Hyaluronan arrests human breast cancer cell growth by prolonging the G0/G1 phase of the cell cycle

摘要

In clinical breast cancer patients,quiescent disseminated tumor cells (DTCs) can persist for a long time in the bone marrow (BM) under the influence of microenvironmental cues.As a high molecular weight polysaccharide,hyaluronan (HA) not only has been shown to regulate cancer processes including cell invasion,metastasis,migration,and proliferation,but also is a major component of the BM extracellular matrix.Here,we tested whether HA promotes breast cancer cell quiescence through detecting cell proliferation,cell cycle phase distribution,and the expression of cell cyclerelated regulator proteins.In our results,HA slowed the growth and prolonged the G0/G1 phase of the highly metastatic,bone-seeking human breast cancer MDA-MB-231BO cell line,which is consistent with results that HA activated p38α/β,inhibited phospho-ERK1/2 levels and reduced the ERK/p38 signaling ratio.Additionally,we examined the crucial cell cycle factors p21cip1 and Cyclin D1,both of which influence the transition from G1 to S phase.The results revealed that p21cip1 expression was up-regulated by HA,which was consequently accompanied by a decrease in Cyclin D1 level.Further research with a 3D culture model indicated that HA maintained low Ki-67 and high p21cip1 expression levels in MDA-MB-231BO cells.In summary,our work revealed that HA might contribute to DTC quiescence.