Apelin and apelin receptor expression in renal cell carcinoma

Abstract

BACKGROUND: The APLNR (apelin receptor) has been shown to be an essential gene for cancer immunotherapy, with deficiency in APLNR leading to immunotherapy failure. The aim of this study is to investigate the expression of APLN (apelin) and APLNR in patients with renal cell carcinoma (RCC), and its association with clinicopathological parameters and survival. METHODS: Three well-characterised patient cohorts with RCC were used: Study cohort 1 (clear-cell RCC; APLN/APLNR mRNA expression; n = 166); TCGA validation cohort (clear-cell RCC; APLN/APLNR mRNA expression; n = 481); Study cohort 2 (all RCC subtypes; APLNR protein expression/immunohistochemistry; n = 300). Associations between mRNA/protein expression and clinicopathological variables/patients' survival were tested statistically. RESULTS: While APLN showed only very weak association with tumour histological grade (TCGA cohort), APLNR/mRNA protein expression correlate significantly with ccRCC aggressiveness. APLNR is expressed in tumour vasculature and tumour cells at different levels, and these expression levels associate with tumour aggressiveness in opposing directions. APLNR expression was negatively correlated with PD-L1 expression by tumour cells in a subset of patients with ccRCC. APLNR expression in either compartment is an independent prognostic factor for survival of patients with ccRCC. CONCLUSION: The APLNR/APLN-system appears to play an important role in ccRCC, warranting further clinical investigation.

Characterization of the Prognostic Values of the CXCR1-7 in Clear Cell Renal Cell Carcinoma (ccRCC) Microenvironment

“…According to our results and a previous study, the interactions among CXCRs, CXCL1, and CCL5 may mediate the regulatory T cells' participation in ccRCC progression (Wang et al, 2019). Recently, APLN receptor (APLNR) was considered to be an essential gene for tumor immunotherapy, which can modulate the function of CD8+T cells, but the immunological effects of the APLN/APLNR axis in ccRCC remain unknown (Tolkach et al, 2019). On the basis of previous research and our current results, we speculate that CXCRs may interact with APLN/APLNR axis to regulate the immune state of the tumor microenvironment in ccRCC.…”

Construct a circRNA/miRNA/mRNA regulatory network to explore potential pathogenesis and therapy options of clear cell renal cell carcinoma

“…PTGER3, CDCT2 and APLN have positive effects on overall survival time, but CXCL5 and GRM4 have negative effects on it. Research demonstrated that APLN could interact with APLN receptor, which is a G-protein-coupled receptor, which may influence the aggressive of ccRCC and the effect of immune therapy 56 . And C-X-C chemokine receptor 4 (CXCR4) is the major chemokine receptor in solid tumors.…”

Tumor angiogenesis: causes, consequences, challenges and opportunities

“…In another glioma study targeting APLNR with a competitive antagonist reduced tumor growth in mice [190]. In a renal cell carcinoma study, APLNR expression in a subset of patients was found to be negatively correlated with tumor PD-L1 expression [177]. This also indicates a role of APLN/APLNR signaling in the regulation of immunological processes, which needs to be further investigated.…”

“…The APLN/APLNR pathway is upregulated in malignant cells in many tumor types [174,176,177], as well as in tumor endothelial cells [178], and elevated Apelin levels are associated with disease progression and poor clinical outcome [176,[179][180][181]. Apelin expression in tumors is regulated by hypoxia [181] and is suggested to promote tumor growth in several ways.…”