Blocking the autocrine regulatory loop of Gankyrin/STAT3/CCL24/CCR3 impairs the progression and pazopanib resistance of clear cell renal cell carcinoma

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.

Gankyrin activates the hedgehog signalling to drive metastasis in osteosarcoma

“…Our previous study showed that gankyrin is an oncoprotein that is frequently up‐regulated in OS 5 . In addition, increasing evidence suggests that gankyrin is involved in the occurrence and progression of various tumours 6‐8 . Nevertheless, the potential role of gankyrin in OS metastasis is still unclear.…”

Nodal histiocytic sarcoma with prominent eosinophilic infiltration: expression of eotaxin-2 on tumor cells

“…Although a high level of eotaxin mRNA expression was detected in Hodgkin lymphoma, especially nodular sclerosis [ 18 ], eotaxin was expressed on fibroblasts rather than Hodgkin/Reed-Sternberg cells themselves [ 19 ]. Eotaxin-3 mRNA expression was detected in some cases of follicular lymphoma [ 20 ], and multiple reports on cancers associated with eotaxin-2 expression exist [ 21 – 23 ]. In clear cell renal cell carcinoma, patients with high eotaxin-2 expression had poor survival rates [ 21 ].…”

“…Eotaxin-3 mRNA expression was detected in some cases of follicular lymphoma [ 20 ], and multiple reports on cancers associated with eotaxin-2 expression exist [ 21 – 23 ]. In clear cell renal cell carcinoma, patients with high eotaxin-2 expression had poor survival rates [ 21 ]. In hepatocellular carcinoma, eotaxin-2 contributes to malignancy via the angiogenesis pathway and indicates a poor prognosis [ 22 ].…”

Identification of an independent immune-genes prognostic index for renal cell carcinoma

“…Given that targeted treatment for advanced and metastatic ccRCC has been fully developed, response to treatment is diverse [ 12 ]. Identification of molecular mechanisms and relevant prognostic factors may be critical to the treatment of ccRCC [ 13 ]. The prognosis of the tumor is closely connected with TME, particularly when considering the tumor immune microenvironment [ 14 , 15 ].…”