Abstract
Dysfunction of nuclear factor-κB (NF-κB) signaling has been causally associated with numerous human malignancies. Although the NF-κB family of genes has been implicated in endometrial carcinogenesis, information regarding the involvement of central regulators of NF-κB signaling in human endometrial cancer (EC) is limited. Here, we investigated the specific roles of canonical and noncanonical NF-κB signaling in endometrial tumorigenesis. We found that NF-κB RelB protein, but not RelA, displayed high expression in EC samples and cell lines, with predominant elevation in endometrioid adenocarcinoma (EEC). Moreover, tumor cell-intrinsic RelB was responsible for the abundant levels of c-Myc, cyclin D1, Bcl-2 and Bcl-xL, which are key regulators of cell cycle transition, apoptosis and proliferation in EEC. In contrast, p27 expression was enhanced by RelB depletion. Thus, increased RelB in human EC is associated with enhanced EEC cell growth, leading to endometrial cell tumorigenicity. Our results reveal that regulatory RelB in noncanonical NF-κB signaling may serve as a therapeutic target to block EC initiation.
Highlights
Endometrial carcinoma (EC) ranks as one of the most frequent gynecological malignancies, and the incidence continues to rise.[1]
We identified an upregulation of the alternative avian reticuloendotheliosis viral oncogene related B (RelB)/Nuclear factor-κB (NF-κB) in EC compared with normal controls, and this increased expression manifested a clear trend toward endometrioid adenocarcinoma (EEC) (Figures 1a and b)
To examine the association between upregulated RelB and tumor stage and histological type, we further analyzed the TMA-2 data and correlated RelB expression with clinicopathological parameters. These results revealed that increased RelB expression was not significantly associated with the Federation of Gynecology and Obstetrics (FIGO) EEC stage (Figures 1h and i)
Summary
Endometrial carcinoma (EC) ranks as one of the most frequent gynecological malignancies, and the incidence continues to rise.[1]. Advances in EC diagnosis currently allow for early intervention with surgery or adjuvant radiochemotherapy tailored to histology, which has markedly improved the overall survival of EC patients.[3] EEC patients with advanced stages present with more aggressive tumors and tend to have a poorer prognosis than NEEC patients.[4] Similar trends are noted for patients diagnosed under 40 years of age who seek to preserve fertility; remarkably, this population is quickly growing.[5] Confronted with this situation, non-invasive targeted therapeutic strategies with minimal side effects are urgently needed.[6].
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