Increased Bcl-xL Expression in Pancreatic Neoplasia Promotes Carcinogenesis by Inhibiting Senescence and Apoptosis

Kenji Ikezawa; Hayato Hikita; Minoru Shigekawa; Kiyoshi Iwahashi; Hidetoshi Eguchi; Ryotaro Sakamori; Tomohide Tatsumi; Tetsuo Takehara

doi:10.1016/j.jcmgh.2017.02.001

Increased Bcl-xL Expression in Pancreatic Neoplasia Promotes Carcinogenesis by Inhibiting Senescence and Apoptosis

Cell Mol Gastroenterol Hepatol. 2017 Feb 20;4(1):185-200.e1. doi: 10.1016/j.jcmgh.2017.02.001. eCollection 2017 Jul.

Authors

Kenji Ikezawa¹, Hayato Hikita¹, Minoru Shigekawa¹, Kiyoshi Iwahashi¹, Hidetoshi Eguchi², Ryotaro Sakamori¹, Tomohide Tatsumi¹, Tetsuo Takehara¹

Affiliations

¹ Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
² Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.

Abstract

Background & aims: Bcl-xL, an anti-apoptotic Bcl-2 family protein, is overexpressed in 90% of pancreatic ductal adenocarcinoma (PDAC) cases. However, Bcl-xL expression in pancreatic intraepithelial neoplasias (PanINs) and its significance in PDAC carcinogenesis remain unclear. The aim of this study was to elucidate the significance of Bcl-xL expression in PanINs.

Methods: We investigated the expression levels of Bcl-xL in pancreas-specific KrasG12D (P-KrasG12D) mice and human PanINs and PDAC. We examined the impact of Bcl-xL expression on Kras-mutated pancreatic neoplasia using Bcl-xL-overexpressing P-KrasG12D mice and Bcl-xL-knockout P-KrasG12D mice.

Results: In P-KrasG12D mice, the number of PanINs increased and their grades progressed with age. In total, 55.6% of these mice developed PDAC at 12-14 months. According to the immunohistochemistry of mouse pancreas and human resected specimens, Bcl-xL expression was increased significantly in PanIN-1 compared with that in normal pancreatic ducts, and augmented further with the progression of pancreatic neoplasia in PanIN-2/3 and PDAC. Oncogene-induced senescence was observed frequently in PanIN-1, but rarely was detected in PanIN-2/3 and PDAC. Bcl-xL overexpression significantly accelerated the progression to high-grade PanINs and PDAC and reduced the survival of P-KrasG12D mice. Bcl-xL overexpression in P-KrasG12D mice suppressed oncogene-induced senescence in PanIN-1 and inhibited apoptosis in PanIN-3. Bcl-xL deficiency in P-KrasG12D mice induced cellular senescence in PanIN-2/3.

Conclusions: Bcl-xL expression increases with the progression from PanIN-1 to PDAC, whereas oncogene-induced senescence decreases. Bcl-xL overexpression increases PDAC incidence rates by inhibiting oncogene-induced senescence and apoptosis in PanINs. Conversely, Bcl-xL deficiency induced senescence in PanINs. Anti-Bcl-xL treatments may have the potency to suppress the progression from PanINs to PDAC.

Keywords: Bcl-2 Family Protein; IHC, immunohistochemistry; KO, knockout; Kras; P-KrasG12D, Pdx1-Cre LSL-KrasG12D; PDAC, pancreatic ductal adenocarcinoma; PanIN, pancreatic intraepithelial neoplasia; PanINs; SA–β-gal, senescence-associated β-galactosidase; TUNEL, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling; Tg, transgenic; siRNA, small interfering RNA.