Previous studies have shown that ELA possesses anti-apoptototic activity [15, 19]. Although the role of ELA in cancer has been investigated in a limited number of studies [20, 21], several studies have shown that apelin, which is the other endogenous ligand of APRLN, is overexpressed in many tumour tissues and cell lines, and the apelin/APLNR system plays a role in the regulation of cancer cell growth and migration [22,23,24].
In the present study, ELA levels were significantly higher in patients with CLL than in control group patients. This finding supports the anti-apoptotic effects of ELA and the apelinergic system reported in the literature.
Seo et al. showed that DNA damage-induced hnRNP L upregulates p53 expression [25].
Li et al. showed that ELA downregulates the interaction between hnRNPL and p53 [26], resulting in an anti-apoptotic effect. Additionally, Ganguly et al. reported increased ELA gene expression levels in glioblastoma cells and that an association exists between upregulated expression of ELA and poor prognosis [21]. Yi et al. reported increased ELA expression levels in ovarian cancer cells. Disruption of ELA expression in these cell lines suppressed cell growth, cell migration and cell cycle progression. They showed that ELA exerted this effect independently of APLNR, affecting cell growth and cell cycle progression in a p53-dependent manner. Loss of ELA in cells expressing high levels of p53 caused a decrease in cell number due to cell death, and this resulted from p53-induced cell apoptosis [20]. Mouse double minute 2 (MDM2) is a critical negative regulator of tumour suppressor p53 and plays a key role in controlling its transcriptional activity, protein stability and nuclear localisation. MDM2 expression is upregulated in many cancers, resulting in a loss of p53-dependent activities, such as apoptosis and cell cycle arrest [27]. The PI3K/Akt signalling pathway has been shown to play a critical role in the tumourigenesis of haematopoietic cells. Activation of the PI3K/Akt pathway occurs even in the early stages of tumour development, and it correlates with poor prognosis and therapeutic resistance in various human cancers [15, 28]. ELA activates the PI3K/AKT/mTORC1 signal to promote the progression of hESC cell cycle and protein translation and blocks stress-induced apoptosis. These pathways are the main signals reported to be correlated with apoptosis. MDM2 also inhibits p53 through this pathway. It has been suggested that the apelinergic system may inhibit apoptosis through these common pathways (7–11, 28).
hnRNPC is a negative regulator of p53. A previous study showed that the 1–41 p53 region, which is the region where p53 binds to Mdm2, also interacts with hnRNPC. These results show that hnRNPC may be synergistic with Mdm2 in regulating p53 stability. Doxorubicin competes with p53 for binding to the RNA recognition motif of hnRNPC, thereby enhancing p53 stability and triggering p53-dependent apoptosis [29]. ELA, which has been shown to possess anti-apoptotic activity, has been shown to interact with the CXCR4a signalling pathway, one of the chemokines [15, 19]. Chemokines are produced by cancer-associated fibroblasts, a component of stromal cells, and affect metastatic potential and site-specific spread of cancer cells. The stromal cell-derived factor-1 (SDF-1/CXCL12) belongs to the family of CXC chemokines. The effects of CXCL12 in many cancer types, including its role in promoting local invasion and distant metastasis from lung cancer metastasis, have been described [30,31,32]. Wang et al. showed that CXCL12 blocks apoptosis in human adenocarcinoma cell line via CXCR4. They observed that the expression levels of Bcl-2 and bcl-xl in the adenocarcinoma cell line increased with CXCL12 therapy and decreased with CXCR4 antagonist and JAK2 inhibitor therapy [33]. In summary, ELA and the apelinergic system have been shown to inhibit apoptosis in several steps (via bcl-2, bcl-xl, mdm2, hnRPLN, p53, and PI3K/Akt/mTORC1). Based on these results, it can be suggested that ELA and the apelinergic system play a central role in the pathogenesis of CLL.
In the present study, we showed that serum ELA levels were significantly high in patients with CLL. This finding indicates that ELA contributes to the development of CLL, which is consistent with the findings of other studies in the literature.
Venetoclax is a bcl-2 inhibitor and idasanutlin is a MDM2 inhibitor, and both are indicated for use in CLL. Venetoclax + idasanutlin have been suggested to be an effective treatment for relapsed/refractory acute myeloid leukaemia (AML) [34]. However, inhibition of ELA or the apelinergic system will exert the effect of both venetoclax and idasanutlin. In other words, inhibition of the apelinergic system alone can provide a treatment as effective as venetoclax and idasanutlin or even a combination of the two. Yi et al. showed that human ELA can downregulate p53 protein levels and activity in cancer cells instead of working as a p53 activator. Although ovarian cancer cells are typically normal type p53, no studies have assessed whether there is a correlation between p53 mutation status and ELA expression levels in ovarian cancer [20].
Because the number of patients with TP53 mutation was insufficient in the present study, we could not perform a statistically significant evaluation. However, future studies evaluating a sufficient number of patients will be valuable for CLL, in which TP53 mutations occur frequent. The results of our study provide evidence that ELA and the apelinergic system can be valuable in targeted therapy and may also be useful in predicting patient prognosis, response to treatment and follow-up. More comprehensive studies are needed to address these issues.