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Cell proliferation, migration and invasion were assessed using Cell Counting Kit\u20108 and transwell assays, respectively. The expression of E\u2010cadherin, N\u2010cadherin, vimentin and matrix metalloproteinases (MMP\u20102, MMP\u20107 and MMP\u20109) was evaluated by Western blotting and\/or qRT\u2010PCR. The gelatinase activity of MMP\u20102 and MMP\u20109 in conditioned media was detected using gelatin zymography. The phosphorylation status of AKT, GSK3\u03b2, p38, JNK and ERK1\/2 MAPK was determined by Western blotting.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The migration and invasion ability of HPNE cells was increased after the introduction of the mutated <jats:italic>KRAS<\/jats:italic> gene, together with an increased expression of MMP\u20102. These effects were further enhanced by the simultaneous administration of insulin. The use of MMP\u20102 siRNA confirmed that MMP\u20102 was involved in the regulation of cell invasion. Furthermore, there was a concentration\u2010 and time\u2010dependent increase in gelatinase activity after insulin treatment, which could be reversed by an insulin receptor tyrosine kinase inhibitor (HNMPA\u2010(AM)<jats:sub>3<\/jats:sub>). In addition, insulin markedly enhanced the phosphorylation of PI3K\/AKT, p38, JNK and ERK1\/2 MAPK pathways, with wortmannin or LY294002 (a PI3K\u2010specific inhibitor) and PD98059 (a MEK1\u2010specific inhibitor) significantly inhibiting the insulin\u2010induced increase in MMP\u20102 gelatinolytic activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Taken together, these results suggest that insulin induced migration and invasion in HPNE and HPNE\u2010mut\u2010<jats:italic>KRAS<\/jats:italic> through PI3K\/AKT and ERK1\/2 activation, with MMP\u20102 gelatinolytic activity playing a vital role in this process. These findings may provide a new therapeutic target for preventing carcinogenesis and the evolution of pancreatic cancer with a background of hyperinsulinemia.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cpr.12575","type":"journal-article","created":{"date-parts":[[2019,3,6]],"date-time":"2019-03-06T07:25:49Z","timestamp":1551857149000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Insulin promotes invasion and migration of <i>KRAS<sup>G12D<\/sup><\/i> mutant HPNE cells by upregulating MMP\u20102 gelatinolytic activity via ERK\u2010 and PI3K\u2010dependent signalling"],"prefix":"10.1111","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4065-1054","authenticated-orcid":false,"given":"Guangfu","family":"Wang","sequence":"first","affiliation":[{"name":"Pancreas Center First Affiliated Hospital of Nanjing Medical University Nanjing China"},{"name":"Pancreas Institute, Nanjing Medical University Nanjing 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