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

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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.

Original languageEnglish
Pages (from-to)185-200.e1
JournalCMGH
Volume4
Issue number1
DOIs
Publication statusPublished - Jul 2017

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All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Cite this

Ikezawa, K., Hikita, H., Shigekawa, M., Iwahashi, K., Eguchi, H., Sakamori, R., ... Takehara, T. (2017). Increased Bcl-xL Expression in Pancreatic Neoplasia Promotes Carcinogenesis by Inhibiting Senescence and Apoptosis. CMGH, 4(1), 185-200.e1. https://doi.org/10.1016/j.jcmgh.2017.02.001