An emerging role for BAG3 in gynaecological malignancies

Abstract

BAG3, a member of the BAG family of co-chaperones, is a multidomain protein with a role in several cellular processes, including the control of apoptosis, autophagy and cytoskeletal dynamics. The expression of bag3 is negligible in most cells but can be induced by stress stimuli or malignant transformation. In some tumours, BAG3 has been reported to promote cell survival and resistance to therapy. The expression of BAG3 has been documented in ovarian, endometrial and cervical cancers, and studies have revealed biochemical and functional connections of BAG3 with proteins involved in the survival, invasion and resistance to therapy of these malignancies. BAG3 expression has also been shown to correlate with the grade of dysplasia in squamous intraepithelial lesions of the uterine cervix. Some aspects of BAG3 activity, such as its biochemical and functional interaction with the human papillomavirus proteins, could help in our understanding of the mechanisms of oncogenesis induced by the virus. This review aims to highlight the potential value of BAG3 studies in the field of gynaecological tumours.

Fig. 1. BAG3 structural domains/motifs involved in the regulatory protein–protein interactions of major cellular pathways.

(Orange = BAG domain; Purple = WW domain; Green, Ile-Pro-Val (IPV) motif; Yellow = Proline-rich domain (PxxP)). Key functional/interaction domains of BAG3, major BAG3 interactors and associated cellular events are depicted.

Fig. 2. BAG3 interactors in apoptosis.

BAG3 interactors and downstream effectors in cellular processes involved in the inhibition of cellular apoptosis.

Fig. 3. Paracrine loop operated by cancer cell-secreted BAG3 on macrophages surrounding the tumour.

BAG3 binding through its receptor IFITM2 stimulate macrophages to produce cytokines such as IL-6 and IL-10 that promote tumour development.

Fig. 4. BAG3 interactors in cancer.

BAG3 interactors and downstream effectors in cellular processes involved in the promotion of cell motility, invasion and metastasisation of cancer cells.

Fig. 5. Cellular processes upregulated by BAG3 expression in gynaecological malignancies.

Summary of the reported evidence in BAG3-dependent upregulation of key cellular processes in a ovarian, b endometrial, c cervical cancer.

Fig. 6. Mature miRNAs derive from longer double-stranded primary transcripts (pri-miRNA), processed in the nucleus and folded in a hairpin loop structure (pre-miRNA).

Pre-miRNAs are then exported to the cytoplasm (through Exportin 5) where they are first cleaved by Dicer and later processed by RISC (RNA-induced silencing complex) to form the mature miRNA (miR-4312). RISC, that includes Ago 2 (Protein argonaute 2), also participates in the identification of miRNAs’ targets. Interfering with BAG3 levels it was simultaneously observed an upregulation of miR-4312 and a disruption of Hur factor binding to IL-8 mRNA. This produces IL-8 mRNA degradation by lowering migration and invasion process of cancer cells.