Abstract
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.
Highlights
Karyopherin alpha 2 (KPNA2) promotes tumor growth in hepatocellular carcinoma (HCC)
Transcriptional factor pleomorphic adenoma gene 1 (PLAG1) is promoted into nucleus by KPNA2 We applied co-immunoprecipitation using a polyclonal antibody of KPNA2 and proteins acquired from the assays were used for detection of PLAG1, with ACTB as a negative control
The association of PLAG1 with KPNA2 was confirmed in two HCC cell lines, as PLAG1, but not ACTB, could be detected in the precipitate enriched by KPNA2 antibody (Figure 1a)
Summary
Karyopherin alpha 2 (KPNA2) promotes tumor growth in hepatocellular carcinoma (HCC). Plenty of researches have performed to explore mechanisms underlying the initiation, propagation and development of HCC [3,4]. It raised the hypothesis that KPNA2 might affect cancer cells through the translocation of cancer-associated transcriptional factors. Previous report has indicated the direct association of KPNA2 with a zinc-finger transcription factors pleomorphic adenoma gene 1 (PLAG1) by the yeast twohybrid system [13], suggesting PLAG1 might be one of critical mediators of KPNA2 effects in malignant diseases. Whether KPNA2 might associate with PLAG1 and assist PLAG1 nucleus import to activate downstream effectors in HCC remains unclassified. We explored the functional interaction of KPNA2 with PLAG1 and the clinical significance of the mechanism in HCC
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