Valle Oseguera Cendy A, Spencer Juliet V
Department of Biology, University of San Francisco, 2130 Fulton Street, San Francisco, CA 94117 USA.
Cancer Cell Int. 2017 Feb 13;17:24. doi: 10.1186/s12935-017-0399-5. eCollection 2017.
While 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.
MDA-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 - 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 (), a scaffolding protein that regulates cytoskeletal rearrangements and is frequently lost in metastatic tumors.
HCMV, 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.
虽然一些乳腺癌的风险因素已广为人知，但其他因素的影响，尤其是病毒感染，仍不明确。人巨细胞病毒（HCMV）在普通人群中广泛存在，分子和流行病学证据均表明HCMV与乳腺癌之间存在联系。HCMV蛋白cmvIL - 10是一种强大的免疫功能抑制剂，也已被证明可促进乳腺癌细胞的增殖和迁移。在本研究中，研究了cmvIL - 10对肿瘤细胞通过模拟基底膜侵袭的影响。
MDA - MB - 231乳腺癌细胞在通过基质胶层侵袭时，在存在纯化的cmvIL - 10或含有分泌的cmvIL - 10的HCMV感染细胞的上清液时，侵袭能力显著增强。转录谱分析显示，cmvIL - 10改变了几个与转移相关基因的表达。暴露于cmvIL - 10导致更高的mRNA水平、更高的蛋白质表达和增加的酶活性。用cmvIL - 10处理还增加了尿激酶型纤溶酶原受体（uPAR）和纤溶酶原激活物抑制剂 - 1（PAI - 1）的表达，这两种物质可刺激MMP - 3活性，并且先前已被确定为乳腺癌患者的不良预后标志物。最后，用cmvIL - 10处理的MDA - MB - 231细胞显示转移抑制因子1（）显著下调，该因子是一种调节细胞骨架重排的支架蛋白，在转移性肿瘤中经常缺失。
HCMV，特别是分泌的病毒细胞因子cmvIL - 10，可诱导促进细胞迁移和侵袭的细胞变化。这些发现表明HCMV可能与促进乳腺癌细胞的恶性扩散有关，并表明抗病毒治疗可能是某些患者化疗的有益补充。
