Suppression of pancreatic cancer liver metastasis by secretion-deficient ITIH5.

Autor: Young ED; Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA., Manley SJ; Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA., Beadnell TC; Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA., Shearin AE; Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA., Sasaki K; Department of Digestive Surgery, Breast and Thyroid Surgery, Kagoshima University, Kagoshima, Japan., Zimmerman R; Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA., Kauffman E; Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA., Vivian CJ; Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA., Parasuram A; Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA., Iwakuma T; Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA., Grandgenett PM; Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA., Hollingsworth MA; Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA., O'Neil M; Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA., Welch DR; Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA. dwelch@kumc.edu.; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA. dwelch@kumc.edu.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2021 Jan; Vol. 124 (1), pp. 166-175. Date of Electronic Publication: 2020 Oct 07.
DOI: 10.1038/s41416-020-01093-z
Abstrakt: Background: Previously, we identified ITIH5 as a suppressor of pancreatic ductal adenocarcinoma (PDAC) metastasis in experimental models. Expression of ITIH5 correlated with decreased cell motility, invasion and metastasis without significant inhibition of primary tumour growth. Here, we tested whether secretion of ITIH5 is required to suppress liver metastasis and sought to understand the role of ITIH5 in human PDAC.
Methods: We expressed mutant ITIH5 with deletion of the N-terminal secretion sequence (ITIH5Δs) in highly metastatic human PDAC cell lines. We used a human tissue microarray (TMA) to compare ITIH5 levels in uninvolved pancreas, primary and metastatic PDAC.
Results: Secretion-deficient ITIH5Δs was sufficient to suppress liver metastasis. Similar to secreted ITIH5, expression of ITIH5Δs was associated with rounded cell morphology, reduced cell motility and reduction of liver metastasis. Expression of ITIH5 is low in both human primary PDAC and matched metastases.
Conclusions: Metastasis suppression by ITIH5 may be mediated by an intracellular mechanism. In human PDAC, loss of ITIH5 may be an early event and ITIH5-low PDAC cells in primary tumours may be selected for liver metastasis. Further defining the ITIH5-mediated pathway in PDAC could establish future therapeutic exploitation of this biology and reduce morbidity and mortality associated with PDAC metastasis.
Databáze: MEDLINE
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