4.8 Article

Ki-67 regulates global gene expression and promotes sequential stages of carcinogenesis

出版社

NATL ACAD SCIENCES
DOI: 10.1073/pnas.2026507118

关键词

Ki-67; cancer; genetically modified mice; transcription

资金

  1. Ligue Nationale Contre le Cancer (LNCC)
  2. World-Wide Cancer Research (WWCR)
  3. University of Montpellier
  4. French National Cancer Institute (INCa)
  5. LNCC Grants [EL2013.LNCC/DF, EL2018.LNCC/DF]
  6. WWCR Grant [16-0006]
  7. INCa Grant [PLBIO18-094]
  8. Programme Operationnel FEDER-FSE 2014-2020 Languedoc Roussillon
  9. SIRIC Montpellier Cancer Grant [INCa_Inserm_DGOS_12553]
  10. European Regional Development Foundation
  11. Occitanie region (FEDER-FSE 2014-2020 Languedoc Roussillon)

向作者/读者索取更多资源

Ki-67, while not necessary for cell proliferation, plays a crucial role in tumor initiation, growth, and metastasis. Its absence leads to changes in the transcriptome and immune response, making cancer cells more susceptible to drugs and immune attacks.
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 immunesuppressive 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.

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