Skip to main content

Clinical significance of autophagic protein LC3 levels and its correlation with XIAP expression in hepatocellular carcinoma

Medical Oncology volume 31, Article number: 108 (2014) Cite this article

Abstract

Autophagy is a cellular recycling process to enable cell survival in less favorable conditions through degradation of their unnecessary cellular components and utilization of the breakdown components. Autophagy also plays an important role in tumor pathology. In this study, we detected autophagy protein light chain 3 (LC3) and X-linked inhibitor of apoptosis protein (XIAP) in hepatocellular carcinoma (HCC) tissue specimens to assess their role in HCC tumorigenesis and progression. We analyzed expression of LC3, XIAP, and Ki-67 proteins immunohistochemically in surgical specimen of 150 HCC and 136 nontumor hepatic tissues. The levels of LC3 and XIAP proteins were compared between tumor and nontumoral parenchyme. The data showed that LC3 expression was increased in HCC compared with nontumoral parenchyma. LC3 expression was significantly associated with male gender, large tumor size, advanced tumor stages, and worse relapse-free and overall survival (OS). In contrast, XIAP expression was associated with small tumor size, early tumor stage, and better relapse-free and OS. In contrast, XIAP expression was associated with small tumor size, early tumor stage, and better relapse-free and OS. Furthermore, expression of LC3 and XIAP was inversely associated in HCC tissue specimens. In conclusion, increase in autophagic LC3 activity and low XIAP expression could be useful to predict the worse HCC prognosis.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol. 2013;47(Suppl):S2–6.

    PubMed Central  PubMed  Article  Google Scholar 

  2. Jemal A, Simard EP, Dorell C, Noone AM, Markowitz LE, Kohler B, et al. Annual Report to the Nation on the Status of Cancer, 1975-2009, featuring the burden and trends in human papillomavirus(HPV)-associated cancers and HPV vaccination coverage levels. J Natl Cancer Inst. 2013;105:175–201.

    PubMed Central  PubMed  Article  Google Scholar 

  3. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    PubMed  Article  Google Scholar 

  4. Gluer AM, Cocco N, Laurence JM, Johnston ES, Hollands MJ, Pleass HC, et al. Systematic review of actual 10-year survival following resection for hepatocellular carcinoma. HPB (Oxford). 2012;14:285–90.

    Article  Google Scholar 

  5. De Duve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol. 1966;28:435–92.

    PubMed  Article  Google Scholar 

  6. Weidberg H, Shvets E, Elazar Z. Biogenesis and cargo selectivity of autophagosomes. Annu Rev Biochem. 2011;80:125–56.

    CAS  PubMed  Article  Google Scholar 

  7. Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer. 2007;7:961–7.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  8. Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402:672–6.

    CAS  PubMed  Article  Google Scholar 

  9. Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147:728–41.

    CAS  PubMed  Article  Google Scholar 

  10. Martinet W, De Meyer GR, Andries L, Herman AG, Kockx MM. In situ detection of starvation-induced autophagy. J Histochem Cytochem. 2006;54:85–96.

    CAS  PubMed  Article  Google Scholar 

  11. Yoshimori T. Autophagy: a regulated bulk degradation process inside cells. Biochem Biophys Res Commun. 2004;313:453–8.

    CAS  PubMed  Article  Google Scholar 

  12. Miller LK. An exegesis of IAPs: salvation and surprises from BIR motifs. Trends Cell Biol. 1999;9:323–8.

    CAS  PubMed  Article  Google Scholar 

  13. Salvesen GS, Duckett CS. IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol. 2002;3:401–10.

    CAS  PubMed  Article  Google Scholar 

  14. Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature. 1997;388:300–4.

    CAS  PubMed  Article  Google Scholar 

  15. Eckelman BP, Salvesen GS, Scott FL. Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep. 2006;7:988–94.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  16. Shaw TJ, Lacasse EC, Durkin JP, Vanderhyden BC. Downregulation of XIAP expression in ovarian cancer cells induces cell death in vitro and in vivo. Int J Cancer. 2008;122:1430–4.

    CAS  PubMed  Article  Google Scholar 

  17. Dai Y, Qiao L, Chan KW, Zou B, Ma J, Lan HY, et al. Loss of XIAP sensitizes rosiglitazone-induced growth inhibition of colon cancer in vivo. Int J Cancer. 2008;122:2858–63.

    CAS  PubMed  Article  Google Scholar 

  18. Zhang S, Ding F, Luo A, Chen A, Yu Z, Ren S, et al. XIAP is highly expressed in esophageal cancer and its downregulation by RNAi sensitizes esophageal carcinoma cell lines to chemotherapeutics. Cancer Biol Ther. 2007;6:973–80.

    CAS  PubMed  Google Scholar 

  19. Mizutani Y, Nakanishi H, Li YN, Matsubara H, Yamamoto K, Sato N, et al. Overexpression of XIAP expression in renal cell carcinoma predicts a worse prognosis. Int J Oncol. 2007;30:919–25.

    CAS  PubMed  Google Scholar 

  20. Giagkousiklidis S, Vellanki SH, Debatin KM, Fulda S. Sensitization of pancreatic carcinoma cells for gamma-irradiation-induced apoptosis by XIAP inhibition. Oncogene. 2007;26:7006–16.

    CAS  PubMed  Article  Google Scholar 

  21. Huang X, Wu Z, Mei Y, Wu M. XIAP inhibits autophagy via XIAP-Mdm2-p53 signalling. EMBO J. 2013;32:2204–16.

    CAS  PubMed  Article  Google Scholar 

  22. Edge SB. American Joint Committee on Cancer. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.

    Google Scholar 

  23. Edmondson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer. 1954;7:462–503.

    CAS  PubMed  Article  Google Scholar 

  24. Yang XH, Feng ZE, Yan M, Hanada S, Zuo H, Yang CZ, et al. XIAP is a predictor of cisplatin-based chemotherapy response and prognosis for patients with advanced head and neck cancer. PLoS One. 2012;7:e31601.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  25. Sivridis E, Koukourakis MI, Zois CE, Ledaki I, Ferguson DJ, Harris AL, et al. LC3A-positive light microscopy detected patterns of autophagy and prognosis in operable breast carcinomas. Am J Pathol. 2010;176:2477–89.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  26. Ogier-Denis E, Codogno P. Autophagy: a barrier or an adaptive response to cancer. Biochim Biophys Acta. 2003;1603:113–28.

    CAS  PubMed  Google Scholar 

  27. Spowart JE, Townsend KN, Huwait H, Eshragh S, West NR, Ries JN, et al. The autophagy protein lc3a correlates with hypoxia and is a prognostic marker of patient survival in clear cell ovarian cancer. J Pathol. 2012;228(4):437–47.

    CAS  Google Scholar 

  28. Karpathiou G, Sivridis E, Koukourakis MI, Mikroulis D, Bouros D, Froudarakis ME, et al. Light-chain 3A autophagic activity and prognostic significance in non-small cell lung carcinomas. Chest. 2011;140:127–34.

    PubMed  Article  Google Scholar 

  29. Notte A, Leclere L, Michiels C. Autophagy as a mediator of chemotherapy-induced cell death in cancer. Biochem Pharmacol. 2011;82:427–34.

    CAS  PubMed  Article  Google Scholar 

  30. Levine B. Cell biology: autophagy and cancer. Nature. 2007;446:745–7.

    CAS  PubMed  Article  Google Scholar 

  31. Hu F, Han J, Zhai B, Ming X, Zhuang L, Liu Y, et al. Blocking autophagy enhances the apoptosis effect of bufalin on human hepatocellular carcinoma cells through endoplasmic reticulum stress and JNK activation. Apoptosis. 2014;19:210–23.

    CAS  PubMed  Article  Google Scholar 

  32. Song J, Guo X, Xie X, Zhao X, Li D, Deng W, et al. Autophagy in hypoxia protects cancer cells against apoptosis induced by nutrient deprivation through a Beclin1-dependent way in hepatocellular carcinoma. J Cell Biochem. 2011;112:3406–20.

    CAS  PubMed  Article  Google Scholar 

  33. Xi SY, Lu JB, Chen JW, Cao Y, Luo RZ, Wu QL, et al. The “stone-like” pattern of LC3A expression and its clinicopathologic significance in hepatocellular carcinoma. Biochem Biophys Res Commun. 2013;431:760–6.

    CAS  PubMed  Article  Google Scholar 

  34. Song YJ, Zhang SS, Guo XL, Sun K, Han ZP, Li R, et al. Autophagy contributes to the survival of CD133 + liver cancer stem cells in the hypoxic and nutrient-deprived tumor microenvironment. Cancer Lett. 2013;339:70–81.

    CAS  PubMed  Article  Google Scholar 

  35. Mah LY, Ryan KM. Autophagy and cancer. Cold Spring Harb Perspect Biol. 2012;4:a008821.

    PubMed Central  PubMed  Article  Google Scholar 

  36. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008;451:1069–75.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  37. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A. 2003;100:15077–82.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  38. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003;112:1809–20.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  39. Wang J, Pan XL, Ding LJ, Liu DY, Da-Peng L, Jin T. Aberrant expression of Beclin-1 and LC3 correlates with poor prognosis of human hypopharyngeal squamous cell carcinoma. PLoS One. 2013;8:e69038.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  40. Tang JY, Hsi E, Huang YC, Hsu NC, Chu PY, Chai CY. High LC3 expression correlates with poor survival in patients with oral squamous cell carcinoma. Hum Pathol. 2013;44:2558–62.

    CAS  PubMed  Article  Google Scholar 

  41. Lee YJ, Ha YJ, Kang YN, Kang KJ, Hwang JS, Chung WJ, et al. The autophagy-related marker LC3 can predict prognosis in human hepatocellular carcinoma. PLoS One. 2013;8:e81540.

    PubMed Central  PubMed  Article  Google Scholar 

  42. Sumalatha KR, Abiramasundari G, Chetan GK, Divya T, Sudhandiran G, Sreepriya M. XIAP inhibitor and antiestrogen embelin abrogates metastasis and augments apoptosis in estrogen receptor positive human breast adenocarcinoma cell line MCF-7. Mol Biol Rep. 2014;41:935–46.

    CAS  PubMed  Article  Google Scholar 

  43. Ren Y, Han X, Yu K, Sun S, Zhen L, Li Z, et al. microRNA-200c downregulates XIAP expression to suppress proliferation and promote apoptosis of triple-negative breast cancer cells. Mol Med Rep. 2014;10:315–21.

    CAS  PubMed  Google Scholar 

  44. Kumar D, Shankar S, Srivastava RK. Rottlerin-induced autophagy leads to the apoptosis in breast cancer stem cells: molecular mechanisms. Mol Cancer. 2013;12:171.

    PubMed Central  PubMed  Article  Google Scholar 

  45. Wang N, Feng Y, Zhu M, Siu FM, Ng KM, Che CM. A novel mechanism of XIAP degradation induced by timosaponin AIII in hepatocellular carcinoma. Biochim Biophys Acta. 2013;1833:2890–9.

    CAS  PubMed  Article  Google Scholar 

  46. Singh BN, Kumar D, Shankar S, Srivastava RK. Rottlerin induces autophagy which leads to apoptotic cell death through inhibition of PI3 K/Akt/mTOR pathway in human pancreatic cancer stem cells. Biochem Pharmacol. 2012;84:1154–63.

    CAS  PubMed  Article  Google Scholar 

  47. Sakemi R, Yano H, Ogasawara S, Akiba J, Nakashima O, Fukahori S, et al. X-linked inhibitor of apoptosis (XIAP) and XIAP-associated factor-1 expressions and their relationship to apoptosis in human hepatocellular carcinoma and non-cancerous liver tissues. Oncol Rep. 2007;18:65–70.

    PubMed  Google Scholar 

  48. Shiraki K, Sugimoto K, Yamanaka Y, Yamaguchi Y, Saitou Y, Ito K, et al. Overexpression of X-linked inhibitor of apoptosis in human hepatocellular carcinoma. Int J Mol Med. 2003;12:705–8.

    CAS  PubMed  Google Scholar 

  49. Shi YH, Ding WX, Zhou J, He JY, Xu Y, Gambotto AA, et al. Expression of X-linked inhibitor-of-apoptosis protein in hepatocellular carcinoma promotes metastasis and tumor recurrence. Hepatology. 2008;48:497–507.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  50. Che Y, Ye F, Xu R, Qing H, Wang X, Yin F, et al. Co-expression of XIAP and cyclin D1 complex correlates with a poor prognosis in patients with hepatocellular carcinoma. Am J Pathol. 2012;180:1798–807.

    CAS  PubMed  Article  Google Scholar 

  51. Augello C, Caruso L, Maggioni M, Donadon M, Montorsi M, Santambrogio R, et al. Inhibitors of apoptosis proteins (IAPs) expression and their prognostic significance in hepatocellular carcinoma. BMC Cancer. 2009;9:125.

    PubMed Central  PubMed  Article  Google Scholar 

Download references

Acknowledgments

This work was supported in part by a Grant from the Natural Science Foundation of Anhui Province (#1208085MH169), Key University Natural Science Foundation of Anhui (#KJ2011z211), and Specialized Research Fund for the Doctoral Program of Higher Education (#20133420120006).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Affiliations

  1. Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China

    Wen-Yong Wu, Chang-Le Zhang & Xiang-Ling Meng

  2. Department of Pathology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, People’s Republic of China

    Zheng-Sheng Wu

  3. Department of Pathology, Gachon University Gil Medical Center, Incheon, Korea

    Hyunchul Kim

Authors
  1. Wen-Yong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyunchul Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chang-Le Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiang-Ling Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zheng-Sheng Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zheng-Sheng Wu.

Additional information

Wen-Yong Wu and Hyunchul Kim have contributed equally to this work.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wu, WY., Kim, H., Zhang, CL. et al. Clinical significance of autophagic protein LC3 levels and its correlation with XIAP expression in hepatocellular carcinoma. Med Oncol 31, 108 (2014). https://doi.org/10.1007/s12032-014-0108-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-014-0108-3

Keywords

  • Autophagy
  • LC3
  • XIAP
  • Hepatocellular carcinoma