Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression
Maïté Rielland, David J. Cantor, Richard Graveline, Cristina Hajdu, Lisa Mara, Beatriz de Diego Diaz, George Miller, Gregory David
Maïté Rielland, David J. Cantor, Richard Graveline, Cristina Hajdu, Lisa Mara, Beatriz de Diego Diaz, George Miller, Gregory David
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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 6

SIN3B levels correlate with an inflammatory response in both human pancreatic tissue and cancer cells.

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SIN3B levels correlate with an inflammatory response in both human pancr...
(A) Immunohistochemical staining for SIN3B, p-STAT3, and IL-1α in human pancreatic tissue microarrays. Representative IHC staining is shown for normal pancreas, pancreas presenting pancreatitis, PanINs, and PDAC. (B) Immunohistochemical staining for DEC1 and IL-1α in human pancreatic tissue microarrays. Representative IHC staining is shown for normal pancreas, pancreas presenting pancreatitis, PanINs, and PDAC. Scale bars: 50 μm. (C) Quantitative PCR for SIN3B and IL1A mRNA expression in AsPc1 pancreatic cancer cells infected with empty vector (black bars) or shRNA against SIN3B (shSIN3B, gray bars). *P < 0.005; **P < 0.05. shSIN3B mRNA expression levels are relative to the empty vector expression levels.