title: Importin-α1 as a novel prognostic target for hepatocellular carcinoma.
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.
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yoshitake
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.forename: Kaoru
authors.initials: K
authors.lastname: Mogushi
authors.forename: Arihiro
authors.initials: A
authors.lastname: Aihara
authors.forename: Ayano
authors.initials: A
authors.lastname: Murakata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsumura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mitsunori
authors.forename: Mahmut
authors.initials: M
authors.lastname: Yasen
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ban
authors.forename: Norio
authors.initials: N
authors.lastname: Noguchi
authors.forename: Takumi
authors.initials: T
authors.lastname: Irie
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kudo
authors.forename: Noriaki
authors.initials: N
authors.lastname: Nakamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Shigeki
authors.initials: S
authors.lastname: Arii
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D006503:Hepatic Veins / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011169:Portal Vein / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D034741:RNA, Small Interfering / Q000235:genetics; D028901:alpha Karyopherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; D028901:alpha Karyopherins; C087978:karyopherin alpha 2