ICAM3 mediates inflammatory signaling to promote cancer cell stemness

Abstract

In this study, we present a medium throughput siRNA screen platform to identify inflammation genes that regulate cancer cell stemness. We identified several novel candidates that decrease OCT4 expression and reduce the ALDH+ subpopulation both of which are characteristic of stemness. Furthermore, one of the novel candidates ICAM3 up-regulates in the ALDH+ subpopulation, the side population and the developed spheres. ICAM3 knockdown reduces the side population, sphere formation and chemo-resistance in MDA-MB-231 human breast cancer cells and A549 lung cancer cells. In addition, mice bearing MDA-MB-231-shICAM3 cells develop smaller tumors and fewer lung metastases versus control. Interestingly, ICAM3 recruits and binds to Src by the YLPL motif in its intracellular domain which further activates the PI3K-AKT phosphorylation cascades. The activated p-AKT enhances SOX2 and OCT4 activity and thereby maintains cancer cell stemness. Meanwhile, the p-AKT facilitated p50 nuclear translocation/activation enhances p50 feedback and thereby promotes ICAM3 expression by binding to the ICAM3 promoter region. On this basis, Src and PI3K inhibitors suppress ICAM3-mediated signaling pathways and reduce chemo-resistance which results in tumor growth suppression in vitro and in vivo. In summary, we identify a potential CSC regulator and suggest a novel mechanism by which ICAM3 governs cancer cell stemness and inflammation.

Biomarkers of Vascular Injury and Type 2 Diabetes: A Prospective Study, Systematic Review and Meta-Analysis

“…ICAM3, a glycoprotein shed by activated leukocytes [15], was demonstrated to be responsible for tethering apoptotic cells to phagocytes, and thus, indicates an increased inflammatory state [14]. Furthermore, ICAM3 has been shown to promote carcinogenesis via pro-inflammatory effects in experimental studies [63]. Results from the present study were unexpected considering that ICAM3 was previously positively associated with prevalent T2D in our cohort, in cross-sectional analyses [23].…”

Three inflammation‐related genes could predict risk in prognosis and metastasis of patients with breast cancer

“…A total of 156 candidate genes were screened from these 1027 inflammation‐related genes by a medium throughput RNAi screen platform . And then, 14 significant genes were collected from these 156 primary screening genes in breast cancers between with and without metastasis ( P < 0.15, t test method, Table ).…”

Aspirin mediates histone methylation that inhibits inflammation-related stemness gene expression to diminish cancer stemness via COX-independent manner

“…Hoechst 33342 dye was added at a final concentration of 7 μg/ml (231), 8 μg/ml (A549), and 10 μg/ml (HepG2) in the presence or absence of 10 μM fumitremorgin C (FTC). The following steps were described previously [8,23].…”

“…Cells were collected and rinsed to remove serum, then dissociated to single-cell suspension in serum-free DMEM/F12 medium supplemented with 100 IU/ml penicillin, 100 μg/ml streptomycin, 20 ng/ml human recombinant epidermal growth factor (hREGF), 20 ng/ml human recombinant basic fibroblast growth factor (bFGF), and 2% B27 supplement (Invitrogen). Cells were subsequently cultured in ultra-low attachment 24-well plates at a density of 500 cells per well [8], then treated with aspirin all the time until the spheres were formed.…”

“…3 × 10 6 A549-luci cells were inoculated s.c into each mouse. For inhibitor treatment assay, 23 days after tumor cells injection, mice were first treated intraperitoneally with aspirin 25 mg/kg or KDM6A/B inhibitor (GSK J1, 100 mg/kg) or Src inhibitor (a new specific high-efficient Src inhibitor [8,24], 20 mg/kg) or PI3K inhibitor (LY294002, 70 mg/kg) or Lifitegrast (20 mg/kg). DMSO used as the control.…”