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Defective Beclin-1 and elevated hypoxia-inducible factor (HIF)-1α expression are closely linked to tumorigenesis, differentiation, and progression of hepatocellular carcinoma

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Tumor Biology

Abstract

Hepatocellular carcinoma (HCC) is an aggressive cancer with a poor prognosis. Autophagy and hypoxia have been involved in HCC tumorigenesis. In the present study, we examined the relationship between Beclin-1 expression and hypoxia-inducible factor (HIF)-1α expression in HCC by immunohistochemistry on 65 tumor specimens. Their correlations with clinicopathological features were also explored. There was a loss of Beclin-1 protein expression in 49.2 % of HCC. Beclin-1 expression was only significantly correlated with virus infection status (p = 0.025) and marginally associated with HCC grade (p = 0.057). Forty-two tumors (64.6 %) showed high HIF-1α expression, and it was significantly associated with large tumor size (p = 0.003), multifocal tumors (p = 0.038), and advanced stage (p = 0.043). Beclin-1 expression was significantly associated with HIF-1α expression (p = 0.001). HCC cases were further stratified according to their hypoxia status into hypoxic and normoxic groups. In the hypoxic group, Beclin-1 expression was negatively correlated with HCC high tumor grade (p < 0.001), advanced stage (p = 0.013), large size (p = 0.002), and multifocal tumors (p = 0.047). In the normoxic group, no significant relations between Beclin-1 expression and any of the clinicopathological parameters were identified. Our findings that reduced Beclin-1 and high HIF-1α expression are associated with the development and progression of HCC may provide molecular therapeutic targets toward inhibiting HCC development and progression.

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References

  1. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:e1264–73.

    Article  Google Scholar 

  2. Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in Egypt: results of the national population-based cancer registry program. J Cancer Epidemiol. 2014;2014(437971):1–18.

    Article  Google Scholar 

  3. Abdel-Hamid NM, Nazmy MH, Mahmoud AW, Fawzy MA, Youssof M. A survey on herbal management of hepatocellular carcinoma. World J Hepatol. 2011;3:175–83.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wong CC, Kai AK, Ng IO. The impact of hypoxia in hepatocellular carcinoma metastasis. Front Med. 2013;8:33–41.

    Article  PubMed  Google Scholar 

  5. Scaggiante B, Kazemi M, Pozzato G, Dapas B, Farra R, Grassi M, et al. Novel hepatocellular carcinoma molecules with prognostic and therapeutic potentials. World J Gastroenterol. 2014;20:1268–88.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kundu M, Thompson CB. Autophagy: basic principles and relevance to disease. Annu Rev Pathol. 2008;3:427–55.

    Article  CAS  PubMed  Google Scholar 

  7. Sun Q, Fan W, Zhong Q. Regulation of Beclin 1 in autophagy. Autophagy. 2009;5:713–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Edinger AL, Thompson CB. Defective autophagy leads to cancer. Cancer Cell. 2003;4:422–4.

    Article  CAS  PubMed  Google Scholar 

  9. Kang KF, Wang XW, Chen XW, Kang ZJ, Zhang X, Wilbur RR, et al. Beclin 1 and nuclear factor-κBp65 are upregulated in hepatocellular carcinoma. Oncol Lett. 2013;5:1813–8.

    PubMed  PubMed Central  Google Scholar 

  10. Mabjeesh NJ, Amir S. Hypoxia-inducible factor (HIF) in human tumorigenesis. Histol Histopathol. 2007;22:559–72.

    CAS  PubMed  Google Scholar 

  11. Wilson KG, Tennant AD, McKeating AJ. Hypoxia inducible factors in liver disease and hepatocellular carcinoma: current understanding and future directions. J Hepatol. 2014;61:1397–406.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem. 2008;283:10892–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dong M, Wan X, Yuan ZY, Wei L, Fan XJ, Wang T, et al. Low expression of Beclin 1 and elevated expression of HIF-1 α refine distant metastasis risk and predict poor prognosis of ER-positive, HER2-negative breast cancer. Med Oncol. 2013;30:355–65.

    Article  PubMed  Google Scholar 

  14. Edge SB, Byrd DR, Compton CC, et al. American Joint Committee on Cancer. American Joint Committee on Cancer staging manual. 7th ed. New York: Springer; 2010. p. 175.

    Google Scholar 

  15. Ding ZB, Shi YH, Zhou J, Qiu SJ, Xu Y, Dai Z, et al. Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma. Cancer Res. 2008;15:9167–75.

    Article  Google Scholar 

  16. Xiang ZL, Zeng ZC, Fan J, Tang ZY, He J, Zeng HY, et al. The expression of HIF-1α in primary hepatocellular carcinoma and its correlation with radiotherapy response and clinical outcome. Mol Biol Rep. 2012;39:2021–9.

    Article  CAS  PubMed  Google Scholar 

  17. Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011;10:1533–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cui J, Gong Z, Shen HM. The role of autophagy in liver cancer: molecular mechanisms and potential therapeutic targets. Biochim Biophys Acta. 1836;2013:15–26.

    Google Scholar 

  19. Gozuacik D, Kimchi A. Autophagy as a cell death and tumor suppressor mechanism. Oncogene. 2004;12:2891–906.

    Article  Google Scholar 

  20. Chen Y, Lu Y, Lu C, Zhang L. Beclin-1 expression is a predictor of clinical outcome in patients with esophageal squamous cell carcinoma and correlated to hypoxia-inducible factor (HIF)-1alpha expression. Pathol Oncol Res. 2009;15:487–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Qiu DM, Wang GL, Chen L, Xu YY, He S, Cao XL, et al. The expression of beclin-1, an autophagic gene, in hepatocellular carcinoma associated with clinical pathological and prognostic significance. BMC Cancer. 2014;9:327–40.

    Article  Google Scholar 

  22. Yao Q, Chen J, Lv Y, Wang T, Zhang J, Fan J, et al. The significance of expression of autophagy-related gene Beclin, Bcl-2, and Bax in breast cancer tissues. Tumour Biol. 2011;32:1163–71.

    Article  CAS  PubMed  Google Scholar 

  23. Won KY, Kim GY, Lim SJ, Kim YW. Decreased Beclin-1 expression is correlated with the growth of the primary tumor in patients with squamous cell carcinoma and adenocarcinoma of the lung. Hum Pathol. 2012;43:62–8.

    Article  CAS  PubMed  Google Scholar 

  24. Wu X, Chen J, Cao Q, Dong M, Lin Q, Fan XJ, et al. Beclin 1 activation enhances chemosensitivity and predicts a favorable outcome for primary duodenal adenocarcinoma. Tumor Biol. 2013;34:713–22.

    Article  CAS  Google Scholar 

  25. Koneri K, Goi T, Hirono Y, Katayama K, Yamaguchi A. Beclin 1 gene inhibits tumor growth in colon cancer cell lines. Anticancer Res. 2007;27:1453–7.

    CAS  PubMed  Google Scholar 

  26. Lee SJ, Kim HP, Jin Y, Choi AM, Ryter SW. Beclin 1 deficiency is associated with increased hypoxia-induced angiogenesis. Autophagy. 2011;7:829–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mathew R, Kongara S, Beaudoin B, Karp M, Bray K, Degenhardt K, et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 2007;21:1367–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wan XB, Fan XJ, Chen MY, Xiang J, Huang PY, Guo L, et al. Elevated Beclin 1 expression is correlated with HIF-1alpha in predicting poor prognosis of nasopharyngeal carcinoma. Autophagy. 2010;6:395–404.

    Article  CAS  PubMed  Google Scholar 

  29. Tang JY, Fang YY, Hsi E, Huang YC, Hsu NC, Yang WC, et al. Immunopositivity of Beclin1 and ATG5 as indicators of survival and disease recurrence in oral squamous cell carcinoma. Anticancer Res. 2013;33:5611–6.

    PubMed  Google Scholar 

  30. Tang H, Da L, Mao Y, Li Y, Li D, Xu Z, et al. Hepatitis B virus X protein sensitizes cells to starvation-induced autophagy via up-regulation of beclin 1 expression. Hepatology. 2009;49:60–71.

    Article  CAS  PubMed  Google Scholar 

  31. Shrivastava S, BhanjaChowdhury J, Steele R, Ray R, Ray RB. Hepatitis C virus upregulates Beclin1 for induction of autophagy and activates mTOR signaling. J Virol. 2012;86:8705–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nath B, Levin I, Csak T, Petrasek J, Mueller C, Kodys K, et al. Hepatocyte specific hypoxia-inducible factor-1alpha is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice. Hepatology. 2011;53:1526–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Qu A, Taylor M, Xue X, Matsubara T, Metzger D, Chambon P, et al. Hypoxia inducible transcription factor 2alpha promotes steatohepatitis through augmenting lipid accumulation, inflammation, and fibrosis. Hepatology. 2011;54:472–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wilson GK, Brimacombe CL, Rowe IA, Reynolds GM, Fletcher NF, Stamataki Z, et al. A dual role for hypoxia inducible factor-1alpha in the hepatitis C virus life cycle and hepatoma migration. J Hepatol. 2012;56:803–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dai CX, Gao Q, Qiu SJ, Ju MJ, Cai MY, Xu YF, et al. Hypoxia-inducible factor-1alpha, in association with inflammation, angiogenesis and MYC, is a critical prognostic factor in patients with HCC after surgery. BMC Cancer. 2009;9:418–29.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Xiang ZL, Zeng ZC, Fan J, Tang ZY, Zeng HY, Gao DM. Gene expression profiling of fixed tissues identified hypoxia-inducible factor-1alpha, VEGF, and matrix metalloproteinase-2 as biomarkers of lymph node metastasis in hepatocellular carcinoma. Clin Cancer Res. 2011;17:5463–72.

    Article  CAS  PubMed  Google Scholar 

  37. Zheng SS, Chen XH, Yin X, Zhang BH. Prognostic significance of HIF-1alpha expression in hepatocellular carcinoma: a meta-analysis. PLoS One. 2013;8(e65753):1–7.

    CAS  Google Scholar 

  38. McFarlane S, Nicholl MJ, Sutherland JS, Preston CM. Interaction of the human cytomegalovirus particle with the host cell induces hypoxia-inducible factor 1 alpha. Virology. 2011;414:83–90.

    Article  CAS  PubMed  Google Scholar 

  39. Darekar S, Georgiou K, Yurchenko M, Yenamandra SP, Chachami G, Simos G, et al. Epstein-Barr virus immortalization of human B-cells leads to stabilization of hypoxia-induced factor 1 alpha, congruent with the Warburg effect. PLoS One. 2012;7(e42072):1–8.

    Google Scholar 

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Authors and Affiliations

  1. Pathology Department, Faculty of Medicine, Minia University, Minia, 61111, Egypt

    Nisreen A. A. Osman & Dalia M. Abd El-Rehim

  2. Tropical Medicine Department, Faculty of Medicine, Minia University, Minia, Egypt

    Inas M. Kamal

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  1. Nisreen A. A. Osman
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  2. Dalia M. Abd El-Rehim
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  3. Inas M. Kamal
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Correspondence to Nisreen A. A. Osman.

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Osman, N.A.A., Abd El-Rehim, D.M. & Kamal, I.M. Defective Beclin-1 and elevated hypoxia-inducible factor (HIF)-1α expression are closely linked to tumorigenesis, differentiation, and progression of hepatocellular carcinoma. Tumor Biol. 36, 4293–4299 (2015). https://doi.org/10.1007/s13277-015-3068-0

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  • DOI: https://doi.org/10.1007/s13277-015-3068-0

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