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The expression of HIF-1α in primary hepatocellular carcinoma and its correlation with radiotherapy response and clinical outcome

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Abstract

The purpose of this study was to evaluate the relationship between hypoxia-inducible factor-1α (HIF-1α) protein expression in hepatocellular carcinoma (HCC), and responses of abdominal metastatic lymph nodes (LNs) from HCC patients treated with external beam radiotherapy (EBRT). HIF-1α immunohistochemical staining was performed on tissue microarrays (TMAs) of primary HCC specimens from 69 HCC patients with abdominal LN metastases. All patients received abdominal metastatic LN EBRT at the Department of Radiation Oncology at Zhongshan Hospital. A receiver-operating characteristic (ROC)-based approach and logistical regression analysis were used to determine the predictive value of HIF-1α expression in primary tumors with HCC metastatic LN EBRT response. Kaplan–Meier curves and log-rank tests were used to analyze patient survival. Cox proportional hazards regression model was used to analyze independent prognostic factors. HIF-1α expression was correlated with blood hemoglobin (Hb: r = −0.280, P = 0.020), response of abdominal metastatic LNs to EBRT (r = 0.286, P = 0.017), locoregional recurrence (r = 0.278, P = 0.021), and cancer-specific deaths (r = 0.298, P = 0.013). HIF-1α expression was predictive of EBRT response of metastatic LNs [area under the curve (AUC): 0.646; 95% confidence interval (CI): 0.499–0.793; P = 0.047], locoregional recurrence (AUC: 0.657; 95% CI: 0.509–0.805; P = 0.049) and cancer-specific deaths (AUC: 0.671; 95% CI: 0.531–0.812; P = 0.035). Patients with tumors exhibiting high HIF-1α expression had significantly poorer overall survival (OS) than those with low tumor expression of HIF-1α (P = 0.016). Multivariate analysis showed that Hb (P = 0.035), vascular invasion (P = 0.026), Child-Pugh score (P < 0.001), intrahepatic tumor control (P < 0.001), and HIF-1α (P = 0.020) were independent prognosis factors for OS of HCC patients after receiving abdominal metastatic LN EBRT. HIF-1α expression in primary HCCs was associated with EBRT response of abdominal metastatic LNs and poor prognosis.

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References

  1. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics 2002. CA Cancer J Clin 55:74–108

    Article  PubMed  Google Scholar 

  2. Natsuizaka M, Omura T, Akaike T, Kuwata Y, Yamazaki K, Sato T, Karino Y, Toyota J, Suga T, Asaka M (2005) Clinical features of hepatocellular carcinoma with extrahepatic metastases. J Gastroenterol Hepatol 20:1781–1787

    Article  PubMed  Google Scholar 

  3. Michaelson JS, Chen LL, Silverstein MJ, Cheongsiatmoy JA, Mihm MC Jr, Sober AJ, Tanabe KK, Smith BL, Younger J (2009) Why cancer at the primary site and in the lymph nodes contributes to the risk of cancer death. Cancer 115:5084–5094

    Article  PubMed  Google Scholar 

  4. Zeng ZC, Tang ZY, Fan J, Qin LX, Ye SL, Zhou J, Sun HC, Wang BL, Wang JH (2005) Consideration of role of radiotherapy for lymph node metastases in patients with HCC: retrospective analysis for prognostic factors from 125 patients. Int J Radiat Oncol Biol Phys 63:1067–1076

    Article  PubMed  Google Scholar 

  5. Silva P, Slevin NJ, Sloan P, Valentine H, Cresswell J, Ryder D, Price P, Homer JJ, West CM (2008) Prognostic significance of tumor hypoxia inducible factor-1alpha expression for outcome after radiotherapy in oropharyngeal cancer. Int J Radiat Oncol Biol Phys 72:1551–1559

    Article  PubMed  CAS  Google Scholar 

  6. Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Turley H, Talks K, Gatter KC, Harris AL (2002) Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys 53:1192–1202

    Article  PubMed  CAS  Google Scholar 

  7. Schrijvers ML, van der Laan BF, de Bock GH, Pattje WJ, Mastik MF, Menkema L, Langendijk JA, Kluin PM, Schuuring E, van der Wal JE (2008) Overexpression of intrinsic hypoxia markers HIF1alpha and CA-IX predict for local recurrence in stage T1–T2 glottic laryngeal carcinoma treated with radiotherapy. Int J Radiat Oncol Biol Phys 72:161–169

    Article  PubMed  CAS  Google Scholar 

  8. Ye QH, Qin LX, Forgues M, He P, Kim JW, Peng AC, Simon R, Li Y, Robles AI, Chen Y, Ma ZC, Wu ZQ, Ye SL, Liu YK, Tang ZY, Wang XW (2003) Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med 9:416–423

    Article  PubMed  CAS  Google Scholar 

  9. Xiang ZL, Zeng ZC, Tang ZY, Fan J, Sun HC, Wu WZ, Tan YS (2009) Increased expression of vascular endothelial growth factor-C and nuclear CXCR4 in hepatocellular carcinoma is correlated with lymph node metastasis and poor outcome. Cancer J 15:519–525

    Article  PubMed  Google Scholar 

  10. Xiang ZL, Zeng ZC, Tang ZY, Fan J, Zhuang PY, Liang Y, Tan YS, He J (2009) Chemokine receptor CXCR4 expression in hepatocellular carcinoma patients increases the risk of bone metastases and poor survival. BMC Cancer 9:176

    Article  PubMed  Google Scholar 

  11. Xiang ZL, Zeng ZC, Tang ZY, Fan J, Sun HC, Tan YS (2011) Expression of cytokeratin 19 and matrix metalloproteinase 2 predicts lymph node metastasis in hepatocellular carcinoma. Mol Biol Rep 38:3531–3539

    Article  PubMed  CAS  Google Scholar 

  12. Qian YB, Zhang JB, Wu WZ, Fang HB, Jia WD, Zhuang PY, Zhang BH, Pan Q, Xu Y, Wang L, Tang ZY, Sun HC (2006) P48 is a predictive marker for outcome of postoperative interferon-alpha treatment in patients with hepatitis B virus infection-related hepatocellular carcinoma. Cancer 107:1562–1569

    Article  PubMed  Google Scholar 

  13. Kurokawa T, Miyamoto M, Kato K, Cho Y, Kawarada Y, Hida Y, Shinohara T, Itoh T, Okushiba S, Kondo S, Katoh H (2003) Overexpression of hypoxia-inducible-factor 1alpha (HIF-1alpha) in oesophageal squamous cell carcinoma correlates with lymph node metastasis and pathologic stage. Br J Cancer 89:1042–1047

    Article  PubMed  CAS  Google Scholar 

  14. Ercolani G, Grazi GL, Ravaioli M, Grigioni WF, Cescon M, Gardini A, Del Gaudio M, Cavallari A (2004) The role of lymphadenectomy for liver tumors: further considerations on the appropriateness of treatment strategy. Ann Surg 239:202–209

    Article  PubMed  Google Scholar 

  15. Vaupel P (2004) Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol 14:198–206

    Article  PubMed  Google Scholar 

  16. Knocke TH, Weitmann HD, Feldmann HJ, Selzer E, Pötter R (1999) Intra-tumoral pO2-measurements as predictive assay in the treatment of carcinoma of the uterine cervix. Radiother Oncol 53:99–104

    Article  PubMed  CAS  Google Scholar 

  17. Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, Becker A, Adam M, Molls M, Dunst J, Terris DJ, Overgaard J (2005) Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy: an international multi-center study. Radiother Oncol 77:18–24

    Article  PubMed  Google Scholar 

  18. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW (1999) Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res 59:5830–5835

    PubMed  CAS  Google Scholar 

  19. Kwon HC, Kim SH, Oh SY, Lee S, Kwon KA, Choi HJ, Park KJ, Kim HJ, Roh MS (2010) Clinicopathological significance of p53, hypoxia-inducible factor 1{alpha}, and vascular endothelial growth factor expression in colorectal cancer. Anticancer Res 30:4163–4168

    PubMed  Google Scholar 

  20. Eckert AW, Schutze A, Lautner MH, Taubert H, Schubert J, Bilkenroth U (2010) HIF-1alpha is a prognostic marker in oral squamous cell carcinomas. Int J Biol Markers 25:87–92

    PubMed  Google Scholar 

  21. Batmunkh E, Shimada M, Morine Y, Imura S, Kanemura H, Arakawa Y, Hanaoka J, Kanamoto M, Sugimoto K, Nishi M (2010) Expression of hypoxia-inducible factor-1 alpha (HIF-1alpha) in patients with the gallbladder carcinoma. Int J Clin Oncol 15:59–64

    Article  PubMed  CAS  Google Scholar 

  22. Dai CX, Gao Q, Qiu SJ, Ju MJ, Cai MY, Xu YF, Zhou J, Zhang BH, Fan J (2009) Hypoxia-inducible factor-1 alpha, in association with inflammation, angiogenesis and MYC, is a critical prognostic factor in patients with HCC after surgery. BMC Cancer 9:418

    Article  PubMed  Google Scholar 

  23. Yohena T, Yoshino I, Takenaka T, Kameyama T, Ohba T, Kuniyoshi Y, Maehara Y (2009) Upregulation of hypoxia-inducible factor-1alpha mRNA and its clinical significance in non-small cell lung cancer. J Thorac Oncol 4:284–290

    Article  PubMed  Google Scholar 

  24. Shimogai R, Kigawa J, Itamochi H, Iba T, Kanamori Y, Oishi T, Shimada M, Sato S, Kawaguchi W, Sato S, Terakawa N (2008) Expression of hypoxia-inducible factor 1alpha gene affects the outcome in patients with ovarian cancer. Int J Gynecol Cancer 18:499–505

    Article  PubMed  CAS  Google Scholar 

  25. Vaupel P, Mayer A, Hockel M (2006) Impact of hemoglobin levels on tumor oxygenation: the higher, the better? Strahlenther Onkol 182:63–71

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Supported by Grant No. 30973500 from the National Natural Science Foundation of China and Youth Science Foundation of Zhongshan Hospital.

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Authors and Affiliations

  1. Department of Radiation Oncology, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai, 200032, China

    Zuo-Lin Xiang, Zhao-Chong Zeng & Jian He

  2. Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China

    Jia Fan & Zhao-You Tang

  3. Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China

    Hai-Ying Zeng

  4. Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA

    Joe Y. Chang

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  1. Zuo-Lin Xiang
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  2. Zhao-Chong Zeng
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  3. Jia Fan
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  4. Zhao-You Tang
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  5. Jian He
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Correspondence to Zhao-Chong Zeng.

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Xiang, ZL., Zeng, ZC., Fan, J. et al. The expression of HIF-1α in primary hepatocellular carcinoma and its correlation with radiotherapy response and clinical outcome. Mol Biol Rep 39, 2021–2029 (2012). https://doi.org/10.1007/s11033-011-0949-1

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  • DOI: https://doi.org/10.1007/s11033-011-0949-1

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