Abstract
Specific kinds of interleukin (IL) receptors are known to mediate lymphocyte proliferation and survival. However, recent reports have suggested that the high expression of IL4Rα and IL13Rα1 in tumor tissue might be associated with tumorigenesis in several kinds of tumor. We found that a significant association between mRNA level of IL4Rα or IL13Rα1 and the poor prognosis of renal cell carcinoma (RCC) from the public database (http://www.oncolnc.org/). Then, we evaluated the clinicopathological significance of the immunohistochemical expression of IL4Rα and IL13Rα1 in 199 clear cell RCC (CCRCC) patients. The individual and co-expression patterns of IL4Rα and IL13Rα1 were significantly associated with cancer-specific survival (CSS) and relapse-free survival (RFS) in univariate analysis. Multivariate analysis indicated IL4Rα-positivity and co-expression of IL4Rα and IL13Rα1 as the independent indicators of shorter CSS and RFS of CCRCC patients. For the in vitro evaluation of the oncogenic role of IL4Rα and IL13Rα1 in RCC, we knock-downed IL4Rα or IL13Rα1 and observed that the cell proliferation rate was decreased, and the apoptosis rate was increased in A498 and ACHN cells. Furthermore, we examined the possible role of Janus kinase 2 (JAK2), well-known down-stream tyrosine kinase under the heterodimeric receptor complex of IL4Rα and IL13Rα1. Interestingly, JAK2 interacted with Forkhead box O3 (FOXO3) to cause tyrosine-phosphorylation of FOXO3. Silencing IL4Rα or JAK2 in A498 and ACHN cells reduced the interaction between JAK2 and FOXO3. Moreover, pharmacological inhibition of JAK2 induced the nuclear localization of FOXO3, leading to increase apoptosis and decrease cell proliferation rate in A498 and ACHN cells. Taken together, these results suggest that IL4Rα and IL13Rα1 might be involved in the progression of RCC through JAK2/FOXO3 pathway, and their expression might be used as the novel prognostic factor and therapeutic target for RCC patients.
Highlights
In 2018, about 65,000 Americans were diagnosed with kidney cancer
Janus kinase 2 (JAK2) interacted with Forkhead box O3 (FOXO3) to cause tyrosine-phosphorylation of FOXO3. These results suggest that IL4Rα and interleukin13 receptor α1α1 (IL13Rα1) might be involved in the progression of Renal cell carcinoma (RCC) through JAK2/FOXO3 pathway, and their expression might be used as the novel prognostic factor and promising therapeutic target for RCC patients
We investigated a biochemical mechanism to explain the relationship between IL4Rα and IL13Rα1 expressions, as well as the shorter survival see in clear cell renal cell carcinoma (CCRCC) patients [99]
Summary
In 2018, about 65,000 Americans were diagnosed with kidney cancer. About 15,000 died of this disease [1]. Renal cell carcinoma (RCC) is the most common subtype (about 90%) of kidney cancer. 80% of RCC are classified into clear cell renal cell carcinoma (CCRCC) [2,3]. At the time of initial diagnosis, more than 30% of the patients had metastasis and 20–40% of the patients had systemic metastasis after surgery [4]. Surgical resection is the first and effective treatment option for the early stage kidney cancer. It is still needed to understand the detail molecular mechanism of RCC development for efficient care
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