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

Wen-Lang Fan,Yuan-Ming Yeh,Tsung-Ta Liu,Tse-Yen Yang,Chao-Wei Lee,Tsung-Chieh Lin,Wei-Ming Lin

doi:10.3390/biom11030431

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.

Highlights

Emerging evidence has demonstrated leptin’s roles in regulating cancer progression, including tumor proliferation, metastasis, angiogenesis, and drug resistance [1]
Leptin was previously characterized as a peptide hormone secreted by adipocytes, and it functions as the ligand of leptin receptor (LEPR), which regulates energy expenditure and hunger [3,4]
85% of Renal cell carcinoma (RCC) patients are diagnosed as subtype of RCC, clear cell RCC [9]. ccRCC is insensitive to traditional radiotherapy or chemotherapy, and the most common therapeutic strategy is nephrectomy [10]

Summary

Introduction

Emerging evidence has demonstrated leptin’s roles in regulating cancer progression, including tumor proliferation, metastasis, angiogenesis, and drug resistance [1]. Recent findings have shown leptin and leptin receptor expression beyond traditional tissues, thereby suggesting the signaling pathway’s pivotal role outside of its physiological modulation. Several tissues express leptin, including the placenta, stomach, fibroblasts, mammary epithelium, and skeletal muscle [5,6,7,8]. CcRCC is insensitive to traditional radiotherapy or chemotherapy, and the most common therapeutic strategy is nephrectomy [10]. Approximately 20 to 30% of patients have distant metastases at the time of diagnosis, and around 30% of patients in the aforementioned cohort progress to local recurrence or distant metastasis after nephrectomy for localized disease [11,12]

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