Skip to main content

Advertisement

SpringerLink
Log in

Importin-α1 as a Novel Prognostic Target for Hepatocellular Carcinoma

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Perturbations in the nuclear microenvironment, including transport systems, play a critical role in malignant progression, but the nuclear import abnormalities remain unclear in hepatocarcinogenesis. We analyzed the role of importin in hepatocellular carcinoma (HCC).

Methods

Gene expression profiling of the importin family was performed in HCC tissues. The significance of importin protein expression was analyzed in vitro as well as clinicopathologically.

Results

According to the microarray profiles, the importin-α1 was dominantly overexpressed in HCC tissues as compared to the adjacent noncancerous tissues. By means of human HCC cell lines, a knockdown of importin-α1 by its siRNA greatly reduced cellular proliferation by 15.2–26.6% (P < 0.005). Immunohistochemical analysis on tissue samples demonstrated cancer-specific overexpression in 36.3% of HCCs. The overexpression of importin-α1 was correlated statistically with high levels of alfa-fetoprotein (P = 0.0017), the tumor number (P = 0.0116), histological dedifferentiation (P = 0.0054), tumor morphology (P = 0.0433), portal vein invasion (P = 0.0007), hepatic vein invasion (P = 0.0081), Fc (P = 0.0367), Fc-inf (P = 0.0122), and the tumor, node, metastasis stage (P = 0.0026); this resulted in a significantly poorer prognosis in both overall survival (P = 0.0164) and recurrence-free survival (P = 0.0101). Multivariate analysis of recurrence-free survival revealed importin-α1 expression to be a statistically significant factor (P = 0.0361). In addition, early recurrence after curative resection was observed more frequently in the importin-α1-positive group as compared to the negative group (P = 0.0023). The multivariate analysis identified importin-α1 as the only independent predictor of early recurrence after HCC resection (odds ratio = 5.291, P = 0.0191).

Conclusions

Because importin-α1 might be closely associated with HCC progression, further analysis should be pursued to evaluate it as a novel prognostic target.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Poon RT, Fan ST, Wong J. Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg. 2000;232:10–24.

    Article  Google Scholar 

  2. Shimada M, Takenaka K, Gion T, et al. Prognosis of recurrent hepatocellular carcinoma: a 10-year surgical experience in Japan. Gastroenterology. 1996;111:720–6.

    Article  PubMed  CAS  Google Scholar 

  3. Poon RT, Fan ST, Lo CM, Liu CL, Wong J. Intrahepatic recurrence after curative resection of hepatocellular carcinoma: long-term results of treatment and prognostic factors. Ann Surg. 1999;229:216–22.

    Article  PubMed  CAS  Google Scholar 

  4. Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group of Japan. Hepatology. 2000;32:1224–9.

    Article  PubMed  CAS  Google Scholar 

  5. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 2008;48:1312–27.

    Article  PubMed  CAS  Google Scholar 

  6. Zaidi SK, Young DW, Javed A, et al. Nuclear microenvironments in biological control and cancer. Nat Rev Cancer. 2007;7:454–63.

    Article  PubMed  CAS  Google Scholar 

  7. Chahine MN, Pierce GN. Therapeutic targeting of nuclear protein import in pathological cell conditions. Pharmacol Rev. 2009;61:358–72.

    Article  PubMed  CAS  Google Scholar 

  8. Kutay U, Mühlhäusser P. Cell biology: taking a turn into the nucleus. Nature. 2006;442:991–2.

    Article  PubMed  CAS  Google Scholar 

  9. Görlich D, Kutay U. Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol. 1999;15:607–60.

    Article  PubMed  Google Scholar 

  10. Johnson HM, Subramaniam PS, Olsnes S, Jans DA. Trafficking and signaling pathways of nuclear localizing protein ligands and their receptors. Bioessays. 2004;26:993–1004.

    Article  PubMed  CAS  Google Scholar 

  11. Kaffman A, O’Shea EK. Regulation of nuclear localization: a key to a door. Annu Rev Cell Dev Biol. 1999;15:291–339.

    Article  PubMed  CAS  Google Scholar 

  12. Cyert MS. Regulation of nuclear localization during signaling. J Biol Chem. 2001;276:20805–8.

    Article  PubMed  CAS  Google Scholar 

  13. Fukasawa K. Oncogenes and tumour suppressors take on centrosomes. Nat Rev Cancer. 2007;7:911–24.

    Article  PubMed  CAS  Google Scholar 

  14. Pascale RM, Simile MM, Calvisi DF, et al. Role of HSP90, CDC37, and CRM1 as modulators of P16(INK4A) activity in rat liver carcinogenesis and human liver cancer. Hepatology. 2005;42:1310–9.

    Article  PubMed  CAS  Google Scholar 

  15. Quackenbush J. Microarray analysis and tumor classification. N Engl J Med. 2006;354:2463–72.

    Article  PubMed  CAS  Google Scholar 

  16. Hoshida Y, Villanueva A, Kobayashi M, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med. 2008;359:1995–2004.

    Article  PubMed  CAS  Google Scholar 

  17. Tanaka S, Arii S, Yasen M, et al. Aurora kinase B is a predictive factor for the aggressive recurrence of hepatocellular carcinoma after curative hepatectomy. Br J Surg. 2008;95:611–9.

    Article  PubMed  CAS  Google Scholar 

  18. Park JH, Koh KC, Choi MS, et al. Analysis of risk factors associated with early multinodular recurrences after hepatic resection for hepatocellular carcinoma. Am J Surg. 2006;192:29–33.

    Article  PubMed  Google Scholar 

  19. Yokoo H, Kondo T, Okano T, et al. Protein expression associated with early intrahepatic recurrence of hepatocellular carcinoma after curative surgery. Cancer Sci. 2007;98:665–73.

    Article  PubMed  CAS  Google Scholar 

  20. Lu X, Zhao H, Yang H, et al. A prospective clinical study on early recurrence of hepatocellular carcinoma after hepatectomy. J Surg Oncol. 2009;100:488–93.

    Article  PubMed  Google Scholar 

  21. Tanaka S, Pero SC, Taguchi K, et al. Specific peptide ligand for Grb7 signal transduction protein and pancreatic cancer metastasis. J Natl Cancer Inst. 2006;98:491–8.

    Article  PubMed  CAS  Google Scholar 

  22. Bressac B, Galvin KM, Liang TJ, Isselbacher KJ, Wands JR, Ozturk M. Abnormal structure and expression of p53 gene in human hepatocellular carcinoma. Proc Natl Acad Sci USA. 1990;87:1973–7.

    Article  PubMed  CAS  Google Scholar 

  23. Komlodi-Pasztor E, Trostel S, Sackett D, Poruchynsky M, Fojo T. Impaired p53 binding to importin: a novel mechanism of cytoplasmic sequestration identified in oxaliplatin-resistant cells. Oncogene. 2009;28:3111–20.

    Article  PubMed  CAS  Google Scholar 

  24. Marchenko ND, Hanel W, Li D, Becker K, Reich N, Moll UM. Stress-mediated nuclear stabilization of p53 is regulated by ubiquitination and importin-alpha3 binding. Cell Death Differ. 2010;17:255–67.

    Article  PubMed  CAS  Google Scholar 

  25. Chook YM, Blobel G. Karyopherins and nuclear import. Curr Opin Struct Biol. 2001;11:703–15.

    Article  PubMed  CAS  Google Scholar 

  26. Kau TR, Way JC, Silver PA. Nuclear transport and cancer: from mechanism to intervention. Nat Rev Cancer. 2004;4:106–17.

    Article  PubMed  CAS  Google Scholar 

  27. Dahl E, Kristiansen G, Gottlob K, et al. Molecular profiling of laser-microdissected matched tumor and normal breast tissue identifies karyopherin alpha2 as a potential novel prognostic marker in breast cancer. Clin Cancer Res. 2006;12:3950–60.

    Article  PubMed  CAS  Google Scholar 

  28. Dankof A, Fritzsche FR, Dahl E, et al. KPNA2 protein expression in invasive breast carcinoma and matched peritumoral ductal carcinoma in situ. Virchows Arch. 2007;451:877–81.

    Article  PubMed  CAS  Google Scholar 

  29. Winnepenninckx V, Lazar V, Michiels S, et al. Melanoma Group of the European Organization for Research and Treatment of Cancer. Gene expression profiling of primary cutaneous melanoma and clinical outcome. J Natl Cancer Inst. 2006;98:472–82.

    Article  PubMed  CAS  Google Scholar 

  30. Gluz O, Wild P, Meiler R, et al. Nuclear karyopherin alpha2 expression predicts poor survival in patients with advanced breast cancer irrespective of treatment intensity. Int J Cancer. 2008;123:1433–8.

    Article  PubMed  CAS  Google Scholar 

  31. Stein GS, Davie JR, Knowlton JR, Zaidi SK. Nuclear microenvironments and cancer. J Cell Biochem. 2008;104:1949–52.

    Article  PubMed  CAS  Google Scholar 

  32. Tanaka S, Arii S. Molecularly targeted therapy for hepatocellular carcinoma. Cancer Sci. 2009;100:1–8.

    Article  PubMed  CAS  Google Scholar 

  33. Fornerod M, Ohno M, Yoshida M, Mattaj IW. CRM1 is an export receptor for leucine-rich nuclear export signals. Cell. 1997;90:1051–60.

    Article  PubMed  CAS  Google Scholar 

  34. Kudo N, Matsumori N, Taoka H, et al. Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region. Proc Natl Acad Sci USA. 1999;96:9112–7.

    Article  PubMed  CAS  Google Scholar 

  35. Mutka SC, Yang WQ, Dong SD, et al. Identification of nuclear export inhibitors with potent anticancer activity in vivo. Cancer Res. 2009;69:510–7.

    Article  PubMed  CAS  Google Scholar 

  36. Newlands ES, Rustin GJ, Brampton MH. Phase I trial of elactocin. Br J Cancer. 1996;74:648–9.

    Article  PubMed  CAS  Google Scholar 

  37. Vigneri P, Wang JY. Induction of apoptosis in chronic myelogenous leukemia cells through nuclear entrapment of BCR-ABL tyrosine kinase. Nat Med. 2001;7:228–34.

    Article  PubMed  CAS  Google Scholar 

  38. Aloisi A, Di Gregorio S, Stagno F, et al. BCR-ABL nuclear entrapment kills human CML cells: ex vivo study on 35 patients with the combination of imatinib mesylate and leptomycin B. Blood. 2006;107:1591–8.

    Article  PubMed  CAS  Google Scholar 

  39. Kosugi S, Hasebe M, Entani T, Takayama S, Tomita M, Yanagawa H. Design of peptide inhibitors for the importin alpha/beta nuclear import pathway by activity-based profiling. Chem Biol. 2008;15:940–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by a Grant-in Aid for Scientific Research and Health Labor Sciences Research Grant, Japan. We thank Ayumi Shioya for her technical assistance.

Author information

Authors and Affiliations

  1. Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    Kenichiro Yoshitake MD, Shinji Tanaka MD, PhD, FACS, Arihiro Aihara MD, PhD, Ayano Murakata MD, Satoshi Matsumura MD, Yusuke Mitsunori MD, Mahmut Yasen MD, PhD, Daisuke Ban MD, PhD, Norio Noguchi MD, PhD, Takumi Irie MD, PhD, Atsushi Kudo MD, PhD, Noriaki Nakamura MD, PhD & Shigeki Arii MD, PhD

  2. Information Center for Medical Sciences, Tokyo Medical and Dental University, Tokyo, Japan

    Kaoru Mogushi PhD & Hiroshi Tanaka PhD

Authors
  1. Kenichiro Yoshitake MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shinji Tanaka MD, PhD, FACS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kaoru Mogushi PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arihiro Aihara MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ayano Murakata MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Satoshi Matsumura MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yusuke Mitsunori MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mahmut Yasen MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Daisuke Ban MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Norio Noguchi MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takumi Irie MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Atsushi Kudo MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Noriaki Nakamura MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Hiroshi Tanaka PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Shigeki Arii MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shinji Tanaka MD, PhD, FACS.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 51 kb)

Supplementary material 2 (DOC 46 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoshitake, K., Tanaka, S., Mogushi, K. et al. Importin-α1 as a Novel Prognostic Target for Hepatocellular Carcinoma. Ann Surg Oncol 18, 2093–2103 (2011). https://doi.org/10.1245/s10434-011-1569-7

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-011-1569-7

Keywords

Search

Navigation