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Background: To 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. Method: The 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. Results: The 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 (P RSK4 = 0. 002; P MMP-9 = 0. 002; P CD44 = 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 (P RSK4 = 0.019; P CD44 = 0.026; P MMP-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. Conclusions: 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.

ObjectiveAccumulating experimental evidence has identified the beneficial effects of the anti-aging protein, serum soluble α-Klotho, on longevity, and the cardiovascular system. Although a previous study has revealed the predictive value of α-Klotho on total cardiovascular disease (CVD), the associations between α-Klotho and specific CVDs, including congestive heart failure (CHF), coronary heart disease (CHD), myocardial infarction (MI), and stroke, remains to be fully elucidated in humans.MethodsFor 8,615 adults in the 2007 to 2016 National Health and Nutrition Examination Survey, stratified multivariable logistic regression models, restricted cubic spline curves, and subgroup analyses were used to evaluate the associations between α-Klotho and the four specific CVDs.ResultsIn the quartile analyses, compared to those in the highest quartile, participants in the lowest level of α-Klotho were significantly associated with CHF [odds ratio (OR) = 1.46, 95% CI: 1.09–1.97] and MI (1.33, 1.02–1.74), which was not the case for CHD (1.12, 0.91–1.38) or stroke (0.96, 0.73–1.25). Each unit increment in the ln-transformed α-Klotho concentrations was only positively associated with a 38 and 24% reduction in the prevalence of CHF and MI, respectively. Restricted cubic spline curves indicated that the α-Klotho was correlated with CHF and MI in linear-inverse relationships.ConclusionThe present findings suggested that the serum soluble α-Klotho is significantly associated with the prevalence of CHF and MI. To better determine whether α-Klotho is a specific biomarker of CVD, particularly for CHD and stroke, further research in humans is needed.

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