Importin-α1 as a Novel Prognostic Target for Hepatocellular Carcinoma

Yoshitake, Kenichiro; Tanaka, Shinji; Mogushi, Kaoru; Aihara, Arihiro; Murakata, Ayano; Matsumura, Satoshi; Mitsunori, Yusuke; Yasen, Mahmut; Ban, Daisuke; Noguchi, Norio; Irie, Tetsumi; Kudo, Atsushi; Nakamura, Noriaki; Tanaka, Hiroshi; Arii, Shigeki

doi:10.1245/s10434-011-1569-7

Cited by 50 publications

(64 citation statements)

References 39 publications

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“…Consistent with previous report [12], the positive KPNA2 expression was almost tumor specific, as only non-tumoral tissues of 11 HCC patients showed positive KPNA2 expression. Besides, the positive nucleus staining of PLAG1 in tumors was more frequent than in non-tumoral tissues (Table 2), further supporting the role of PLAG1 in HCC.…”

Section: The Co-enrichment Of Nucleus Plag1 and Kpna2 In Vivosupporting

confidence: 89%

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Pleomorphic adenoma gene 1 mediates the role of Karyopherin alpha 2 and has prognostic significance in hepatocellular carcinoma

Yuan

Yang

et al. 2014

J Exp Clin Cancer Res

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Background: Karyopherin alpha 2 (KPNA2) promotes tumor growth in hepatocellular carcinoma (HCC). We aimed to determine the content and clinical significance of mechanism underlying. Methods: The association of transcriptional factor pleomorphic adenoma gene 1 (PLAG1) with KPNA2 was explored by co-immunoprecipitation. In vitro gain-and loss-of-function models were established to explore the functional interaction. Clinical samples from 314 HCC patients were applied to explore the clinical significance. Results: We found that PLAG1 could associate with KPNA2 and be promoted into nucleus by KPNA2. The increment of proliferative and metastatic abilities by KPNA2 over-expression can be significantly retarded by PLAG1 inhibition. The co-enrichment of KPNA2 and PLAG1 in nucleus is observed in clinical samples and can distinguish patients with the worst prognosis. The positive PLAG1 expression is an independent risk factor of recurrence free survival (HR: 1.766, 1.315-2.371; P = 0.000) and overall survival (HR: 1.589, 1.138-2.220; P = 0.007). Especially for patients with positive KPNA2 staining (N = 152), the positive PLAG1 expression is the sole risk factor for both recurrence free survival (HR: 1.749, 1.146-2.670; P = 0.010) and overall survival (HR: 1.662, 1.007-2.744; P = 0.047).

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Section: The Co-enrichment Of Nucleus Plag1 and Kpna2 In Vivosupporting

confidence: 89%

“…Recent studies have illustrated that KPNA2 might be a critical oncogene and a potential prognostic biomarker in malignant diseases including HCC [8][9][10][11]. Furthermore, KPNA2 knock-down could significantly inhibit HCC proliferation [12]. But till now, the mechanistic evidence of KPNA2 in HCC was obscure and deserved to be explored.…”

Section: Introductionmentioning

confidence: 99%

Pleomorphic adenoma gene 1 mediates the role of Karyopherin alpha 2 and has prognostic significance in hepatocellular carcinoma

Yuan

Yang

et al. 2014

J Exp Clin Cancer Res

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“…The staining was assessed by two separate investigators who were blind to the patient characteristics. The positive KPNA2 and PLAG1 staining was defined as nucleus staining in more than 5% cells [12]. …”

Section: Methodsmentioning

confidence: 99%

“…Recent studies have illustrated that KPNA2 might be a critical oncogene and a potential prognostic biomarker in malignant diseases including HCC [8]–[11]. Furthermore, KPNA2 knock-down could significantly inhibit HCC proliferation [12]. But till now, the mechanistic evidence of KPNA2 in HCC was obscure and deserved to be explored.…”

Section: Introductionmentioning

confidence: 99%

Pleomorphic adenoma gene 1 mediates the role of karyopherin alpha 2 and has prognostic significance in hepatocellular carcinoma

Yuan

Yang

et al. 2014

J Exp Clin Cancer Res

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BackgroundKaryopherin alpha 2 (KPNA2) promotes tumor growth in hepatocellular carcinoma (HCC). We aimed to determine the content and clinical significance of mechanism underlying.MethodsThe association of transcriptional factor pleomorphic adenoma gene 1 (PLAG1) with KPNA2 was explored by co-immunoprecipitation. In vitro gain- and loss-of-function models were established to explore the functional interaction. Clinical samples from 314 HCC patients were applied to explore the clinical significance.ResultsWe found that PLAG1 could associate with KPNA2 and be promoted into nucleus by KPNA2. The increment of proliferative and metastatic abilities by KPNA2 over-expression can be significantly retarded by PLAG1 inhibition. The co-enrichment of KPNA2 and PLAG1 in nucleus is observed in clinical samples and can distinguish patients with the worst prognosis. The positive PLAG1 expression is an independent risk factor of recurrence free survival (HR: 1.766, 1.315-2.371; P = 0.000) and overall survival (HR: 1.589, 1.138-2.220; P = 0.007). Especially for patients with positive KPNA2 staining (N = 152), the positive PLAG1 expression is the sole risk factor for both recurrence free survival (HR: 1.749, 1.146-2.670; P = 0.010) and overall survival (HR: 1.662, 1.007-2.744; P = 0.047).ConclusionsThe nuclear import of PLAG1 by KPNA2 is essential for the role of KPNA2 in HCC cells and is significant to predict poor survival of HCC patients after hepatectomy.

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“…3−12 The elevated expression of KPNA2 has been correlated with poor prognosis and is associated with tumor invasiveness [8][9][10][11]13,14 The lung adenocarcinoma cell lines CL1-0 and CL1-5 were derived from a 64-year-old man with poorly differentiated lung adenocarcinoma. A transwell invasion chamber was used to progressively select more invasive cancer cell populations from parental CL1 cells.…”

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confidence: 99%

Quantitative Proteomics Reveals a Novel Role of Karyopherin Alpha 2 in Cell Migration through the Regulation of Vimentin–pErk Protein Complex Levels in Lung Cancer

Wang

et al. 2015

J. Proteome Res.

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Karyopherin alpha 2 (KPNA2) is overexpressed in various human cancers and is associated with cancer invasiveness and poor prognosis. Herein, to understand the essential role of KPNA2 protein complexes in cancer progression, we applied stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomic strategy combined with immunoprecipitation (IP) to investigate the differential KPNA2 protein complexes in lung adenocarcinoma cell lines with different invasiveness potentials. We found that 64 KPNA2-interaction proteins displayed a 2-fold difference in abundance between CL1-5 (high invasiveness) and CL1-0 (low invasiveness) cells. Pathway map analysis revealed that the formation of complexes containing KPNA2 and cytoskeleton-remodeling-related proteins, including actin, beta tubulin, tubulin heterodimers, vimentin, keratin 8, keratin 18, and plectin, was associated with cancer invasiveness. IP demonstrated that the levels of KPNA2-vimentin-pErk complexes were significantly higher in CL1-5 cells than in CL1-0 cells. The KPNA2-vimentin-pErk complex was also up-regulated in the advanced stage compared with the early-stage lung adenocarcinoma tissues. Importantly, the levels of pErk as well as cell migration ability were significantly reduced in KPNA2-knockdown cells; however, migration was restored by treatment with pErk phosphatase inhibitors. Collectively, our results demonstrate the usefulness of a SILAC-based proteomic strategy for identifying invasiveness-associated KPNA2 protein complexes and provide new insight into the KPNA2-mediated modulation of cell migration.

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Importin-α1 as a Novel Prognostic Target for Hepatocellular Carcinoma

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

Cited by 50 publications

References 39 publications

Pleomorphic adenoma gene 1 mediates the role of Karyopherin alpha 2 and has prognostic significance in hepatocellular carcinoma

Pleomorphic adenoma gene 1 mediates the role of Karyopherin alpha 2 and has prognostic significance in hepatocellular carcinoma

Pleomorphic adenoma gene 1 mediates the role of karyopherin alpha 2 and has prognostic significance in hepatocellular carcinoma

Quantitative Proteomics Reveals a Novel Role of Karyopherin Alpha 2 in Cell Migration through the Regulation of Vimentin–pErk Protein Complex Levels in Lung Cancer

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