Clinical and biological significance of PIM1 kinase in osteosarcoma

Abstract

Osteosarcoma is the most prevalent histological form of primary malignant bone tumor. The majority of osteosarcoma patients have limited alternative therapeutic options and metastatic patients generally have a poor prognosis. Proto-oncogene serine/ threonine-protein kinase PIM1 is associated with growth and survival of many kinds of tumor cells. However, the role of PIM1 in osteosarcoma remains largely unknown. In this study, we investigated the functional and therapeutic relevance of PIM1 as a putative target in osteosarcoma. We found PIM1 was highly expressed in various osteosarcoma cell lines and in tumor tissues from osteosarcoma patients. Tissue microarray and immunohistochemistry analysis showed that the overall and disease-free survival rate of patients with high levels of PIM1 protein expression were significantly shorter than patients with low levels. High levels of PIM1 were also associated with present metastasis and can be considered as an independent prognostic factor in osteosarcoma patients. Knockdown of PIM1 expression by synthetic siRNA or shRNA greatly inhibited cell growth, migration, and invasion. Moreover, these changes accompanied with down-regulation of anti-apoptotic protein Bcl-2. The similar results were obtained in osteosarcoma cells treated with PIM1 specific inhibitor (SMI-4a). These results suggest that PIM1 kinase is critical for the growth and metastasis of osteosarcoma cells and can be a potential therapeutic target for osteosarcoma treatment. ß

Expression and function of PIM kinases in osteosarcoma

“…Nevertheless, in this present study, we demonstrated that all three PIM kinases were expressed in a majority of OS samples, but only positive expression of PIM1 was associated with poorer prognosis for overall survival of OS patients. The prognostic value of PIM1 in OS patients was also reported in the previous study (44). However, our univariate and multivariate Cox regression analyses indicated the three PIM kinases are not good predictors for overall survival of OS patients.…”

“…Some studies have reported that nuclear accumulation of PIM1 is necessary for its biologic effects and may correlate with tumor progression and disease stage (37,38). In the previous study, Liao et al reported that the cellular 34 kDa PIM1 isoform staining in OS tissues was predominantly nuclear (44). However, in our study, nuclear PIM1 localization was not dominant in our OS samples, and PIM1 nuclear staining accounted for 36.4% in the PIM1 positive group.…”

“…The literature on expression of PIM kinases in OS is extremely limited, Lu et al reported that the PIM1 gene locus (6p12-21) is a common amplification event in OS (43). More recently, during the course of this work, Liao et al reported five out of seven OS tissue samples had high expression of PIM1 protein, and 77.2% (88/144) OS specimens from 70 patients exhibited PIM1 immunostaining on the OS cell nucleus (44). Both of these studies indicated that PIM1 is expressed in OS and may therefore play an important role.…”

Pim1 supports human colorectal cancer growth during glucose deprivation by enhancing the Warburg effect

“…IHC results were evaluated by two certificated pathologists who were blinded to patient information. Pim1 expression was evaluated and quantified based on the intensity and extent of staining . Briefly, cytoplasmic and/or nuclear staining of Pim1 was assigned an intensity score (0 [no staining], 1 [weak], 2 [moderate], and 3 [strong]) and an extent score (0 [no staining], 1 [<10% cells], 2 [10%‐50% cells], 3 [>50% cells]).…”

Targeting programmed cell death ligand 1 by CRISPR/Cas9 in osteosarcoma cells

“…Osteosarcoma TMAs were generated as described previously [32, 33]. PD-L1 expression was evaluated by immunohistochemistry as previously described [34].…”