Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression
Maïté Rielland, … , George Miller, Gregory David
Maïté Rielland, … , George Miller, Gregory David
Published April 1, 2014
Citation Information: J Clin Invest. 2014;124(5):2125-2135. https://doi.org/10.1172/JCI72619.
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Research Article Oncology

Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is strikingly resistant to conventional therapeutic approaches. We previously demonstrated that the histone deacetylase–associated protein SIN3B is essential for oncogene-induced senescence in cultured cells. Here, using a mouse model of pancreatic cancer, we have demonstrated that SIN3B is required for activated KRAS-induced senescence in vivo. Surprisingly, impaired senescence as the result of genetic inactivation of Sin3B was associated with delayed PDAC progression and correlated with an impaired inflammatory response. In murine and human pancreatic cells and tissues, levels of SIN3B correlated with KRAS-induced production of IL-1α. Furthermore, evaluation of human pancreatic tissue and cancer cells revealed that Sin3B was decreased in control and PDAC samples, compared with samples from patients with pancreatic inflammation. These results indicate that senescence-associated inflammation positively correlates with PDAC progression and suggest that SIN3B has potential as a therapeutic target for inhibiting inflammation-driven tumorigenesis.

Authors

Maïté Rielland, David J. Cantor, Richard Graveline, Cristina Hajdu, Lisa Mara, Beatriz de Diego Diaz, George Miller, Gregory David

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Figure 1

Genetic inactivation of Sin3B delays progression of KRASG12D-driven PanINs.

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Genetic inactivation of Sin3B delays progression of KRASG12D-driven PanI...
(A) Representative 6-month-old pancreata from Sin3Bp+/– KraspG12D and Sin3Bp–/– KraspG12D mice. (B) H&E staining in 8- and 24-week-old Sin3B+/ KraspG12D and Sin3Bp–/– KraspG12D pancreata. (C) Immunochemistry for CK19 in 8-week-old Sin3B+/– KraspG12D and Sin3Bp–/– KraspG12D pancreata. (D) Alcian blue staining for mucin in 8-week-old Sin3B+/– KraspG12D and Sin3Bp–/– KraspG12D pancreata. (E) Number of duct-like structures per field in 6- to 8-week-old (6/8 weeks) and 24-week-old pancreata. Black bars represent Sin3Bp+/– KraspG12D pancreas and gray bars represent Sin3Bp–/– KraspG12D pancreas. (F) Number of normal ducts (ND), metaplastic lesions (ML), PanIN1 (P1), PanIN2 (P2), and PanIN3 (P3) per field in 6- to 8-week-old mice. Black bars represent Sin3Bp+/– KraspG12D pancreas, and gray bars represent Sin3Bp–/– KraspG12D pancreas. (G) Number of normal ducts, metaplastic lesions, PanIN1, PanIN2, and PanIN3 per field in 24-week-old mice. Black bars represent Sin3Bp+/– KraspG12D pancreas, and gray bars represent Sin3Bp–/– KraspG12D pancreas. (H) Kaplan-Meier Survival curve of Sin3Bp+/– KraspG12D mice (black, n = 42) and Sin3Bp–/– KraspG12D mice (red, n = 26). P < 0.05 at 300 days.