Prognostic significance of hepatocyte growth factor activator inhibitor type 1 (HAI-1) immunoreactivity in pancreatic ductal adenocarcinoma

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Abstract

Objective

Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-bound serine protease inhibitor that is expressed on the surface of epithelial cells. Evidence has suggested that decreased cell surface HAI-1 in carcinoma cells results in enhanced invasiveness. However, little is known regarding the expression of HAI-1 in pancreatic ductal adenocarcinoma (PDAC). This study aimed to analyze HAI-1 expression in PDAC and its impact on patient prognosis.

Results

HAI-1 immunohistochemistry was performed on samples from 67 PDAC cases. HAI-1 expression was increased in intraepithelial neoplasia compared to the adjacent non-neoplastic ductal epithelium. Of the 67 samples tested, 58% (39/67) of PDAC cases showed diffuse (> 75%) immunoreactivity in PDAC cells. The remaining cases showed reduced HAI-1 immunoreactivity in a substantial number of cancer cells. Although there was no correlation between HAI-1 status and tumor size, histologic grade or lymph node metastasis, diffuse HAI-1 positive cases showed longer disease-free survival (DFS; p = 0.006, log-rank test). In conclusion, HAI-1 is upregulated in pancreatic intraepithelial neoplasia and broadly expressed in PDAC cells. However, PDAC cases having areas of reduced HAI-1 immunoreactivity may show shorter DFS.

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The online version of this article (10.1186/s13104-017-3014-x) contains supplementary material, which is available to authorized users.

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TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial-mesenchymal transition.

H. Jung, K. Lee, S Park … (2008)

TMPRSS4 is a novel type II transmembrane serine protease found at the cell surface that is highly expressed in pancreatic, colon and gastric cancer tissues. However, the biological functions of TMPRSS4 in cancer are unknown. Here we show, using reverse transcription-PCR, that TMPRSS4 is highly elevated in lung cancer tissues compared with normal tissues and is also broadly expressed in a variety of human cancer cell lines. Knockdown of TMPRSS4 by small interfering RNA treatment in lung and colon cancer cell lines was associated with reduction of cell invasion and cell-matrix adhesion as well as modulation of cell proliferation. Conversely, the invasiveness, motility and adhesiveness of SW480 colon carcinoma cells were significantly enhanced by TMPRSS4 overexpression. Furthermore, overexpression of TMPRSS4 induced loss of E-cadherin-mediated cell-cell adhesion, concomitant with the induction of SIP1/ZEB2, an E-cadherin transcriptional repressor, and led to epithelial-mesenchymal transition events, including morphological changes, actin reorganization and upregulation of mesenchymal markers. TMPRSS4-overexpressing cells also displayed markedly increased metastasis to the liver in nude mice upon intrasplenic injection. Taken together, these studies suggest that TMPRSS4 controls the invasive and metastatic potential of human cancer cells by facilitating an epithelial-mesenchymal transition; TMPRSS4 may be a potential therapeutic target for cancer treatment.

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The role of type II transmembrane serine protease-mediated signaling in cancer.

Lauren M. Tanabe, Karin List (2017)

Pericellular proteases have long been implicated in carcinogenesis. Previous research focused on these proteins, primarily as extracellular matrix (ECM) protein-degrading enzymes which allowed cancer cells to breach the basement membrane and invade surrounding tissue. However, recently, there has been a shift in the view of cell surface proteases, including serine proteases, as proteolytic modifiers of particular targets, including growth factors and protease-activated receptors, which are critical for the activation of oncogenic signaling pathways. Of the 176 human serine proteases currently identified, a subset of 17, known as type II transmembrane serine proteases (TTSPs). Many have been shown to be relevant to cancer progression since they were first identified as a family around the turn of the century. To this end, altered expression of TTSPs appeared as a trademark of several tumor types. However, the substrates and underlying signaling pathways remained unclear. Localization of these proteins to the cell surface places them in the unique position to mediate signal transduction between the cell and its surrounding environment. Many of the TTSPs have already been shown to play key roles in processes such as postnatal development, tissue homeostasis, and tumor progression, which share overlapping molecular mechanisms. In this review, we summarize the current knowledge regarding the role of the TTSP family in pro-oncogenic signaling.

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Mechanisms of Hepatocyte Growth Factor Activation in Cancer Tissues

Makiko Kawaguchi, Hiroaki Kataoka (2014)

Hepatocyte growth factor/scatter factor (HGF/SF) plays critical roles in cancer progression through its specific receptor, MET. HGF/SF is usually synthesized and secreted as an inactive proform (pro-HGF/SF) by stromal cells, such as fibroblasts. Several serine proteases are reported to convert pro-HGF/SF to mature HGF/SF and among these, HGF activator (HGFA) and matriptase are the most potent activators. Increased activities of both proteases have been observed in various cancers. HGFA is synthesized mainly by the liver and secreted as an inactive pro-form. In cancer tissues, pro-HGFA is likely activated by thrombin and/or human kallikrein 1-related peptidase (KLK)-4 and KLK-5. Matriptase is a type II transmembrane serine protease that is expressed by most epithelial cells and is also synthesized as an inactive zymogen. Matriptase activation is likely to be mediated by autoactivation or by other trypsin-like proteases. Recent studies revealed that matriptase autoactivation is promoted by an acidic environment. Given the mildly acidic extracellular environment of solid tumors, matriptase activation may, thus, be accelerated in the tumor microenvironment. HGFA and matriptase activities are regulated by HGFA inhibitor (HAI)-1 (HAI-1) and/or HAI-2 in the pericellular microenvironment. HAIs may have an important role in cancer cell biology by regulating HGF/SF-activating proteases.

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Author and article information

Contributors

Chihiro Sakugawa: chihiro_sakugawa@med.miyazaki-u.ac.jp

Yukihiro Haruyama: yukihiro_haruyama@med.miyazaki-u.ac.jp

Hiroyuki Tanaka: hiroyuki_tanaka@med.miyazaki-u.ac.jp

Tsuyoshi Fukushima: fukuchan@med.miyazaki-u.ac.jp

Makiko Kawaguchi: kawaguchi@med.miyazaki-u.ac.jp

Hiroaki Kataoka:

ORCID: http://orcid.org/0000-0001-9948-0451

+81-985-852809 , mejina@med.miyazaki-u.ac.jp

Journal

Journal ID (nlm-ta): BMC Res Notes

Journal ID (iso-abbrev): BMC Res Notes

Title: BMC Research Notes

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-0500

Publication date (Electronic): 4 December 2017

Publication date PMC-release: 4 December 2017

Publication date Collection: 2017

Volume: 10

Electronic Location Identifier: 674

Affiliations

ISNI 0000 0001 0657 3887, GRID grid.410849.0, Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, , University of Miyazaki, ; 5200 Kihara, Kiyotake, Miyazaki, Japan

Author information

Hiroaki Kataoka http://orcid.org/0000-0001-9948-0451

Article

Publisher ID: 3014

DOI: 10.1186/s13104-017-3014-x

PMC ID: 5715503

PubMed ID: 29202869

SO-VID: 46460a23-2b5c-4124-b903-abe8db7802ed

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 25 July 2017

Date accepted : 28 November 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001700, Ministry of Education, Culture, Sports, Science and Technology;

Award ID: 16H05175

Award Recipient : Hiroaki Kataoka

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ScienceOpen disciplines: Medicine

Keywords: hai-1,spint1,pancreatic ductal adenocarcinoma,immunohistochemistry

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ScienceOpen disciplines: Medicine

Keywords: hai-1, spint1, pancreatic ductal adenocarcinoma, immunohistochemistry

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Prognostic significance of hepatocyte growth factor activator inhibitor type 1 (HAI-1) immunoreactivity in pancreatic ductal adenocarcinoma

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Most cited references 21

TMPRSS4 promotes invasion, migration and metastasis of human tumor cells by facilitating an epithelial-mesenchymal transition.

The role of type II transmembrane serine protease-mediated signaling in cancer.

Mechanisms of Hepatocyte Growth Factor Activation in Cancer Tissues

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