Institut de Génétique Moléculaire de Montpellier, CNRS, INSERM, University of Montpellier, 34293 Montpellier, France.
Equipe Labellisée Ligue 2018, Ligue Nationale Contre le Cancer, 75013 Paris, France.
Proc Natl Acad Sci U S A. 2021 Mar 9;118(10). doi: 10.1073/pnas.2026507118.
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.
Ki-67 是一种核蛋白，存在于所有增殖的脊椎动物细胞中。在这里，我们证明，尽管 Ki-67 不是细胞增殖所必需的，但它的基因缺失会抑制肿瘤发生、生长和转移的每一个步骤。缺乏 Ki-67 的小鼠对化学或遗传诱导的肠道肿瘤形成具有抗性。在已建立的癌细胞中，Ki-67 敲除会导致整个转录组重构，改变上皮-间充质平衡，并抑制干细胞特征。当移植到小鼠体内时，尽管细胞增殖率正常，但肿瘤生长速度减慢，转移被阻断。然而，Ki-67 的缺失也会下调主要组织相容性复合体 I 类抗原的呈递，并且在 4T1 同源乳腺癌模型中，导致免疫抑制环境，阻止肿瘤早期消退。最后，参与外源性代谢的基因下调，细胞对各种药物类别变得敏感。我们的结果表明，Ki-67 使细胞适应环境所需的转录程序成为可能。这促进了致癌作用和耐药性的多个步骤，但可能使癌细胞更容易受到抗肿瘤免疫反应的影响。
