Human cytomegalovirus interleukin-10 enhances matrigel invasion of MDA-MB-231 breast cancer cells

Abstract

BackgroundWhile some risk factors for breast cancer are well-known, the influence of other factors, particularly virus infection, remains unclear. Human cytomegalovirus (HCMV) is widespread in the general population, and both molecular and epidemiological evidence has indicated links between HCMV and breast cancer. The HCMV protein cmvIL-10 is a potent suppressor of immune function that has also been shown to promote proliferation and migration of breast cancer cells. In this study, the impact of cmvIL-10 on tumor cell invasion through a simulated basement membrane was investigated.ResultsMDA-MB-231 breast cancer cells exhibited invasion through a matrigel layer that was significantly enhanced in the presence of either purified cmvIL-10 or supernatants from HCMV-infected cells containing secreted cmvIL-10. Transcriptional profiling revealed that cmvIL-10 altered expression of several genes implicated in metastasis. Exposure to cmvIL-10 resulted in higher MMP-3 mRNA levels, greater protein expression, and increased enzymatic activity. Treatment with cmvIL-10 also increased expression of both urokinase plasminogen receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1), which can stimulate MMP-3 activity and have previously been identified as poor prognostic markers in breast cancer patients. Finally, MDA-MB-231 cells treated with cmvIL-10 showed significant downregulation of metastasis suppressor 1 (MTSS1), a scaffolding protein that regulates cytoskeletal rearrangements and is frequently lost in metastatic tumors.ConclusionsHCMV, and in particular the secreted viral cytokine, cmvIL-10, can induce cellular changes that facilitate cell migration and invasion. These findings indicate that HCMV may be associated with promoting the malignant spread of breast cancer cells and suggest that antiviral treatment may be a useful complement to chemotherapy in some patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-017-0399-5) contains supplementary material, which is available to authorized users.

Identification of UL69 Gene and Protein in Cytomegalovirus-Transformed Human Mammary Epithelial Cells

“…Knowing that UL69 protein represents the HCMV homolog of ICP27, it compromises the STING signaling pathway and type I IFN production, which might favor viral immune evasion and further cancer cell proliferation and migration (50,51). Furthermore, a previous study indicated a potential role of the viral immunomodulator cytokine IL-10 during HCMV infection in enhancing breast tumor development and metastasis (52). Likewise, HCMV IL-10 exposed MCF-7 human breast cancer cells showed a significant upregulation of matrix metalloproteinase-10 (MMP-10) gene expression, thus promoting excessive proliferation and tissue invasion (53).…”

The effect of interleukin 10 polymorphisms on breast cancer susceptibility in Han women in Shaanxi Province

“…A large number of association studies have found that polymorphisms of IL-10 are involved in the susceptibility to many diseases, such as Bechcet's disease [24], systemic lupus erythematosus [25], and ulcerative colitis [26]. Meanwhile, some studies have indicated that IL-10 plays a vital role in the progression, invasion, migration, and growth of breast cancer [27,28]. These results indicated that polymorphisms of IL-10 have an effect on the development of breast…”

The Human Cytomegalovirus, from Oncomodulation to Oncogenesis

“…Activation of STAT3 results from the binding of cmvIL10 to the IL-10 receptor [ 74 , 75 , 76 , 77 ], and has been described in breast cancer, ovarian cancer with poor prognosis, and to increase the spread of glioma cancer stem cells in malignant glioma [ 78 , 79 , 80 ]. In addition, exposure of MDA-MB-231 and MCF-7 cells to cmvIL-10 favors their proliferation, their migration and the metastatic spread due to cell surface expression of IL-10R [ 81 , 82 , 83 ] ( Table 1 , Figure 2 ).…”

“…Thus, in HMECs and nearby tissue macrophages, a restricted viral replication could account for a specific tumor microenvironment, which might shape the viral fitness [ 134 ]. Further, the tumoral microenvironment could be modulated by HCMV-infected HMECs with both up- and downregulation of genes involved in angiogenesis (upregulation: IL-6, SERPINE1, THBS1, S100A4, EGF; downregulation: ID1, SLIT2) and proteolysis (upregulation: MMP9; downregulation: CST6, CTSD) [ 83 ]. In addition, the presence of tumor cancer stem cells (CSCs) has been reported to favor the propagation and invasiveness of the tumor [ 135 ].…”