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Involvement of AF1q/MLLT11 in the progression of ovarian cancer.

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.

SUBMITTER: Tiberio P

PROVIDER: S-EPMC5410301 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Involvement of AF1q/MLLT11 in the progression of ovarian cancer.

Tiberio Paola P Lozneanu Ludmila L Angeloni Valentina V Cavadini Elena E Pinciroli Patrizia P Callari Maurizio M Carcangiu Maria Luisa ML Lorusso Domenica D Raspagliesi Francesco F Pala Valentina V Daidone Maria Grazia MG Appierto Valentina V

Oncotarget 20170401 14

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 ...[more]

PMID: 28423573

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Project description:BackgroundFenretinide (4-HPR) is a synthetic retinoid that exhibits potent antitumor and chemopreventive activities against different malignancies, including ovarian tumors. We previously showed that in ovarian cancer cells, 4-HPR induces apoptosis through a signaling cascade starting from reactive oxygen species (ROS) generation and involving endoplasmic reticulum (ER) stress response, Jun N-terminal Kinase (JNK) activation, and induction of the proapoptotic PLAcental Bone morphogenetic protein (PLAB). Since recent studies have shown that the oncogene ALL1-fused from chromosome 1q (AF1q), a retinoic acid target gene, is implicated in apoptosis induction by several therapeutic agents, we investigated its possible involvement in the apoptosis induced by 4-HPR in ovarian cancer cells.Methodology/principal findingsProtein expression analysis, performed in ovarian cancer cells and extended to other histotypes (breast, neuroblastoma, and cervical), revealed that 4-HPR enhanced AF1q expression in cancer cells sensitive to the retinoid but not in resistant cells. Through gene silencing, AF1q was found functionally involved in 4-HPR-induced apoptosis in A2780, an ovarian cancer cell line highly sensitive to retinoid growth inhibitory and apoptotic effects. Inhibition of the signaling intermediates of the 4-HPR apoptotic cascade showed that AF1q upregulation was depended on prior generation of ROS, induction of ER stress response, JNK activation, and PLAB upmodulation. Finally, we found that direct overexpression of AF1q, in the absence of external stimuli, increased apoptosis in ovarian cancer cell lines.Conclusions/significanceThe study expands the knowledge of the 4-HPR mechanism of action, which has not yet been completely elucidated, identifying AF1q as a novel mediator of retinoid anticancer activity. In addition, we demonstrate, for the first time, that AF1q plays a role in the onset of basal apoptosis in ovarian cancer cells, thus providing new information about the activity of this protein whose biologic functions are mostly unknown.

Dataset Information

Involvement of AF1q/MLLT11 in the progression of ovarian cancer.

Publications

Involvement of AF1q/MLLT11 in the progression of ovarian cancer.

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