Hattrup Christine L, Gendler Sandra J
Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
Breast Cancer Res. 2006;8(4):R37. doi: 10.1186/bcr1515.
MUC1 is an oncoprotein whose overexpression correlates with aggressiveness of tumors and poor survival of cancer patients. Many of the oncogenic effects of MUC1 are believed to occur through interaction of its cytoplasmic tail with signaling molecules. As expected for a protein with oncogenic functions, MUC1 is linked to regulation of proliferation, apoptosis, invasion, and transcription.
To clarify the role of MUC1 in cancer, we transfected two breast cancer cell lines (MDA-MB-468 and BT-20) with small interfering (si)RNA directed against MUC1 and analyzed transcriptional responses and oncogenic events (proliferation, apoptosis and invasion).
Transcription of several genes was altered after transfection of MUC1 siRNA, including decreased MAP2K1 (MEK1), JUN, PDGFA, CDC25A, VEGF and ITGAV (integrin alphav), and increased TNF, RAF1, and MMP2. Additional changes were seen at the protein level, such as increased expression of c-Myc, heightened phosphorylation of AKT, and decreased activation of MEK1/2 and ERK1/2. These were correlated with cellular events, as MUC1 siRNA in the MDA-MB-468 line decreased proliferation and invasion, and increased stress-induced apoptosis. Intriguingly, BT-20 cells displayed similar levels of apoptosis regardless of siRNA, and actually increased proliferation after MUC1 siRNA.
These results further the growing knowledge of the role of MUC1 in transcription, and suggest that the regulation of MUC1 in breast cancer may be more complex than previously appreciated. The differences between these two cell lines emphasize the importance of understanding the context of cell-specific signaling events when analyzing the oncogenic functions of MUC1, and caution against generalizing the results of individual cell lines without adequate confirmation in intact biological systems.
MUC1是一种癌蛋白，其过表达与肿瘤的侵袭性及癌症患者的不良预后相关。MUC1的许多致癌作用被认为是通过其胞质尾部与信号分子的相互作用而发生的。正如具有致癌功能的蛋白质所预期的那样，MUC1与增殖、凋亡、侵袭和转录的调节有关。
为了阐明MUC1在癌症中的作用，我们用针对MUC1的小干扰（si）RNA转染了两种乳腺癌细胞系（MDA-MB-468和BT-20），并分析了转录反应和致癌事件（增殖、凋亡和侵袭）。
转染MUC1 siRNA后，几个基因的转录发生了改变，包括MAP2K1（MEK1）、JUN、PDGFA、CDC25A、VEGF和ITGAV（整合素αv）表达降低，以及TNF、RAF1和MMP2表达增加。在蛋白质水平上还观察到其他变化，如c-Myc表达增加、AKT磷酸化增强，以及MEK1/2和ERK1/2激活减少。这些变化与细胞事件相关，因为MDA-MB-468细胞系中的MUC1 siRNA降低了增殖和侵袭，并增加了应激诱导的凋亡。有趣的是，无论siRNA如何，BT-20细胞的凋亡水平相似，并且在MUC1 siRNA处理后实际上增殖增加。
这些结果进一步加深了我们对MUC1在转录中作用的认识，并表明乳腺癌中MUC1的调节可能比以前认为的更为复杂。这两种细胞系之间的差异强调了在分析MUC1的致癌功能时理解细胞特异性信号事件背景的重要性，并提醒在完整生物系统中没有充分证实的情况下不要对单个细胞系的结果进行普遍化。
