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Browsing by Author "Häkkänen, Iina"

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  • Häkkänen, Iina (2022)
    Colorectal cancer (CRC) is one of the most common types of cancers, encompassing approximately 10 % of all cancer cases worldwide. Regulation of cell proliferation and cell fate decisions is crucial for maintaining cellular homeostasis and preventing CRC initiation, a process in which the Wingless (Wnt)/β-catenin signalling pathway is known to play an important role. For instance, somatic mutations occurring in the Apc gene lead to aberrant activation of the Wnt/β-catenin pathway, which further leads to the accumulation of β-catenin into the nucleus where the TCF/LEF transcription factors, including TCF1, TCF3, TCF4, and LEF1, bind β-catenin to activate downstream Wnt target genes and promote CRC development. TCF1 is encoded by the gene Tcf7 that can be alternatively spliced to produce long (p45) and short (p33) isoforms whose function in CRC development has remained poorly understood. Previously, deletion of Tcf7 has been found to increase intestinal adenoma formation in mice with one mutated Apc allele (ApcMin/+), which are predisposed to development of multiple intestinal adenomas. To study how heterozygous deletion of the p45 isoforms affects intestinal adenoma formation and the cellular transcriptome, we have studied ApcMin/+ mice, which have a heterozygous mutation of Tcf7 gene encoding only the p33 isoform (AmTp45∆/+). In our study, we used immunohistochemistry and RT-qPCR together with a single-cell RNA sequencing (scRNA-seq) analysis. Heterozygous deletion of the p45 isoforms in the ApcMin/+ mice dramatically increased the numbers of intestinal tumours, spleen size and its white pulp areas but it had no effect on cell proliferation or expression of the Wnt-target gene Prox1 in intestinal adenomas. In addition, ApcMin/+ mice with both heterozygous p45 and Lef1 deletions developed significantly more intestinal tumours. Without the Apc mutation, neither of these mouse models developed intestinal adenomas or spleen abnormalities. RT-qPCR analysis showed decreased expression of Tcf7 in the small intestine of the AmTp45∆/+ mice. scRNA-seq analysis revealed that the AmTp45∆/+ mice downregulated various Wnt antagonists and stem cell markers and upregulated several genes that function in different metabolic pathways. Overall, these results support the concept that Tcf7 functions in synergy with Apc to repress intestinal malignancy. Our results establish a basis for comparison of the relative importance and specific functions of the TCF/LEF1 family members in CRC development.