Endogenous Gastrin Collaborates With Mutant KRAS in Pancreatic Carcinogenesis

Sandeep Nadella, Julian Burks, Matthew Huber, Juan Wang, Hong Cao, Bhaskar Kallakury, Robin D. Tucker, Simina M. Boca, Ashley Jermusyck, Irene Collins, Eveline E. Vietsch, Mariaelena Pierobon, K. Alex Hodge, Waxing Cui, Laufey T. Amundadottir, Emanuel Petricoin, Narayan Shivapurkar, Jill P. Smith*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Objective The KRAS gene is the most frequently mutated gene in pancreatic cancer, and no successful anti-Ras therapy has been developed. Gastrin has been shown to stimulate pancreatic cancer in an autocrine fashion. We hypothesized that reactivation of the peptide gastrin collaborates with KRAS during pancreatic carcinogenesis. Methods LSL-KrasG12D/+; P48-Cre (KC) mutant KRAS transgenic mice were crossed with gastrin-KO (GKO) mice to develop GKO/KC mice. Pancreata were examined for 8 months for stage of pancreatic intraepithelial neoplasia lesions, inflammation, fibrosis, gastrin peptide, and microRNA expression. Pancreatic intraepithelial neoplasias from mice were collected by laser capture microdissection and subjected to reverse-phase protein microarray, for gastrin and protein kinases associated with signal transduction. Gastrin mRNA was measured by RNAseq in human pancreatic cancer tissues and compared to that in normal pancreas. Results In the absence of gastrin, PanIN progression, inflammation, and fibrosis were significantly decreased and signal transduction was reversed to the canonical pathway with decreased KRAS. Gastrin re-expression in the PanINs was mediated by miR-27a. Gastrin mRNA expression was significantly increased in human pancreatic cancer samples compared to normal human pancreas controls. Conclusions This study supports the mitogenic role of gastrin in activation of KRAS during pancreatic carcinogenesis.

Original languageEnglish
Pages (from-to)894-903
Number of pages10
Issue number7
StatePublished - 1 Aug 2019
Externally publishedYes


  • Gastrin
  • KRAS
  • PanIN
  • epigenetic
  • microRNA
  • pancreatic cancer


Dive into the research topics of 'Endogenous Gastrin Collaborates With Mutant KRAS in Pancreatic Carcinogenesis'. Together they form a unique fingerprint.

Cite this