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

• Published in: Cell death & disease Vol. 11; no. 2; p. 117
• Main Authors: Wang, Chao, Wang, Yuning, Hong, Tianyu, Cheng, Bing, Gan, Sishun, Chen, Linbao, Zhang, Jing, Zuo, Li, Li, Jian, Cui, Xingang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.02.2020; Springer Nature B.V
• Subjects: 13/21; 13/51; 13/89; 38/77; 631/67/395; 631/67/589/1588/1351; 96/31; Animals; Antibodies; Antineoplastic Agents - pharmacology; Apoptosis; Autocrine Communication - drug effects; Autocrine signalling; Biochemistry; Biomedical and Life Sciences; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - secondary; Cell Biology; Cell Culture; Cell Line, Tumor; Chemokine CCL24 - genetics; Chemokine CCL24 - metabolism; Clear cell-type renal cell carcinoma; Disease Progression; Drug resistance; Drug Resistance, Neoplasm - genetics; Gene Expression Regulation, Neoplastic; Humans; Immunology; Kidney cancer; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Life Sciences; Male; Medical prognosis; Metastases; Metastasis; Mice, Inbred NOD; Mice, SCID; Molecular modelling; Patients; Prognosis; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Pyrimidines - pharmacology; Receptors, CCR3 - genetics; Receptors, CCR3 - metabolism; Signal Transduction; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Statistical analysis; Sulfonamides - pharmacology; Targeted cancer therapy; Tumor Burden - drug effects; Tumorigenicity; Xenograft Model Antitumor Assays
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-2306-6

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.