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Updated: Nov 15, 2025
A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells
Published on: July 3, 2013
Ki-67 regulates global gene expression and promotes sequential stages of carcinogenesis
Karim Mrouj1,2, Nuria Andrés-Sánchez1,2, Geronimo Dubra1,2
1Institut de Génétique Moléculaire de Montpellier, CNRS, INSERM, University of Montpellier, 34293 Montpellier, France.
Abstract:
Ki-67 is a nuclear protein that is expressed in all proliferating vertebrate cells. Here, we demonstrate that, although Ki-67 is not required for cell proliferation, its genetic ablation inhibits each step of tumor initiation, growth, and metastasis. Mice lacking Ki-67 are resistant to chemical or genetic induction of intestinal tumorigenesis. In established cancer cells, Ki-67 knockout causes global transcriptome remodeling that alters the epithelial-mesenchymal balance and suppresses stem cell characteristics. When grafted into mice, tumor growth is slowed, and metastasis is abrogated, despite normal cell proliferation rates. Yet, Ki-67 loss also down-regulates major histocompatibility complex class I antigen presentation and, in the 4T1 syngeneic model of mammary carcinoma, leads to an immune-suppressive environment that prevents the early phase of tumor regression. Finally, genes involved in xenobiotic metabolism are down-regulated, and cells are sensitized to various drug classes. Our results suggest that Ki-67 enables transcriptional programs required for cellular adaptation to the environment. This facilitates multiple steps of carcinogenesis and drug resistance, yet may render cancer cells more susceptible to antitumor immune responses.
Insights
Ki-67 protein, while not essential for cell division, plays a critical role in cancer development. Its absence hinders tumor initiation, growth, and spread, impacting drug resistance and immune evasion.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Ki-67 is a nuclear protein found in proliferating cells.
- Its precise role in tumorigenesis beyond proliferation is not fully understood.
Purpose of the Study:
- To investigate the function of Ki-67 in tumor initiation, growth, and metastasis.
- To explore the impact of Ki-67 ablation on cancer cell transcriptome and drug sensitivity.
Main Methods:
- Gene knockout (ablation) of Ki-67 in mice.
- Induction of intestinal tumorigenesis.
- Grafting of cancer cells into mice.
- Transcriptome analysis.
- Analysis of immune response and drug sensitivity.
Main Results:
- Ki-67 knockout mice are resistant to chemically or genetically induced intestinal tumors.
- Loss of Ki-67 remodels the transcriptome, altering epithelial-mesenchymal balance and suppressing stem cell traits.
- Tumor growth and metastasis are reduced in Ki-67 knockout models.
- Ki-67 loss down-regulates MHC class I presentation, creating an immunosuppressive environment.
- Cells lacking Ki-67 show reduced xenobiotic metabolism and increased sensitivity to certain drugs.
Conclusions:
- Ki-67 facilitates carcinogenesis and drug resistance by enabling transcriptional programs for environmental adaptation.
- While inhibiting tumor progression, Ki-67 loss may enhance susceptibility to anti-tumor immune responses.
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