Abstract
The complement system is readily triggered by the presence of damage-associated molecular patterns on the surface of tumor cells. The complement alternative pathway provides rapid amplification of the molecular stress signal, leading to complement cascade activation to deal with pathogens or malignant cells. Properdin is the only known positive regulator of the alternative pathway. In addition, properdin promotes the phagocytic uptake of apoptotic T cells by macrophages and dendritic cells without activating the complement system, thus, establishing its ability to recognize “altered-self”. Dysregulation of properdin has been implicated in substantial tissue damage in the host, and in some cases, chronic unresolved inflammation. A corollary of this may be the development of cancer. Hence, to establish a correlation between properdin presence/levels in normal and cancer tissues, we performed bioinformatics analysis, using Oncomine and UALCAN. Survival analyses were performed using UALCAN and PROGgeneV2 to assess if properdin can serve as a potential prognostic marker for human lung adenocarcinoma (LUAD), liver hepatocellular carcinoma (LIHC), cervical squamous cell carcinoma (CESC), and pancreatic adenocarcinoma (PAAD). We also analyzed levels of tumor-infiltrating immune cells using TIMER, a tool for characterizing immune cell composition in cancers. We found that in LUAD and LIHC, there was a lower expression of properdin in the tumors compared to normal tissues, while no significant difference was observed in CESC and PAAD. Survival analysis demonstrated a positive association between properdin mRNA expression and overall survival in all 4 types of cancers. TIMER analysis revealed that properdin expression correlated negatively with tumor purity and positively with levels of infiltrating B cells, cytotoxic CD8+ T cells, CD4+ helper T cells, macrophages, neutrophils and dendritic cells in LUAD, CESC and PAAD, and with levels of B cells, CD8+ T cells and dendritic cells in LIHC. Immunohistochemical analysis revealed that infiltrating immune cells were the most likely source of properdin in the tumor microenvironment. Thus, complement protein properdin shows promise as a prognostic marker in cancer and warrants further study.
Highlights
Properdin, a ~50 kDa glycoprotein found at 4–25 mg/ml level in plasma, is the only known positive regulator of the complement system [1, 2]
We initially evaluated the differences in the mRNA level of properdin in LUAD as compared to normal lung tissue, using the Oncomine platform via Hou’s, Okayama’s, Su’s and Bhattacharjee’s datasets (Table 1)
The strength of the correlation was very weak for CD8+ T cells, whereas it was relatively weaker for B cells, CD4+ T cells, macrophages, neutrophils and dendritic cells
Summary
A ~50 kDa glycoprotein found at 4–25 mg/ml level in plasma, is the only known positive regulator of the complement system [1, 2]. Factor B is cleaved by the serine protease, Factor D, into fragments Ba and Bb; Bb remains bound to C3(H2O) non-covalently producing C3 (H2O)Bb, which is stabilized by binding to properdin yielding C3 (H2O)BbP, the alternative pathway fluid-phase C3 convertase [2]. C3(H2O)Bb further cleaves additional molecules of C3 into C3a and C3b [2]; C3b gets deposited on the pathogen cell surface, where it associates with Factor B to generate C3bB, the membranebound C3 proconvertase [4]. Factor D cleaves Factor B in the C3bB complex and binds to properdin to generate the membrane-bound C3 convertase, C3bBbP [4], which cleaves several C3 molecules, leading to C3b deposition on the pathogen surface [9]. The MAC disrupts the cell membrane of the pathogen causing cell lysis [11,12,13]
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