ACKR3 orchestrates Hedgehog signaling to promote renal cell carcinoma progression

Abstract

Renal cell carcinoma (RCC) is the second commonest urological malignant neoplasm and mortality rate of patients with RCC appears to be increasing each year. Thus, further understanding of the molecular mechanisms responsible for the development and progression of RCC is of particular importance. Here, we report that atypical chemokine receptor 3 (ACKR3) orchestrates the Hedgehog (Hh)‐GLI1 signaling to promote RCC progression. The expression of ACKR3 is elevated in RCC tissues, which is associated with malignant and clinical outcomes of RCC, and ACKR3 expression is positively correlated with GLI1 expression in RCC tissues. Mechanically, Hh promotes RCC progression through GLI1‐mediated ACKR3 transcription by the directly binding of GLI1 to ACKR3 gene, while CXCL12–ACKR3 axis simultaneously enhances Hh activation via the binding of ACKR3 to Smoothened (SMO), a receptor in Hh pathway, resulting in the upregulation of SMO phosphorylation that potentiates downstream signal activity and consequently contributes to RCC progression. Thus, our findings may provide with the evidence of developing a novel treatment method with specific target for RCC.

The oncogene MYBL2 promotes the malignant phenotype and suppresses apoptosis through hedgehog signaling pathway in clear cell renal cell carcinoma

“…SMO plays a crucial role as a signal transducer in the Hedgehog pathway, influencing cell apoptosis, migration, and invasion, particularly in ccRCC [ 18 ]. For a deeper comprehension of the relationship between MYBL2 and SMO, we conducted qRT-PCR to investigate the expression profiles of SMO in ccRCC samples.…”

Inflammation and Immunity Gene Expression Patterns and Machine Learning Approaches in Association with Response to Immune-Checkpoint Inhibitors-Based Treatments in Clear-Cell Renal Carcinoma

“…ACKR3 mRNA was significantly overexpressed in progressive disease. ACKR3 is overexpressed in many human cancers, including renal carcinoma, and is correlated with poor prognosis, tumor progression, and metastasis [21,22]. It is important to notice that atypical chemokine receptors (ACKRs) are basic regulatory components of the chemokine network in a wide range of pathological conditions, including cancer, suggesting the need to validate them as novel targets for immunotherapies [23].…”

PUS1 is a novel biomarker for evaluating malignancy of human renal cell carcinoma

“…HEK293T cells were maintained in high glucose DMEM (Hyclone, Logan, UT, USA) supplemented with 10% (v/v) fetal bovine serum (FBS, Life Technologies, Inc., Grand Island, NY). ACHN cells were cultured in MEM medium (Hyclone, USA) supplemented with 10% FBS, and Caki-1, Caki-2, 786-O, OSRC2, A498 and 769P cells were all incubated in RPMI-1640 medium (Hyclone, USA) containing 10% FBS as described previously [ 22 ]. All the cells were grown as a monolayer on plastic cell culture dishes at 37°C in 5% CO 2 .…”