Abstract
The poor prognosis of clear-cell renal cell carcinoma (ccRCC) patients is due to progression and targeted drug resistance, but the underlying molecular mechanisms need further elucidation. This study examined the biological function and related mechanisms of gankyrin in ccRCC based on the results of our previous study. To this end, in vitro functional experiments; in vivo models of subcutaneous tumor formation, lung metastasis, and orthotopic ccRCC; and antibody chip detection, co-IP, ChIP assays were performed to examine the biological role and molecular mechanisms of gankyrin in ccRCC. Two hundred fifty-six ccRCC patients were randomly divided into training and validation cohorts to examine the prognostic value of gankyrin and other markers through IHC and statistical analyses. We observed that the gankyrin-overexpressing ccRCC cell lines 786-O and 769-P exhibited increased proliferation, invasion, migration, tumorigenicity, and pazopanib resistance and decreased apoptosis, while gankyrin knockdown achieved the opposite results. Mechanistically, gankyrin recruited STAT3 via direct binding, and STAT3 binding to the CCL24 promoter promoted its expression. Reciprocally, an increase in autocrine CCL24 enhanced the expression of gankyrin and STAT3 activation via CCR3 in ccRCC, forming a positive autocrine-regulatory loop. Furthermore, in vivo experimental results revealed that blocking the positive loop through gankyrin knockdown or treatment with the CCR3 inhibitor SB328437 reversed the resistance to pazopanib and inhibited lung metastasis in ccRCC. Moreover, a positive correlation between gankyrin and STAT3 or CCL24 expression in ccRCC specimens was observed, and improved accuracy for ccRCC patient prognosis was achieved by combining gankyrin and STAT3 or CCL24 expression with existing clinical prognostic indicators, including the TNM stage and SSIGN score. In summary, targeting the gankyrin/STAT3/CCL24/CCR3 autocrine-regulatory loop may serve as a remedy for patients with advanced ccRCC, and combining gankyrin and STAT3 or CCL24 expression with the current clinical indicators better predicts ccRCC patient prognosis.
Highlights
Renal cell carcinoma (RCC) serves as one of the most common malignant tumors worldwide[1]
Because our previous study showed that the expression of gankyrin positively associates with the targeted drug resistance in RCC10, we investigated the involvement of gankyrin in the resistance of clear-cell renal cell carcinoma (ccRCC) to the first-line targeted drug pazopanib
Based on our previous studies, this study further demonstrated that gankyrin facilitated the progression of ccRCC by activating the positive regulatory loop consisting of STAT3/CCL24/chemokine receptor 3 (CCR3)
Summary
Renal cell carcinoma (RCC) serves as one of the most common malignant tumors worldwide[1]. Wang et al Cell Death and Disease (2020)11:117 targeted therapies have been developed for advanced and metastatic ccRCC, the treatment responses vary, and many patients still experience progression[2]. High gankyrin expression in specimens from patients with tumors indicates disease progression and poor prognosis[6]. Gankyrin facilitates the proliferation, tumorigenicity, metastasis, and drug resistance of tumors through metabolic reprogramming and the mediation of signaling pathways such as the Wnt/β-catenin pathway, NF-κB pathway, PI3K/AKT/HIF-1α/cyclin D1, RhoA/ROCK, and mTORC1 signaling[6,7,8,9]. Our previous study demonstrated that gankyrin is upregulated in RCC specimens, and that high gankyrin expression in RCC patients predicts disease progression and poor prognosis[10]. The biological function and mechanisms of gankyrin in ccRCC have not been examined
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