The Id3/E47 Axis Mediates Cell-Cycle Control in Human Pancreatic Ducts and Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDA) has a 5-year survival rate of less than 5%, and therapeutic advances have been hampered by gaps in our understanding of cell-cycle control in the adult pancreas. Previously, we reported that basic Helix-Loop-Helix (bHLH) transcription factors regulate cell fate specification in the pancreas. In the present study, we found that a repressor of bHLH activity, Id3, was profoundly upregulated in ductal cells in murine models of pancreatitis and pancreatic intraepithelial neoplasia (PanIN). Id3 was also pervasively expressed in neoplastic lesions in human PDA in situ. We hypothesized that an imbalance in bHLH versus Id activity controlled cell growth in PDA. Consistent with this model, cell-cycle progression in PDA cells was impeded by siRNA-mediated depletion of Id3 or overexpression of the bHLH protein E47. The precursors of human PDA are normally quiescent duct cells which do not proliferate in response to high serum or growth factors. The finding that Id3 was expressed in pancreatitis, as well as PDA, suggested that Id3 might induce cell-cycle entry in ducts. To test this hypothesis, primary human pancreatic duct cells were transduced with an adenovirus-expressing Id3. Remarkably, Id3 expression alone was sufficient to trigger efficient cell-cycle entry, as manifested by expression of the proliferation markers Ki67, phospho-cyclin E, and phospho-histone H3. Collectively, the data establish dysregulation of the Id/bHLH axis as an early and sustained feature of ductal pathogenesis and mark this axis as a potential therapeutic target for intervention in pancreatitis and PDA. Mol Cancer Res; 9(6); 782–90. ©2011 AACR.

Id3 upregulates BrdU incorporation associated with a DNA damage response, not replication, in human pancreatic β-cells

“…49 Our demonstration that Id3 expressing β-cells failed to enter the cell cycle was unexpected in the light of our finding that Id3 induces robust cell cycle entry of pancreatic ductal cells. 39 Ductal and β-cells are closely related developmentally; ducts give rise to neogenic β-cells during pancreas embryogenesis, 73 and we have shown that the process can be recapitulated in the adult human pancreas. 5 Therefore, the data appear to reinforce the hypothesis that as β-cells age they lose cell cycle machinery or substrates essential for replication.…”

“…Remarkably, when duct cells and β-cells were isolated from the same donor pancreas, Id3 induced Ki67 expression only in duct cells. 39 Thus, the data reveal a fundamental difference in responsiveness to replication stimuli between the two closely related pancreatic epithelial cell populations.…”

“…39 Due to the fact that duct cells act as β-cell progenitors during development and possibly during regeneration, 5 we hypothesized that β-cells might respond similarly to Id3. Additional support for a role for Id3 in β-cell replication came from the fact that E47 upregulates p57 Kip2 expression and induces growth arrest in a cell line derived from human fetal islets, 40 and that E47 and Ids control p57 Kip2 expression in other tissues.…”

“…S1) similar to our recent findings in primary human pancreatic duct cells. 39 Forty-eight hours following infection, cells were fixed and p57…”

Id2 Collaborates with Id3 To Suppress Invariant NKT and Innate-like Tumors

“…[7] Therefore, they have been deemed as attractive tumor therapeutic targets using small-molecule inhibitors and ID-binding peptides in mouse models and cancer cell lines. [10, 13–16] In contrast, deep sequencing of human Burkitt’s lymphoma samples has revealed loss-of-function mutations in Id3 in a large subset of patients, supporting the tumor suppressor role of ID3 in some contexts. [17–19] Id3 −/− mice have also been reported to develop γδ Hepatosplenic T-cell lymphoma (HSTCL) as a consequence of Vγ1.1 + Vδ6.3 + γδ T cell population expansion.…”