Blocking the autocrine regulatory loop of Gankyrin/STAT3/CCL24/CCR3 impairs the progression and pazopanib resistance of clear cell renal cell carcinoma
Open Access
- 12 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 11 (2), 1-19
- https://doi.org/10.1038/s41419-020-2306-6
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.This publication has 35 references indexed in Scilit:
- LBH589 Inhibits proliferation and metastasis of hepatocellular carcinoma via inhibition of gankyrin/stat3/akt pathwayMolecular Cancer, 2013
- Gankyrin promotes tumor growth and metastasis through activation of IL-6/STAT3 signaling in human cholangiocarcinomaHepatology, 2013
- The C-C motif chemokine ligands CCL5, CCL11, and CCL24 induce the migration of circulating fibrocytes from patients with severe asthmaMucosal Immunology, 2013
- PI3K, ERK, p38 MAPK and integrins regulate CCR3-mediated secretion of mouse and human eosinophil-associated RNasesAllergy, 2013
- Serotonin promotes the proliferation of serum-deprived hepatocellular carcinoma cells via upregulation of FOXO3aMolecular Cancer, 2013
- Autocrine stimulation of clear-cell renal carcinoma cell migration in hypoxia via HIF-independent suppression of thrombospondin-1Scientific Reports, 2012
- Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndromeBlood, 2009
- The oncoprotein gankyrin interacts with RelA and suppresses NF-κB activityBiochemical and Biophysical Research Communications, 2007
- Eotaxin-2 and Colorectal Cancer: A Potential Target for Immune TherapyClinical Cancer Research, 2007
- Up-Regulation of Functional Chemokine Receptor CCR3 in Human Renal Cell CarcinomaClinical Cancer Research, 2005