In this study, we have shown that the expression of IL4Rα and IL13Rα1 are associated with clinicopathological factors related to the progression of STSs, and there was a significant association between the expression of IL4Rα and IL13Rα1 in STSs. Furthermore, there was a positive correlation between the expression of mRNA IL4Rα and IL13Rα1 in glioblastoma multiform [9]. In addition, the expression of IL4Rα and IL13Rα1 were increased in meningioma compared with normal brain tissue [8] and were higher in invasive pituitary adenoma compared to non-invasive pituitary adenoma [7]. In STSs, the expression of mRNA of IL4Rα and IL13Rα1 were higher compared with normal counterpart tissue [STS versus normal (TPM, median expression): IL4Rα; 31.19 for STS and 23.15 for normal, IL13Rα1; 31.15 for STS and 17.33 for normal] and there was a significant correlation between the expression of IL4Rα and IL13Rα1 (Pearson’s R = 0.15, p = 0.016) in the GEPIA public database (http://gepia.cancer-pku.cn. accessed November 15, 2020) [23]. In addition, higher expression of IL4Rα and IL13Rα1 were associated with advanced clinicopathological factors of STSs such as higher tumor stage, cancer metastasis, higher histologic grade, increased mitosis, and tumor necrosis. Furthermore, nuclear and cytoplasmic expression of IL4Rα and IL13Rα1 were associated with shorter survival of STSs. Especially, individual and combined expression patterns of nuclear IL4Rα and IL13Rα1 were independent indicators of poor prognosis of STS patients. Consistently, although nuclear and cytoplasmic expression were not analyzed separately, higher expression of IL4Rα and IL13Rα1 were significantly associated with shorter cancer-specific survival and RFS of clear cell renal cell carcinoma patients [12]. Especially, clear cell renal cell carcinoma patients with co-positivity for the expression of IL4Rα and IL13Rα1 had the shortest survival time [12]. In addition, the prognostic significance of individual expression of IL4Rα or IL13Rα1 has been reported in various human cancers. Higher expression of mRNA and protein of IL4Rα was associated with shorter survival of mesothelioma patients [10]. In breast cancer, higher expression of IL13Rα1 was significantly associated with shorter OS and disease-specific survival [11]. Higher expression of IL13Rα1 mRNA was associated with poor prognosis of glioblastoma patients [9]. Therefore, targeting the IL4R complex might be a therapeutic strategy for cancers with poor prognosis that highly express IL4Rα and IL13Rα1.
The prognostic impact of the expression of IL4Rα and IL13Rα1 in human cancers is related to the role of IL4Rα/IL13Rα1 in cancer-related signaling. Although studies on the role of IL4Rα/IL13Rα1 in STSs has been limited, it has been reported that the IL4Rα/IL13Rα1 receptor complex is involved in tumorigenesis via mechanism the cell cycle, apoptosis, and cellular proliferation [1, 2, 12]. In renal cell carcinoma cells, knock-down of IL4Rα or IL13Rα1 induced cell cycle arrest and apoptosis by suppressing JAK2-mediated phosphorylation of FOXO3 [2]. In rhabdomyosarcoma cells, activation of IL4R with IL4 and IL13 ligands increased tumor growth through activation of STAT6, Akt, or MAPK pathways [16]. In 4T1 breast cancer cells, IL4Rα enhanced tumor growth by mediating IL4-related enhancement of glucose and glutamine metabolism [24]. The silencing of IL4Rα inhibited the growth and invasiveness of pancreatic cancer cells by suppressing the STAT3 and Akt pathways [25]. In colorectal cancer cells, IL13 induced epithelial-to-mesenchymal transition through the STAT6 pathway and was reversed with knock-down of IL13Rα1 [26]. However, there are controversial reports on the role of IL4R in tumorigenesis. In a transgenic mouse model with overexpression of IL4, IL4/IL4Rα suppressed the development of melanoma through activation of the P21-mediated STAT6 pathway and inhibition of anti-apoptotic BCL2 expression [27]. In addition, reduction of IL4R signaling was associated with increased initiation of colorectal cancer development, but reduced cancer progression [28]. This report emphasized that a therapeutic approach carefully targeting IL4R signaling according to the cancer progression stage could be effective [28]. Therefore, although most reports suggest the IL4R complex as a promising therapeutic target of human cancers, a tailred approach according to the specific subtype of cancer is likely to be the most effective.
In our results, both nuclear and cytoplasmic expression of IL4Rα and IL13Rα1 were significantly associated with the survival of STS patients. When considering the role of type II IL4R as a receptor for cytokines, IL4Rα and IL13Rα1 are expected to be localized in the cytoplasmic membrane. However, in this study, their expression in nuclei presented as a more powerful prognostic indicator of STSs compared with their cytoplasmic expression. Therefore, when we searched for the subcellular localization of IL4Rα and IL13Rα1 in a public database, nuclear expression of IL4Rα and IL13Rα1 was presented in The Human Protein Atlas database (https://www.proteinatlas.org. accessed November 15, 2020) [5, 29]. In addition, the expression of IL4Rα and/or IL13Rα1 was observed in both the cytoplasm and nuclei of human cancer tissue samples, such as clear cell renal cell carcinoma [12], squamous cell carcinoma [13], and lung cancer [30]. Moreover, when considering the nuclear and cytoplasmic expression of the molecules related to IL4Rα/IL13Rα1 such as JAK2 and STAT6 based on The Human Protein Atlas, the expression of IL4Rα/IL13Rα1 was expected in both cytoplasm and nuclei [5, 29]. Therefore, it is suggested that the nuclear localization of IL4Rα and IL13Rα1 might have a role in the progression of cancers. However, the significance of the nuclear localization of IL4Rα and IL13Rα1 in the progression of cancer is not clear. One possible explanation might be that IL4Rα/IL13Rα1 are involved in tumorigenesis in association with nuclear proteins related to tumor biology [12]. Recently, it has been reported that IL4Rα/IL13Rα1interact with nuclear protein JAK2 and FOXO3 [30]. In renal cell carcinoma cells, the silencing of IL4Rα expression reduced interaction between JAK2 and FOXO3 and resulted in stabilizing FOXO3 [7]. Therefore, when considering the oncogenic role of JAK2 and tumor-suppressive role of FOXO3, nuclear localization of IL4Rα/IL13Rα1 exerts its role by involving JAK2-FOXO3 interaction in the progression of STSs.
In this study, higher expression of IL4Rα and IL13Rα1 were associated with progression and poor survival of STS patients. Therefore, IL4Rα/IL13Rα1 might be a potential therapeutic target for STS patients. Based on the characteristics of the IL4Rα/IL13Rα1 receptor complex that is activated by both IL4 and IL13 and it stimulates the JAK1/JAK2/STAT6 pathway in solid cancers, IL4/IL13, IL4Rα/IL13Rα1, and JAK1/JAK2/STAT6 might be good therapeutic targets for the treatment of malignant tumors expressing IL4Rα/IL13Rα1. In rhabdomyosarcoma cells, IL4 and IL13 activate cellular proliferation through the JAK/STAT signaling pathway, and blocking IL4R with a neutralizing antibody suppressed tumor progression [16]. Blocking of IL4Rα also induced the apoptosis of breast cancer cells [31, 32]. In renal cell carcinoma cells, knock-down of IL4Rα or IL13Rα1 and pharmacological inhibition of JAK2 induced cell cycle arrest and apoptosis of cancer cells [12]. Similarly, inhibition of JAK2, which is downstream of IL4R, delayed tumor growth in an osteosarcoma xenograft model [17]. In addition, as IL4R is highly expressed in human cancers, receptor-directed anti-tumor therapeutic approaches have been tested. AP-1 (human atherosclerotic plaque-specific peptide-1)-conjugated liposomal conjugate specifically targeted at IL4Rα, showed an anti-cancer effect on IL4Rα-overexpressing colon cancer cells [33]. Furthermore, with respect to treatment of human cancers, one of the important aspects for archiving successful treatment is overcoming the resistance of cancer cells to anti-cancer therapeutics; thus, the regulation of host anti-immune mechanisms is one of the promising therapeutic strategies, and IL4R also might be a potential target to overcome cancer resistance [3]. Colorectal cancer-related cancer-initiating cells evade immune surveillance through IL4/IL4R-mediated inhibition of T cell proliferation [34]. Blocking of IL4R with IL4Rα antagonist or anti-IL4 neutralizing antibodies sensitized CD133-expressing colon cancer stem cells to conventional the chemotherapeutics oxaliplatin and 5-FU [35]. Therefore, when considering the shorter survival of STS patients expressing IL4Rα and IL13Rα1, therapeutics targeting IL4Rα and IL13Rα1 might be novel therapeutic strategems for the treatment of STSs.