Abstract
The functional role of AF1q/MLLT11, an oncogenic factor involved in a translocation t(1;11)(q21;q23) responsible for acute myeloid leukaemia, has been investigated in hematological and solid malignancies and its expression was found to be linked to tumor progression and poor clinical outcome. In addition to its oncogenic function, AF1q has been shown to play a role in the onset of basal and drug-induced apoptosis in cancer cells of different histotypes, including ovarian cancer. Through in vitro, ex vivo, and in silico approaches, we demonstrated here that AF1q is also endowed with protumorigenic potential in ovarian cancer. In ovarian cancer cell lines, stable AF1q overexpression caused activation of epithelial-to-mesenchymal transition and increased motility/migratory/invasive abilities accompanied by gene expression changes mainly related to Wnt signaling and to signaling pathways involving in ERK/p38 activation. The potential role of AF1q in ovarian cancer progression was confirmed by immunohistochemical and in silico analyses performed in ovarian tumor specimens which revealed that the protein was absent in normal ovarian epithelium and became detectable when atypical proliferation was present. Moreover, AF1q was significantly lower in borderline ovarian tumors (i.e., tumors of low malignant potential without stromal invasion) than in invasive tumors, thus corroborating the association between high AF1q expression and increased migratory/invasive cell behavior and confirming its potential role in ovarian cancer progression. Our findings demonstrated, for the first time, that AF1q is endowed with protumorigenic activity in ovarian cancer, thus highlighting a dual behavior (i.e., protumorigenic and proapoptotic functions) of the protein in the malignancy.
Highlights
The ALL1-fused from chromosome 1q (AF1q or MLLT11) gene, located on chromosome 1q21, encodes a small protein of 90 amino acids (9 kDa) with no welldefined functional domains, no significant similarity to other proteins and no clarified biological functions [1]
The functional role of AF1q/MLLT11, an oncogenic factor involved in a translocation t(1;11)(q21;q23) responsible for acute myeloid leukaemia, has been investigated in hematological and solid malignancies and its expression was found to be linked to tumor progression and poor clinical outcome
The A2780 ovarian cancer cell line was stably transfected with a Green Fluorescent Protein (GFP)-tagged AF1q expression plasmid previously shown to increase apoptosis when transiently transfected in the cell line [16]
Summary
The ALL1-fused from chromosome 1q (AF1q or MLLT11) gene, located on chromosome 1q21, encodes a small protein of 90 amino acids (9 kDa) with no welldefined functional domains, no significant similarity to other proteins and no clarified biological functions [1]. An oncogenic function of AF1q has been reported in certain solid tumors, such as thyroid oncocytic and testicular germ cell tumors [8, 9] and, in breast cancer, it has been shown to promote distant metastasis [10,11,12], the molecular mechanisms underlying this function have not yet been fully elucidated. The authors demonstrated that AF1q acts as cofactor for both Wnt and STAT signaling pathways, via direct interaction with T-cell-factor-7 and activation of Src-platelet-derived growth factor subunit B kinase cascade, respectively. In both cases, the binding of AF1q to transcription factors results in transcriptional activation of genes required for tumorigenesis and metastasis
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