Expression and Clinical Value Analysis of CSF2RA in Malignant Tumor Based on Database

Objective: to explore the expression and clinical value of CSF2RA in pan-cancer. Methods: the data was extracted from ONCOMINE, Human Protein Atlas and Kaplan Meier-plotter. The expression level of CSF2RA on cancer tissues and normal tissues, the relationship between CSF2RA and overall survival of cancer patients were analyzed, respectively. Results: CSF2RA mRNA was over-expressed on breast cancer, colorectal cancer, kidney cancer and liver cancer, and CSF2RA protein was over-expressed on melanoma. The expression level of CSF2RA was not associated with overall survival of cancer patients significantly. Conclusion: CSF2RA is over-expression on certain cancers and most immune cells, which maybe contributes to activation of immune system. The high expression of CSF2RA protein on melanoma is maybe associated with adverse outcome of application of GM-CSF.


Introduction
CSF2RA, "Colony stimulating factor 2 receptor alpha subunit (CD116)", is a receptor for GM-CSF (granulocyte-macrophage colony-stimulating factor), and plays a vital role for proliferation, differentiation and functional activation of hematopoietic cells such as macrophages and leukocytes [1]. The absence of GM-CSF or disruption of CSF2RA/GM-CSF pathway would interfere the differentiation of macrophages. It's been reported that CSF2RA is at over-expression in cancer tissues compared to normal tissues, and could enhance immune activity in tumor microenvironment [1] [2]; however, the internal mechanism about it hasn't been explored clearly. Similarly, the ligand, GM-CSF, has been ap-proved for clinical treatment of malignant tumor as an immune adjuvant, to initiate more robust activation of CD4 + and CD8 + T cells, induce rapid maturation of granulocytes, macrophages and specific antigen presentation reaction of dendritic cells and improve neutropenia subsequent after chemotherapy and radiotherapy. Nevertheless, it was reported that the GM-CSF could promote angiogenesis around tumors, inhibit immune response for tumor and facilitate to tumor relapse when GM-CSF was used for anti-tumor therapy, and the GM-CSF seduced negative cytokines to modulate immune suppression, which was possibly related with the expression of CSF2RA protein in tumor tissue [3] [4] [5].
Hence, this study supposes that CSF2RA is associated with cancer significantly, and analyzes expression difference between cancer and normal tissues, relationship between CSF2RA and overall survival of cancer patients, explores its clinical value by mining ONCOMINE, HPA and Kaplan Meier-plotter databases.

Data Retrieval and Preprocessing from Human Protein Atlas Data
The HPA data (https://www.proteinatlas.org/) and the screening conditions are as follows: "Gene: CSF2RA"; the data were collected from "tissue", "cell" and "pathology" columns, respectively.

Expression of Protein of CSF2RA in Multiple Cancers
The expression levels of CSF2RA protein in 20 kind of malignant tumors were summarized from HPA data, as shown in Figure 3. In most cancer tissues of patients, the expression of protein was negative, however, the positive rate of protein in melanoma could reach at 42%. Moreover, the expression level was moderate and even high in melanoma tissues and the protein was primarily expressed on cytoplasm of tumor cells.

CSF2RA and the Prognosis of Cancer Patients
The overall survival analysis of breast cancer, colorectal cancer, kidney cancer  cancer (P > 0.05) and liver cancer (P > 0.05), respectively. Therefore, it's considered that the expression levels of CSF2RA were not associated with overall survival of cancer patients and CSF2RA couldn't be a prognostic factor of cancer patients ( Figure 4).

Expression of CSF2RA in Human Tissues and Cells
The results from HPA data indicated that the expression of CSF2RA is at high level in Granulocytes, Dendritic cells and Monocytes in immune system, and Placenta tissue ( Figure 5(A)). The expression level of CSF2RA on granulocytes was higher than other cells. Beside of placenia tissue, the expressions of CSF2RA on other tissues were relatively low. Similarly, the expression results of cells showed that expression of CSF2RA on Monocytes is at the most high level ( Figure 5(B)). In the blood system, the expression levels of CSF2RA on monocytes, macrophage, kupffer cells and hofbauer cells were relatively higher than other cells.

Discussions
CSF2RA as a tumor-related gene has been approved to be a drug target by FDA. In this study, mRNA of CSF2RA is over-expression in certain cancers such as breast cancer, colorectal cancer, kidney cancer and liver cancer. And the expression on other cancer patients is not significant. In terms of protein expression, it's significantly positive on melanoma tissue and signal of other cancer tissue was negative, which indicates that the CSF2RA protein may be expressed on melanoma cells specifically. CSF2RA participates the biological process by incorporating GM-CSF ligand. According to Figure 5   Currently, it has been reported that GM-CSF had potential to induce immune suppression for cancer, even stimulate the progress of cancer by inducing tumor angiogenesis [5] [9] [10] [11] which was associated with high expression level of ligand such as CSF2RA possibly [3]. Interestingly, CSF2RA protein is overexpression on melanoma significantly. A study presented that GM-CSF could recruit tumor-related macrophages into melanoma site and even enhance the proliferation and invasion of melanoma cells [12]. In addition, Slingluffs and Faries reported that the application of GM-CSF immune adjuvant weakens the anti-tumor immune response in vaccine trial on melanoma [13] [14]. Therefore, the over-expression of CSF2RA protein maybe leads to adverse outcome for cancer treatment with the application of GM-CSF. The clinical value and the molecule mechanism for cancer treatment of CSF2RA on cancer cells needs to be further explored.