ReviewApelin/APJ system and cancer
Introduction
Apelin is a bioactive peptide originally identified from bovine stomach extracts by Tatemoto et al. in 1998 [1]. Apelin has been recognized as the endogenous ligand of the human G protein-coupled receptor APJ (APLNR), a seven-transmembrane receptor related to angiotensin-type 1 receptor [1]. Therefore, the novel discovered ligand was called apelin (APJ Endogenous Ligand). The amino acid (aa) sequence of APJ has strong homology with the angiotensin II type-1 receptor (AT1) (31% for entire sequence and 54% in transmembrane domains), however, angiotensin II does not bind to APJ [2]. The human apelin gene (APLN) is located on chromosome Xq25-q26.1, and encodes a secreted 77-amino acid precursor called preproapelin [3]. The preproapelin with a signal peptide, a prodomain, and a C-terminal peptide, which contain several potential proteolytic cleavage sites for endopeptidases. The preproapelin is cleaved and produces a family of apelin fragments, including apelin-36, apelin-17, apelin-13, apelin-12 and so on [1], [4]. In addition, the pyroglutamate apelin-13, which is protected from exopeptidase degradation [5], was identified as the major apelin isoform in human plasma [6]. The shorter C-terminal peptides consisting of 13 to 19 amino acids were found to exhibit much higher activity than apelin-36 [4].
Apelin/APJ mRNA and protein are widely expressed in the central nervous system (CNS) and the periphery in human and rodents. The APJ mRNA was extensively detected in human CNS, however, the highest mRNA level was found in spinal cord, callosum and bone marrow. The APJ mRNA was found in most of the human peripheral tissues, such as heart, lung, kidney, adipose tissue, muscle, etc., while the highest level were spleen and placenta. The APJ protein was found in human heart, liver, lung, kidney, stomach, etc. [7]. The distribution of apelin mRNA and protein in human or rodents were similar with APJ. The expression sites of apelin/APJ system indicate that they may play a critical role in multiple systems. A wide array of normal physiological processes have been described, including cardiovascular regulation [8], angiogenesis [9], energy metabolism [10], fluid homeostasis [11], the neuroendocrine stress response [12], feeding behavior [13], and pain [14], [15]. Moreover, apelin/APJ signaling is implicated in several pathologies, including heart disease, diabetes, obesity, and cancer [16]. The expression changes of apelin/APJ in cancer patients, tumor tissues, and cancer cell lines were showed in Table 1.
Apelin was required for normal vascular development in the frog embryo [17], and APJ was mainly expressed in the endothelial cells (ECs) of the developing vascular system during embryonic development [18]. Apelin/APJ system is strongly expressed in the adult vessel walls, especially in blood ECs [19]. In human umbilical vein endothelial cells (HUVECs), apelin treatment could increase angiogenic responses, including endothelial cell migration, proliferation and Matrigel® capillary tubelike structure formation [20]. Kasai et al. also found that apelin enhanced migration, proliferation, and capillary-like tube formation of retinal endothelial cell line RF/6A [21]. In vitro, apelin was showed to promote growth of human umbilical ECs and mouse brain microvasculature-derived ECs [17], [22]. Apelin overexpression was reported to enhance the vascularization and increase the in vivo tumor growth in mice [23]. Lacquaniti et al. has reported that serum apelin levels of cancer patients were significantly higher than those measured in healthy subjects, and apelin was gradually increased in increasing stages of cancer (from stage II to IV) [24]. The over- or under-expression patterns of APLN/APLNR in diverse cancer types were shown in Fig. 1, which was obtained from on-line Oncomine software analysis (www.oncomine.com) [25]. Recent reports show that apelin may be as a potentially important proangiogenic factor in cancers [23], [26], [27]. This article summarized the latest research progress about relationship between apelin/APJ system and cancer.
Section snippets
Lung cancer
Berta et al. [28] found that apelin mRNA level was increased in human non-small cell lung cancer (NSCLC) samples, compared with normal lung tissue samples, and high level of apelin protein was related to elevated microvessel densities and poor overall survival. Apelin overexpression in NSCLC cells significantly stimulated tumor growth and microvessel densities and perimeters in vivo. In addition, Yang et al. demonstrate that APJ was detected in human lung adenocarcinoma tissues by
Apelin/APJ system and tumor neoangiogenesis
Accumulating evidence suggests that hypoxia is a major driving force for the initiation of angiogenesis [20], [45], [46], [47]. In response to hypoxia, the transcription of angiogenic genes, such as VEGF, were upregulated by hypoxia-inducible factor (HIF) in adipocytes. It is now well established that angiogenesis is essential for tumor growth and metastasis [48]. The growth of solid tumors is relay on the formation of neovascular, so suppression of tumor-induced neoangiogenes is represents a
Conclusion
Apelin/APJ system was involved in occurrence and/or development of tumors, including lung cancer, gastroesophageal and colonic cancer, hepatocellular carcinoma, prostate cancer and endometrial cancer, oral squamous cell carcinoma and brain cancer, and tumor neoangiogenesis (Fig. 3). However, the mechanism underlying the relationship between apelin/APJ and the tumor genesis and progression is still unclear now. Apelin may be a novel forecasting and diagnostic index for the degree of cancer
Conflict of interest
All authors have no conflict of interests.
Acknowledgments
This study was supported by grants from the Scientific Research Foundation of Henan University (No. 2015YBZR053 & No. 2015YBZR050).
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