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  • Presentation type: PD - PostDoctoral
  • Track: Cellular Biology
  • Keywords: Colorectal cancer; cancer stem cells; TP53;
  • 1 Universidade Federal do Rio de Janeiro

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INTRODUCTION AND OBJECTIVES: It is expected that colorectal cancer (CCR) will be the second and third most frequent cancer among women and men in Brazil in the 2020-22 triennium. In such a scenario, it is of utmost importance to understand the molecular biology of CCR in order to improve its prevention and treatment. More than 75% of CCR tumors harbor mutations in the TP53 gene. In response to genotoxic stressors, TP53 encodes a tumor suppressor protein with a classic role of arresting the cell cycle or inducing programmed cell death to limit the propagation of undesired genome mutations. Recently, many studies have found associations of TP53 mutations with the dynamics of the appearance and resistance of tumor stem cells. In CCR, both normal adult and cancer stem cells have been identified and tracked through the leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) biomarker. Therefore, we aimed to investigate a putative role of TP53 in the appearance of LGR5 positive CCR cancer stem cells. MATERIAL AND METHODS: AOM/DSS is the most used inflammation-driven CCR inducing model in mice, which resembles the human inflammatory CCR. TP53 wild-type (WT), heterozygous (HET) and knock-out (KO) mice were subjected to the AOM/DSS model. CCR tumor samples were collected, snap-frozen and colorectal samples were processed for further hematoxylin-eosin (HE) staining, immunohistochemistry (IHC) and Western Blot (WB) analysis. RESULTS AND CONCLUSION: The KO group lost more body weight in response to the three cycles of the colitis agent dextran sulfate sodium (DSS), as well as more frequent episodes of diarrhea or bleeding in stool, indicating more aggressive colitis. Colonoscopies at the end of the AOM/DSS protocol showed an increased number of tumors in the KO group at the same moment WT and HET had few small or absence of visible tumors, leading to a delayed euthanasia in the WT and HET groups. At euthanasia, intestines were dissected and visible tumor size and number of tumors were higher in the KO group. Western blot analysis of non-tumoral colorectal tissue showed no difference in LGR5 expression in relation to TP53 genotypes, although it indicates a slight trend of decrease in KO group. HE staining showed the presence of well-differentiated in situ and invasive adenocarcinomas in mice. Most tumors presented a polypoid morphology, but we are also evaluating the frequency of the serrated tumors among groups. IHC analysis indicates increased immunostaining of LGR5 in tumors of the KO group, which seems to confirm WB analysis of tumor samples. LGR5 expression also seems to indicate a field effect in colon tissue since its expression might be increased in the adjacent and distant non-tumoral tissue surrounding cancer tissue. Our results, so far, indicate that LGR5 is upregulated in KO tissues, which confirms the importance of TP53 to the regulation of stemness in CCR cancers and to the cancer stem cells.

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