Low expression of PHLPP1 in sacral chordoma and its association with poor prognosis

Abstract

Sacral chordoma is a rare spine tumor with a high recurrence rate even after optimal therapy. Previous studies have demonstrated that the PI3K/AKT pathway plays a pivotal role in chordoma, and high expression of pAKT is associated with poor prognosis. Recently, PHLPP was recognized to be a tumor suppressor that targets AKT. We analyzed the expression of PHLPP1 and AKT2 in 37 chordoma samples and 11 fetal nucleus pulposus samples by immunohistochemical staining. Of the chordoma cases, 40.5% (15/37) showed strong cytoplasmic staining (score ≥3) for PHLPP1, which was significantly lower than the 90.9% (10/11) of fetal nucleus pulposus samples (P = 0.004). Conversely, strong immunohistochemical staining for AKT2 was observed in 75.7% (28/37) of chordoma samples, which was significantly higher than 36.4% (4/11) of fetal nucleus pulposus (P = 0.021). Kaplan-Meier survival curves and log-rank test showed that patients with high expression of PHLPP1 experienced longer progression free survival time than those with low PHLPP1 expression (P = 0.011). Further multivariate Cox regression analysis indicated that PHLPP1 expression level and surgical approaches were independent risk factors for chordoma recurrence (P = 0.023 and P = 0.022). However, PHLPP1 expression was not statistically related to patients' total survival time. Conclusively, our results suggest that PHLPP1 plays a crucial role in sacral chordoma, and may be a promising biomarker for prognosis. Meanwhile, manipulation of PHLPP1 expression is also a potential therapeutic approach for the treatment of sacral chordoma.

Keywords: AKT2; PHLPP1; Sacral chordoma; tumor suppressor.

Figure 1

Representative expression of PHLPP1 and AKT2 in chordoma tissues. A. High expression of PHLPP1 in chordoma. B. Low expression of PHLPP1 in chordoma. C. High expression of AKT2 in chordoma. D. Low expression of AKT2 in chordoma. (magnification ×400).

Figure 2

Comparison of PHLPP1 expression in chordoma and fetal nucleus pulposus tissue. PHLPP1 is expressed at a level approximately 4-fold lower in chordoma than in fetal nucleus pulposus tissue, as shown by RT-qPCR.

Figure 3

Relationship of PFS to PHLPP1 expression. Kaplan-Meier survival analysis curves showed that patients with low expression of PHLPP1 relapsed more easily.