We found that the nucleus import of PLAG1 was aided by KPNA2 and would amplify the transcriptional activities of PLAG1 in HCC. Several genes including IGF-II, CRABP2, CRLF1, CRIP2, which are transcriptional targets of PLAG1, could be up-regulated by enhanced KPNA2. IGF-II is frequently up-regulated in HCC and was enriched in the proliferation subclass of the molecular classification of HCC Staurosporine nmr [27]. Besides, inhibition of IGF-II could impair the proliferation and invasive activities of HCC cells [20]. Furthermore, inhibition of PLAG1 in cell clones with stable KPNA2 over-expression
could abolish the up-regulation of these genes and could counteract the pro-tumoral effects of KPNA2. The result implied that downstream molecular of PLAG1 such as IGF-II might
be partly responsible for the role of KPNA2 in HCC. Although we revealed PLAG1 would be a critical mediator for KPNA2, it is noteworthy that whether other transcriptional factors carried into nucleus by KPNA2 might participate in HCC regulation need to be explored. Cancer classification using biomarkers may effectively define the risk of recurrence, which allows for the use of AZD1152 cell line appropriate treatments to acquire a better prognosis. The prognosis of patients with positive KPNA2 expression could be clustered by the status of PLAG1 nucleus enrichment, validating that the biological effects of KPNA2 relied on the interaction with PLAG1. Besides, for the subgroup of patients with negative PLAG1 expression, AMPK inhibitor the prognostic value of
KPNA2 came to be lost, further confirming that inhibition of PLAG1 could significantly retard the role of KPNA2 in tumor growth and metastasis in vitro as shown in Figure 2b and 2d. Combined with nucleus enrichment of PLAG1, the positive KPNA2 status would be more accurate to predict the prognosis of HCC patients after hepatectomy. Patients with co-existence of positive KPNA2 expression next and positive PLAG1 expression should be closely monitored and receive appropriate adjuvant therapies. However, further investigation should be done to validate the prognostic value of KPNA2 and PLAG1 in other cohort of HCC patients, which would be promising for clinical application to reduce the false positive rate to identify and monitor patients with high recurrent risk after hepatectomy. Conclusions PLAG1 could be impelled into nucleus by interaction with KPNA2, adapter acting in nucleus protein import. Co-enrichment of KPNA2 and PLAG1 in nucleus is observed in clinical samples. The increment of proliferative and metastatic abilities by KPNA2 can be significantly retarded by PLAG1 inhibition.