Gupta Ishita, Jabeen Ayesha, Vranic Semir, Al Moustafa Ala-Eddin, Al-Thawadi Hamda
College of Medicine, Qatar University Health, Qatar University, Doha, Qatar.
Biomedical and Pharmaceutical Research Unit, Qatar University Health, Qatar University, Doha, Qatar.
Front Oncol. 2021 Mar 12;11:630408. doi: 10.3389/fonc.2021.630408. eCollection 2021.
Breast cancer is a leading cause of death in women around the world. Most breast cancer-related deaths are a result of complications from the metastatic spread. Several recent studies reported that high-risk human papillomaviruses (HPVs) and Epstein-Barr virus (EBV) are co-presented in different types of human carcinomas including breast; however, the cooperative effects between high-risk HPVs and EBV oncoproteins in human breast cancer have not been investigated yet. Thus, we herein explored the cooperation outcome between E6/E7 and latent membrane protein 1 (LMP1) oncoproteins of high-risk HPV type 16 and EBV, respectively, in two human breast cancer cell lines, MCF7 and MDA-MB-231. Our data revealed that the cooperation of E6/E7 and LMP1 oncoproteins stimulates cell proliferation and deregulates cell cycle progression of human breast cancer and normal mammary cells; in parallel, we noted that E6/E7/LMP1 incite colony formation of both breast cancer cell lines but not normal cells. More significantly, our results point out that the co-expression of E6/E7 and LMP1 oncoproteins enhances cell motility and invasion of MCF7 and MDA-MB-231 cell lines; this is accompanied by deregulation of epithelial-mesenchymal transition biomarkers including E-cadherin, β-catenin, fascin, and vimentin. The molecular pathway analysis of HPV and EBV oncoproteins cooperation shows that it can enhance the phosphorylation of extracellular signal-regulated kinases (Erk1/Erk2) in addition to β-catenin, which could be behind the effect of this cooperation in our cell models. The study clearly suggests that high-risk HPV and EBV coinfection can play an important role in breast cancer progression Erk1/Erk2 and β-catenin signaling pathways.
乳腺癌是全球女性死亡的主要原因。大多数与乳腺癌相关的死亡是转移扩散并发症的结果。最近的几项研究报告称，高危人乳头瘤病毒（HPV）和爱泼斯坦-巴尔病毒（EBV）共同存在于包括乳腺癌在内的不同类型的人类癌症中；然而，高危HPV和EBV癌蛋白在人类乳腺癌中的协同作用尚未得到研究。因此，我们在此探讨了高危16型HPV的E6/E7和EBV的潜伏膜蛋白1（LMP1）癌蛋白在两种人乳腺癌细胞系MCF7和MDA-MB-231中的协同作用结果。我们的数据显示，E6/E7和LMP1癌蛋白的协同作用刺激了人乳腺癌细胞和正常乳腺细胞的增殖并扰乱了细胞周期进程；同时，我们注意到E6/E7/LMP1促进了两种乳腺癌细胞系的集落形成，但对正常细胞没有作用。更显著的是，我们的结果指出，E6/E7和LMP1癌蛋白的共表达增强了MCF7和MDA-MB-231细胞系的细胞运动性和侵袭能力；这伴随着包括E-钙黏蛋白、β-连环蛋白、丝状肌动蛋白和波形蛋白在内的上皮-间质转化生物标志物的失调。HPV和EBV癌蛋白协同作用的分子途径分析表明，除了β-连环蛋白外，它还能增强细胞外信号调节激酶（Erk1/Erk2）的磷酸化，这可能是这种协同作用在我们细胞模型中发挥作用的背后原因。该研究清楚地表明，高危HPV和EBV共感染可通过Erk1/Erk2和β-连环蛋白信号通路在乳腺癌进展中发挥重要作用。
