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Ki-67 promotes inflammatory signaling governing neutrophil recruitment during respiratory infections

ABSTRACT: Neutrophils defend against respiratory infections but cause acute lung injury (ALI) when excessively recruited to the lung. Early life environmental factors can shape lung development, but how they impact neutrophil recruitment is not known. We show that exposing newborn mice to hyperoxia increases the number of adult alveolar type 1 (AT1) epithelial cells expressing the proliferation marker Ki-67. Although these cells were not proliferating, they express high levels of chemokines that stimulate neutrophil recruitment and ALI when mice were infected with influenza A virus or exposed to lipopolysaccharide (LPS). Neutrophil recruitment and chemokine production were attenuated in Ki-67 hypomorph mice infected with virus or exposed to LPS and enhanced by genetically over-expressing Ki-67 in their lungs. Silencing Ki-67 in a mouse AT1-like cell line reduced basal and IL-1 stimulation of RelA/p65 and NF-B-dependent transcription of the chemokines Cxcl1 and Cxcl5. Our findings reveal a novel role for Ki-67 to modulate the intensity of epithelial proinflammatory shttps://www.ebi.ac.uk/biostudies/submissions/filesignaling controlling neutrophil recruitment. The severity of respiratory infections may be influenced by mitogens and environmental factors that increase expression of Ki-67.

ORGANISM(S): Mus musculus (mouse)

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PROVIDER: S-BSST1960 | biostudies-other |

REPOSITORIES: biostudies-other

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Ki-67 promotes carcinogenesis by enabling global transcriptional programmes

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-02-18 | GSE163114 | GEO

Ki-67 gene expression.

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Project description: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.

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Project description:Distinguishing benign from malignant adrenocortical tumors (ACT) is not always easy, particularly for tumors with unclear malignant potential based on the histopathological features comprised of the Weiss score. Previous studies reported the potential utility of immunohistochemistry (IHC) markers to recognize malignancy, in particular the Insulin-like growth factor 2 (IGF2) and the proliferation marker, Ki-67. However, this information was not compiled before. Therefore, this review aimed to collect the evidence on the potential diagnosis utility of IGF2 and Ki-67 IHC staining. Additionally, a meta-analysis was performed to assess the Ki-67 accuracy to identify adrenocortical carcinoma. The systematic review and meta-analysis were conducted according to the PRISMA guidelines. From the 26 articles included in the systematic review, 21 articles provided individual data for IGF2 (n = 2) or for Ki-67 (n = 19), while 5 studies assessed both markers. IGF2 staining was positive in most carcinomas, in contrast to adenomas. However, the different immunostaining evaluation methods adopted among the studies impeded to perform a meta-analysis to assess IGF2 diagnostic accuracy. In contrast, for the most commonly used cut-off value of 5% stained cells, Ki-67 showed pooled specificity, sensitivity and log diagnostic odds ratio of 0.98 (95% CI 0.95 to 0.99), 0.82 (95% CI 0.65 to 0.92) and 4.26 (95% CI 3.40 to 5.12), respectively. At the 5% cut-off, Ki-67 demonstrated an excellent specificity to recognize malignant ACT. However. the moderate sensitivity observed indicates the need for further studies exploring alternative threshold values. Additionally, more studies using similar approaches are needed to assess the diagnostic accuracy of IGF2.Registration code in PROSPERO: CRD42022370389.

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Phosphatidylinositol 3-kinase-? signaling promotes Campylobacter jejuni-induced colitis through neutrophil recruitment in mice.

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The cell proliferation antigen Ki-67 organises heterochromatin.

Project description:Antigen Ki-67 is a nuclear protein expressed in proliferating mammalian cells. It is widely used in cancer histopathology but its functions remain unclear. Here, we show that Ki-67 controls heterochromatin organisation. Altering Ki-67 expression levels did not significantly affect cell proliferation in vivo. Ki-67 mutant mice developed normally and cells lacking Ki-67 proliferated efficiently. Conversely, upregulation of Ki-67 expression in differentiated tissues did not prevent cell cycle arrest. Ki-67 interactors included proteins involved in nucleolar processes and chromatin regulators. Ki-67 depletion disrupted nucleologenesis but did not inhibit pre-rRNA processing. In contrast, it altered gene expression. Ki-67 silencing also had wide-ranging effects on chromatin organisation, disrupting heterochromatin compaction and long-range genomic interactions. Trimethylation of histone H3K9 and H4K20 was relocalised within the nucleus. Finally, overexpression of human or Xenopus Ki-67 induced ectopic heterochromatin formation. Altogether, our results suggest that Ki-67 expression in proliferating cells spatially organises heterochromatin, thereby controlling gene expression.

| S-EPMC4841783 | biostudies-literature

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