–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. El-Serag HB, Rudolph L. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557–76.

    Article  CAS  PubMed  Google Scholar 

  27. Sumie S, Kawaguchi T, Kuromatsu R, Takata A, Nakano M, Satani M, et al. Total and high molecular weight adiponectin and hepatocellular carcinoma with HCV infection. PLoS One. 2011;6(11):e26840.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Saxena NK, Fu PP, Nagalingam A, Wang J, Handy J, Cohen C et al. Adiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinoma. Gastroenterology. 2010; 139(5):1762–73, 1773 e1–5.

    Google Scholar 

  29. Sharma D, Wang J, Fu PP, Sharma S, Nagalingam A, Mells J, et al. Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis. Hepatology. 2010;52(5):1713–22.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Ogunwobi OO, Beales ILP. Adiponectin stimulates proliferation and cytokine secretion in colonic epithelial cells. Regul Pept. 2006;134(2–3):105–13.

    Article  CAS  PubMed  Google Scholar 

  31. Perez-Tenorio G, Stal O, Group SSBC. Activation of AKT/PKB in breast cancer predicts a worse outcome among endocrine treated patients. Br J Cancer. 2002;86(4):540–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Yamamoto S, Tomita Y, Hoshida Y, Morooka T, Nagano H, Dono K, et al. Prognostic significance of activated Akt expression in pancreatic ductal adenocarcinoma. Clin Cancer Res. 2004;10(8):2846–50.

    Article  CAS  PubMed  Google Scholar 

  33. Schmitz KJ, Wohlschlaeger J, Lang H, Sotiropoulos GC, Malago M, Steveling K, et al. Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. J Hepatol. 2008;48(1):83–90.

    Article  CAS  PubMed  Google Scholar 

  34. He XC, Yin T, Grindley JC, Tian Q, Sato T, Tao WA, et al. PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nat Genet. 2007;39(2):189–98.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study is supported by NSC grants (NSC 97-2320-B-242-001-MY3 to YT Yeh and NSC 99-2314-B-037 -030 -MY2 to SN Wang) and the Department of Health, Executive Yuan, ROC (TAIWAN) grant (DOH100-TD-C-111-002 to MF Hou).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, No. 100, Ziyou 1st Rd., Sanmin Dist., Kaohsiung, 80756, Taiwan, ROC

    Shen-Nien Wang & King-Teh Lee

  2. College of Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, No. 100, Shiquan 1st Rd., Sanmin Dist., Kaohsiung, 80708, Taiwan, ROC

    Shen-Nien Wang & Hsin-Hui Tsai

  3. Department of Pathology, Kaohsiung Municipal Ta-Tung Hospital, No. 68, Zhonghua 3rd Rd., Qianjin Dist., Kaohsiung, 80145, Taiwan, ROC

    Sheau-Fang Yang

  4. Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, No. 151, Jinxue Rd., Daliao Dist., Kaohsiung, 83102, Taiwan, ROC

    Hsin-Hui Tsai & Yao-Tsung Yeh

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  1. Shen-Nien Wang
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  2. Sheau-Fang Yang
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Correspondence to Yao-Tsung Yeh.

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Wang, SN., Yang, SF., Tsai, HH. et al. Increased adiponectin associated with poor survival in hepatocellular carcinoma. J Gastroenterol 49, 1342–1351 (2014). https://doi.org/10.1007/s00535-013-0898-7

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  • DOI: https://doi.org/10.1007/s00535-013-0898-7

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