Abstract
Colorectal cancer (CRC) is the third most commonly occurring cancer worldwide and the fourth most frequent cause of death having an oncological origin. It has been found that transcription factors (TF) dysregulation, leading to the significant expression modifications of genes, is a widely distributed phenomenon regarding human malignant neoplasias. These changes are key determinants regarding tumour’s behaviour as they contribute to cell differentiation/proliferation, migration and metastasis, as well as resistance to chemotherapeutic agents. The forkhead box (FOX) transcription factor family consists of an evolutionarily conserved group of transcriptional regulators engaged in numerous functions during development and adult life. Their dysfunction has been associated with human diseases. Several FOX gene subgroup transcriptional disturbances, affecting numerous complex molecular cascades, have been linked to a wide range of cancer types highlighting their potential usefulness as molecular biomarkers. At least 14 FOX subgroups have been related to CRC pathogenesis, thereby underlining their role for diagnosis, prognosis and treatment purposes.This manuscript aims to provide, for the first time, a comprehensive review of FOX genes’ roles during CRC pathogenesis. The molecular and functional characteristics of most relevant FOX molecules (FOXO, FOXM1, FOXP3) have been described within the context of CRC biology, including their usefulness regarding diagnosis and prognosis. Potential CRC therapeutics (including genome-editing approaches) involving FOX regulation have also been included. Taken together, the information provided here should enable a better understanding of FOX genes’ function in CRC pathogenesis for basic science researchers and clinicians.
Highlights
The forkhead box (FOX) family of transcription factors: an overview The first report of a FOX gene was published in the late 1980s when a mutant model of Drosophila melanogaster was described as having a transformation of the foregut resembling a head-like structure [50, 51]
At least 14 FOX subgroups have been related to Colorectal cancer (CRC) pathogenesis, thereby underlining their role for diagnosis, prognosis and treatment purposes
The results suggested that the expression of genes, secondary to phosphorylated FOXO proteins’ decreased activity in the nucleus, contributed to AKT factors’ growth-promoting function
Summary
The dysfunction of several genes in sporadic and familial cases has been associated with the disease’s aetiology, such as KRAS, BRAF, c-Src, c-Myc, APC, TP53, PIK3CA, MSH2, MLH1, STK11, MSH6, PMS2, APC, CACNA1G, CDKN2A, IGF2, NEUROG1, RUNX3 and SOCS1 [8, 9] Some of these are currently used as clinically useful prognostic and therapeutic biomarkers [10]; since CRC development may take years, its early. TFs recognise 6–12 bp-long DNA sequences located on target gene promoters/enhancers to regulate expression These motifs, known as transcription factor binding sites (TFBS), provide specificity for binding and their occupancy has been related to several variables such as quantity, affinity and availability of regulatory complexes in specific regions [28, 32]. The information provided here should enable a better understanding of FOX genes’ function in CRC pathogenesis for basic science researchers and clinicians
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