<i><scp>ZFP</scp>36L2</i> promotes cancer cell aggressiveness and is regulated by antitumor <i>micro<scp>RNA</scp>‐375</i> in pancreatic ductal adenocarcinoma

<jats:p>Due to its aggressive nature, pancreatic ductal adenocarcinoma (<jats:styled-content style="fixed-case">PDAC</jats:styled-content>) is one of the most lethal and hard‐to‐treat malignancies. Recently developed targeted molecular strategies have contributed to remarkable improvements in the treatment of several cancers. However, such therapies have not been applied to <jats:styled-content style="fixed-case">PDAC</jats:styled-content>. Therefore, new treatment options are needed for <jats:styled-content style="fixed-case">PDAC</jats:styled-content> based on current genomic approaches. Expression of <jats:italic>micro<jats:styled-content style="fixed-case">RNA</jats:styled-content>‐375</jats:italic> (<jats:italic>miR‐375</jats:italic>) was significantly reduced in mi<jats:styled-content style="fixed-case">RNA</jats:styled-content> expression signatures of several types of cancers, including <jats:styled-content style="fixed-case">PDAC</jats:styled-content>. The aim of the present study was to investigate the functional roles of <jats:italic>miR‐375</jats:italic> in <jats:styled-content style="fixed-case">PDAC</jats:styled-content> cells and to identify <jats:italic>miR‐375</jats:italic>‐regulated molecular networks involved in <jats:styled-content style="fixed-case">PDAC</jats:styled-content> aggressiveness. The expression levels of <jats:italic>miR‐375</jats:italic> were markedly downregulated in <jats:styled-content style="fixed-case">PDAC</jats:styled-content> clinical specimens and cell lines (<jats:styled-content style="fixed-case">PANC</jats:styled-content>‐1 and <jats:styled-content style="fixed-case">SW</jats:styled-content>1990). Ectopic expression of <jats:italic>miR‐375</jats:italic> significantly suppressed cancer cell proliferation, migration and invasion. Our <jats:italic>in silico</jats:italic> and gene expression analyses and luciferase reporter assay showed that zinc finger protein 36 ring finger protein‐like 2 (<jats:italic><jats:styled-content style="fixed-case">ZFP</jats:styled-content>36L2</jats:italic>) was a direct target of <jats:italic>miR‐375</jats:italic> in <jats:styled-content style="fixed-case">PDAC</jats:styled-content> cells. Silencing <jats:italic><jats:styled-content style="fixed-case">ZFP</jats:styled-content>36L2</jats:italic> inhibited cancer cell aggressiveness in <jats:styled-content style="fixed-case">PDAC</jats:styled-content> cell lines, and overexpression of <jats:styled-content style="fixed-case">ZFP</jats:styled-content>36L2 was confirmed in <jats:styled-content style="fixed-case">PDAC</jats:styled-content> clinical specimens. Interestingly, Kaplan–Meier survival curves showed that high expression of <jats:styled-content style="fixed-case">ZFP</jats:styled-content>36L2 predicted shorter survival in patients with <jats:styled-content style="fixed-case">PDAC</jats:styled-content>. Moreover, we investigated the downstream molecular networks of the <jats:italic>miR‐375/<jats:styled-content style="fixed-case">ZFP</jats:styled-content>36L2</jats:italic> axis in <jats:styled-content style="fixed-case">PDAC</jats:styled-content> cells. Elucidation of tumor‐suppressive <jats:italic>miR‐375</jats:italic>‐mediated <jats:styled-content style="fixed-case">PDAC</jats:styled-content> molecular networks may provide new insights into the potential mechanisms of <jats:styled-content style="fixed-case">PDAC</jats:styled-content> pathogenesis.</jats:p>