Leptin Is Associated with Poor Clinical Outcomes and Promotes Clear Cell Renal Cell Carcinoma Progression

Abstract

Emerging evidence has shown the oncogenic roles of leptin in modulating cancer progression in addition to its original roles. Analyses of transcriptomic data and patients’ clinical information have revealed leptin’s prognostic significance in renal cell carcinoma (RCC). However, its biological effects on RCC progression have not yet been explored. Clinical and transcriptomic data of a RCC cohort of 603 patients were retrieved from The Cancer Genome Atlas (TCGA) and analyzed to reveal the correlation of leptin with clinical outcomes and the hierarchical clustering of gene signatures based on leptin levels. In addition, cox univariate and multivariate regression analyses, cell migration upon leptin treatment, identification of putative leptin-regulated canonical pathways via ingenuity pathway analysis (IPA), and the investigation of induction of Wnt5a, ROR2, and Jun N-terminal Kinases (JNK) phosphorylation activation were performed. We first observed a correlation of high leptin levels and poor outcomes in RCC patients. Knowledge-based analysis by IPA indicated the induction of cancer cell migration by leptin, which was manifested via direct leptin treatment in the RCC cell lines. In RCC patients with high leptin levels, the planar cell polarity (PCP)/JNK signaling pathway was shown to be activated, and genes in the axis, including CTHRC1, FZD2, FZD10, ROR2, WNT2, WNT4, WNT10B, WNT5A, WNT5B, and WNT7B, were upregulated. All of these genes were associated with unfavorable clinical outcomes. WNT5A and ROR2 are pivotal upstream regulators of PCP/JNK signaling, and their correlations with leptin expression levels were displayed by a Pearson correlation analysis. The inhibition of signal transduction by SP600125 reversed leptin-mediated cell migration properties in RCC cell lines. The results indicate the prognostic impact of leptin on RCC patients and uncover its ability to promote cell migration via PCP/JNK signaling.

Potential Value of Visfatin, Omentin-1, Nesfatin-1 and Apelin in Renal Cell Carcinoma (RCC): A Systematic Review and Meta-Analysis

“…Adipokines induce proliferation and apoptosis in RCC, by up-regulating the p-AMPK and Bcl-xL levels [ 19 ]. Leptin was shown to promote cell migration of RCC cells via the activation of the PCP/JNK signalling pathway [ 20 ]. In contrast, leptin had contradictory findings: its expression was not associated with the development and prognosis of RCC [ 21 ].…”

Leptin and Beyond: Actors in Cancer

“…The association of leptin with poor clinical outcomes in clear cells' renal cell carcinoma (ccRCC) was reported by Fan and colleagues [14]. Clinical information and transcriptomic data of a cohort of 603 ccRCC patients were retrieved from The Cancer Genome Atlas (TCGA) and examined by the authors.…”