Clear cell renal cell carcinoma accounts for about 2% of all cases of cancers, with an annual increase of 1.5-5.9% worldwide [13, 14]. The initial treatment is usually a radical or partial nephrectomy, which remains the mainstay of curative treatment . Unfortunately, ccRCC is resistant to radiation therapy and chemotherapy, but some tumors respond to molecular-targeted therapy. Therefore, identification of specific molecular biomarkers of ccRCC is an essential prerequisite. Although the numerous molecular markers, such as p53, vascular endothelial growth factor (VEGF), hypoxia inducible factor, Ki67 (proliferation), have been investigated as prognostic variables in ccRCC, the molecular mechanisms of the initiation and progression of ccRCC still remain unclear [16, 17]. Massively parallel sequencing analysis showed that DUSP-9 is downregulated in ccRCC .
DUSP-9 is a member of the dual-specificity protein phosphatase subfamily and is expressed only in the placenta, kidney, and during the fetal life. Moreover, DUSP-9 is known to be associated with squamous cell carcinoma (SCC) and can independently induce SCC . DUSP-9 inactivates the target kinases of squamous carcinoma cells by dephosphorylating both the phosphoserine/threonine and phosphotyrosine residues. DUSP-9 negatively regulates members of the mitogen-activated protein (MAP) kinase superfamily (MAPK, p38, SAPK), which are associated with cellular proliferation and differentiation [18–20]. Molly Kulesz-Martin et al. found that DUSP-9 reconstitution resulted in G2-M-associated cell death and microtubule disruption. Loss of DUSP-9 was associated with SCC, and it independently induced SCCs relative to benign tumors in mouse skin. Reconstitution of DUSP-9 expression in malignant tumor cells induces cell death and tumor suppression [6, 21, 22].
However, to our knowledge, the key feature of this study is that this is the first study to report the clinical significance of DUSP-9 in ccRCC. This is also the first study aimed at evaluating the possibility of using DUSP-9 as a clinically potential indicator for disease progression, as well as a prognostic marker for patient survival in tumors.
In this study, we showed that DUSP-9 mRNA and protein expression were significantly different between the ccRCC and the adjacent normal renal tissue samples. Furthermore, immunohistochemical analysis showed that DUSP-9 expression was moderate to low in ccRCCs, while it was high in the adjacent normal tissues. Accordingly, we found that DUSP-9 expression was reduced in a large number of human clinical ccRCC samples. The decreased expression of DUSP-9 was correlated with gender, pathologic stage, Fuhrman grade, tumor size, recurrence, TNM stage, and prognosis. Patients with lower DUSP-9 expression had shorter survival time, and those with higher DUSP-9 expression had a longer survival time. In addition, the relationship of DUSP-9 expression with prognosis was determined in the patients, which were divided into 3 subgroups depending on the pathologic stage. We found that DUSP-9 could be a valuable prognostic marker for ccRCC patients at all disease stages. Consistent with previous reports of other cancers, low-expression of DUSP-9 indicated poor prognosis for patients with ccRCC.
DUSP-9 expression is correlated with low Fuhrman grade. This result did not match with the other correlations. However, in the survival analysis, we found that patients with tumors high DUSP-9 expression had significantly longer overall survival than those with low expression of DUSP-9 either in the Fuhrman grade I subgroup, II subgroup, the stage III sub group, or the stage IV subgroup. We observed that there are more cases with low Fuhrman grade. In addition, this was a single hospital-based, retrospective study. In addition to this observation, we have, in particular, found that DUSP-9 expression is correlated with low Fuhrman grade.
The TNM stage of ccRCC and Fuhrman grade are closely related to its prognosis [23–25]. In our study, the results of univariate Cox regression analysis showed that tumor size, T stage, N stage, metastasis, Fuhrman grade and DUSP-9 expression were significantly associated with overall survival. Furthermore, multivariate Cox regression analysis revealed that only DUSP-9 expression and Fuhrman grade were independent predictors for the overall survival of ccRCC patients. Thus, our findings indicate that the DUSP-9 expression level has a significant correlation with clinicopathological features and is a potential prognostic marker for ccRCC.
Our study was a single hospital-based, retrospective study. It should be pointed out that unmeasured differences may exist and may distort the study results. A multicenter or community-based prospective study with more extensive collection of potential confounders is required. In addition, the correlation of DUSP-9 with the above-mentioned molecular markers needs to be investigated further. Apparently, more studies are required to explore the relationship between the DUSP-9 gene and other genes such as p38 that may be associated with ccRCC.