Abstract
BackgroundTo investigate the expression and function of RSK4, MMP-9 and CD44 in primary clear cell renal cell carcinoma (primary ccRCC) and metastatic clear cell renal cell carcinoma (metastatic ccRCC), as well as the correlation with clinicopathological features of patients.MethodThe expression levels of RSK4, CD44 and MMP-9 in 52 primary ccRCC samples and 48 metastatic ccRCC samples were detected by immunohistochemistry, and the relationship between RSK4, CD44 and MMP-9 expression and clinicopathological features as well as prognosis of metastatic ccRCC patients was statistically analysed. Ectopic RSK4 expression in ccRCC cell lines was performed to determine its effect on cell cycle regulation, tumour invasiveness, and metastatic capability.ResultsThe positive rates of RSK4, MMP-9 and CD44 expression in metastatic ccRCC tissues were 75, 68.75 and 91.7%, respectively, while the rates in primary ccRCC tissues were 44.2, 34.6 and 69.2%, respectively. Thus, the positive rates in metastatic ccRCC were higher than those in primary ccRCC (PRSK4 = 0. 002; PMMP-9 = 0. 002; PCD44 = 0. 001). However, the expression of RSK4, CD44 and MMP-9 was unrelated to age, gender, or metastatic sites (P > 0.05) but was related to WHO/ISUP nucleolar grade (PRSK4 = 0.019; PCD44 = 0.026; PMMP-9 = 0.049). In metastatic ccRCC, expression among the three proteins showed a positive correlation (P = 0.008). Moreover, expression between RSK4 and CD44 (P = 0.019) and MMP-9 and CD44 (P = 0.05) also showed positive correlations, whereas RSK4 and MMP-9 showed no significant correlation (P = 1.00). Molecular studies showed that overexpression of RSK4 could enhance the invasive and migratory abilities of ccRCC cell lines through the regulation of CD44 and MMP-9 expression and vice versa.ConclusionsThe overexpression of RSK4, MMP-9 and CD44 is associated with the invasion and metastasis of ccRCC, indicating that they could be potential prognostic factors and serve as new potential therapeutic targets for ccRCC.
Highlights
To investigate the expression and function of Ribosomal S6 protein kinase 4 (RSK4), MMP-9 and CD44 in primary clear cell renal cell carcinoma and metastatic clear cell renal cell carcinoma, as well as the correlation with clinicopathological features of patients
The overexpression of RSK4, MMP-9 and CD44 is associated with the invasion and metastasis of ccRCC, indicating that they could be potential prognostic factors and serve as new potential therapeutic targets for ccRCC
Expression of RSK4, CD44 and MMP-9 is unregulated in Metastatic renal cell carcinoma (mRCC) than in Primary renal cell carcinoma (pRCC) The positive expression rates of RSK4, CD44 and MMP9 in pRCC were 44.2% (Fig. 1a), 34.6% (Fig. 1b) and 69.2% (Fig. 1c), respectively
Summary
Clinical data A total of 100 consecutive patients with primary ccRCC between 2007 and 2016 were identified from the pathology archives of Xijing Hospital, and 52 pRCC and 48 mRCC samples were included in the study. The pRCC patients consisted of 45 males and 7 females with a mean age of 54.2 years (range: 19–80 years). The mRCC patients consisted of 41 males and 7 females with a mean age of 58.4 years (range: 28–80 years). Based on WHO/ISUP nucleolar grade, 33 cases were categorised as low grade (grade 1– 2), and 15 cases were classified as high grade (grade 3– 4). The metastatic sites included bones (23), soft tissues (10), lungs (6), brains (5), paranephros (1) and gall bladder (1). The median follow-up time was 36 months (range: 6–99 months). The specimen collection and study procedures were approved by the Ethics Committee of Xijing Hospital
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