Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] · 2026
Spink1 promotes the survival of Kras-mutant pancreatic acinar cells.
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Hayashi Hidehiro, Hamada Shin, Matsumoto Ryotaro, Takikawa Tetsuya, Xu Yan, Jie Ren, Nakasuji Hitomi, Abe Toshiaki, Kikuta Kazuhiro, Motohashi Hozumi, Ohmuraya Masaki, Masamune Atsushi
Аннотация
BACKGROUND: Pancreatic cancer remains one of the most intractable malignancies due to its strong therapeutic resistance and the difficulty of early detection. Previous studies have suggested that pancreatic inflammation can promote carcinogenesis. In contrast, the regulatory mechanisms controlling trypsin activity are closely associated with susceptibility to pancreatitis. Genetic variants that lead to sustained trypsin activity-thereby promoting protease activation-have been identified in hereditary pancreatitis. Serine protease inhibitor Kazal type 1 (SPINK1) functions as an endogenous inhibitor of trypsin activity. Deletion of Spink1 in mice causes severe pancreatic atrophy and early postnatal death. In addition to its role in pancreatitis, SPINK1 has been reported to exert cancer-promoting effects in several tumor types by supporting cell survival.
METHODS: In the present study, we investigated whether pancreas-specific deletion of Spink1 affects inflammation and fibrosis after caerulein-induced pancreatitis. We also investigated whether pancreas-specific deletion of Spink1 affects Kras-mutant driven carcinogenesis in mice.
RESULTS: Loss of Spink1 in the pancreas induced histological changes consistent with chronic pancreatitis and was accompanied by muscle atrophy. Moreover, the combination of Spink1 deletion and mutant Kras expression resulted in early lethality due to severe pancreatic atrophy. Heterozygous loss of Spink1 also attenuated the development of pancreatic intraepithelial neoplasia (PanIN), a precancerous lesion induced by mutant Kras.
CONCLUSIONS: These findings demonstrate that SPINK1 supports the early stages of pancreatic carcinogenesis. Targeting SPINK1 may represent a novel preventive strategy to eliminate Kras mutant acinar cells and suppress the initiation of pancreatic cancer.
METHODS: In the present study, we investigated whether pancreas-specific deletion of Spink1 affects inflammation and fibrosis after caerulein-induced pancreatitis. We also investigated whether pancreas-specific deletion of Spink1 affects Kras-mutant driven carcinogenesis in mice.
RESULTS: Loss of Spink1 in the pancreas induced histological changes consistent with chronic pancreatitis and was accompanied by muscle atrophy. Moreover, the combination of Spink1 deletion and mutant Kras expression resulted in early lethality due to severe pancreatic atrophy. Heterozygous loss of Spink1 also attenuated the development of pancreatic intraepithelial neoplasia (PanIN), a precancerous lesion induced by mutant Kras.
CONCLUSIONS: These findings demonstrate that SPINK1 supports the early stages of pancreatic carcinogenesis. Targeting SPINK1 may represent a novel preventive strategy to eliminate Kras mutant acinar cells and suppress the initiation of pancreatic cancer.