Ki-67 is required for maintenance of cancer stem cells but not cell proliferation

Abstract

Ki-67 expression is correlated with cell proliferation and is a prognostic marker for various cancers; however, its function is unknown. Here we demonstrate that genetic disruption of Ki-67 in human epithelial breast and colon cancer cells depletes the cancer stem cell niche. Ki-67 null cells had a proliferative disadvantage compared to wildtype controls in colony formation assays and displayed increased sensitivity to various chemotherapies. Ki-67 null cancer cells showed decreased and delayed tumor formation in xenograft assays, which was associated with a reduction in cancer stem cell markers. Immunohistochemical analyses of human breast cancers revealed that Ki-67 expression is maintained at equivalent or greater levels in metastatic sites of disease compared to matched primary tumors, suggesting that maintenance of Ki-67 expression is associated with metastatic/clonogenic potential. These results elucidate Ki-67's role in maintaining the cancer stem cell niche, which has potential diagnostic and therapeutic implications for human malignancies.

Perichromosomal protein Ki67 supports mitotic chromosome architecture

“…) and for the maintenance of cancer stem cells (Cidado et al . ). The role of Ki67 at the periphery of mitotic chromosomes as a biological surfactant to prevent coalescence has also been proposed (Cuylen et al .…”

“…The cellular roles of Ki67 have been rapidly unraveled by recent studies (Cidado et al . ; Cuylen et al . ; Sobecki et al .…”

“…Contrary to previous expectations, studies with Ki67‐null cells have shown that Ki67 is dispensable for cell proliferation (Cidado et al . ; Sobecki et al . ).…”

Ki67 is a Graded Rather than a Binary Marker of Proliferation versus Quiescence

“…Ki67 depletion results in reduced proliferation in hTERT-RPE1, hTERT-BJ, Swiss-3T3, WI-38, IMR90, MCF7, IM-9, RT-4, and 786–0 cells, but not in others such as MCF10A, DLD-1, HeLa, U2OS, and 293T cells (Cidado et al, 2016; Schlüter et al, 1993; Sobecki et al, 2016; Starborg et al, 1996; Sun et al, 2017; Zheng et al, 2006). Additionally, Ki67 knockout mice develop normally and are fertile (Sobecki et al, 2016).…”

A FUS-LATS1/2 Axis Inhibits Hepatocellular Carcinoma Progression via Activating Hippo Pathway

“…Notably, the tumorseeding ability of FUS-overexpressed cells was significantly decreased at the density of 1 × 10 4 (5/6 vs 3/6) and 1 × 10 3 (4/6 vs 2/6) cells. Concordantly, the staining intensity and number of Ki67, which is required for maintenance of proliferation and stemness [23], were decreased in tumors derived from FUS-overexpressed cells (Fig. 8C and 4D).…”