UBL4A inhibits autophagy-mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting LAMP1
Identifieur interne : 000109 ( Pmc/Curation ); précédent : 000108; suivant : 000110UBL4A inhibits autophagy-mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting LAMP1
Auteurs : Hongze Chen ; Le Li ; Jisheng Hu ; Zhongjie Zhao ; Liang Ji ; Chundong Cheng ; Guangquan Zhang ; Tao Zhang ; Yilong Li ; Hua Chen ; Shangha Pan ; Bei SunSource :
- Journal of Experimental & Clinical Cancer Research : CR [ 0392-9078 ] ; 2019.
Abstract
Ubiquitin-like protein 4A (UBL4A) plays a significant role in protein metabolism and the maintenance of cellular homeostasis. In cancer, UBL4A represses tumorigenesis and is involved in various signaling pathways. Pancreatic ductal adenocarcinoma (PDAC) is still a major cause of cancer-related death and the underlying molecular mechanism of UBL4A and PDAC remains unknown.
First, the prognostic role of UBL4A and its expression in human PDAC patients and in pancreatic cancer cell lines were detected by survival analysis and qRT-PCR, western blotting, and immunohistochemistry. Next, the effects of UBL4A on proliferation and metastasis in pancreatic cancer were evaluated by functional assays in vitro and in vivo. In addition, chloroquine was introduced to determine the role of autophagy in UBL4A-related tumor proliferation and metastasis. Ultimately, coimmunoprecipitation was used to confirm the interaction between UBL4A and lysosome associated membrane protein-1 (LAMP1), and western blotting was performed to explore the UBL4A mechanism.
We found that UBL4A was decreased in PDAC and that high levels of UBL4A correlated with a favorable prognosis. We observed that UBL4A inhibited tumor proliferation and metastasis through suppression of autophagy, a critical intracellular catabolic process that reportedly protects cells from nutrient starvation and other stress conditions. UBL4A caused impaired autophagic degradation in vitro, a crucial process in autophagy, by disturbing the function of lysosomes and contributing to autophagosome accumulation. We found a positive correlation between UBL4A and LAMP1. Furthermore, UBL4A caused lysosomal dysfunction by directly interacting with LAMP1, and LAMP1 overexpression reversed the antitumor effects of UBL4A in pancreatic cancer. In addition, we demonstrated that UBL4A suppressed tumor growth and metastasis in a pancreatic orthotopic tumor model.
These findings suggest that UBL4A exerts an antitumor effect on autophagy-related proliferation and metastasis in PDAC by directly targeting LAMP1. Herein, we describe a novel mechanism of UBL4A that suppresses the progression of pancreatic cancer. UBL4A might be a promising target for the treatment and prognostication of PDAC.
The online version of this article (10.1186/s13046-019-1278-9) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1186/s13046-019-1278-9
PubMed: 31288830
PubMed Central: 6617940
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<author><name sortKey="Zhao, Zhongjie" sort="Zhao, Zhongjie" uniqKey="Zhao Z" first="Zhongjie" last="Zhao">Zhongjie Zhao</name>
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<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Breast Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Cheng, Chundong" sort="Cheng, Chundong" uniqKey="Cheng C" first="Chundong" last="Cheng">Chundong Cheng</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zhang, Guangquan" sort="Zhang, Guangquan" uniqKey="Zhang G" first="Guangquan" last="Zhang">Guangquan Zhang</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zhang, Tao" sort="Zhang, Tao" uniqKey="Zhang T" first="Tao" last="Zhang">Tao Zhang</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Li, Yilong" sort="Li, Yilong" uniqKey="Li Y" first="Yilong" last="Li">Yilong Li</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Chen, Hua" sort="Chen, Hua" uniqKey="Chen H" first="Hua" last="Chen">Hua Chen</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Pan, Shangha" sort="Pan, Shangha" uniqKey="Pan S" first="Shangha" last="Pan">Shangha Pan</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Sun, Bei" sort="Sun, Bei" uniqKey="Sun B" first="Bei" last="Sun">Bei Sun</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">31288830</idno>
<idno type="pmc">6617940</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617940</idno>
<idno type="RBID">PMC:6617940</idno>
<idno type="doi">10.1186/s13046-019-1278-9</idno>
<date when="2019">2019</date>
<idno type="wicri:Area/Pmc/Corpus">000109</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000109</idno>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">UBL4A inhibits autophagy-mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting LAMP1</title>
<author><name sortKey="Chen, Hongze" sort="Chen, Hongze" uniqKey="Chen H" first="Hongze" last="Chen">Hongze Chen</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Li, Le" sort="Li, Le" uniqKey="Li L" first="Le" last="Li">Le Li</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Hu, Jisheng" sort="Hu, Jisheng" uniqKey="Hu J" first="Jisheng" last="Hu">Jisheng Hu</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zhao, Zhongjie" sort="Zhao, Zhongjie" uniqKey="Zhao Z" first="Zhongjie" last="Zhao">Zhongjie Zhao</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Ji, Liang" sort="Ji, Liang" uniqKey="Ji L" first="Liang" last="Ji">Liang Ji</name>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Breast Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Cheng, Chundong" sort="Cheng, Chundong" uniqKey="Cheng C" first="Chundong" last="Cheng">Chundong Cheng</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zhang, Guangquan" sort="Zhang, Guangquan" uniqKey="Zhang G" first="Guangquan" last="Zhang">Guangquan Zhang</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zhang, Tao" sort="Zhang, Tao" uniqKey="Zhang T" first="Tao" last="Zhang">Tao Zhang</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Li, Yilong" sort="Li, Yilong" uniqKey="Li Y" first="Yilong" last="Li">Yilong Li</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Chen, Hua" sort="Chen, Hua" uniqKey="Chen H" first="Hua" last="Chen">Hua Chen</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Pan, Shangha" sort="Pan, Shangha" uniqKey="Pan S" first="Shangha" last="Pan">Shangha Pan</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</nlm:aff>
<wicri:noCountry code="subfield">Heilongjiang China</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Sun, Bei" sort="Sun, Bei" uniqKey="Sun B" first="Bei" last="Sun">Bei Sun</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</nlm:aff>
<wicri:noCountry code="subfield">150001 Heilongjiang Province China</wicri:noCountry>
</affiliation>
</author>
</analytic>
<series><title level="j">Journal of Experimental & Clinical Cancer Research : CR</title>
<idno type="ISSN">0392-9078</idno>
<idno type="eISSN">1756-9966</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p id="Par1">Ubiquitin-like protein 4A (UBL4A) plays a significant role in protein metabolism and the maintenance of cellular homeostasis. In cancer, UBL4A represses tumorigenesis and is involved in various signaling pathways. Pancreatic ductal adenocarcinoma (PDAC) is still a major cause of cancer-related death and the underlying molecular mechanism of UBL4A and PDAC remains unknown.</p>
</sec>
<sec><title>Methods</title>
<p id="Par2">First, the prognostic role of UBL4A and its expression in human PDAC patients and in pancreatic cancer cell lines were detected by survival analysis and qRT-PCR, western blotting, and immunohistochemistry. Next, the effects of UBL4A on proliferation and metastasis in pancreatic cancer were evaluated by functional assays in vitro and in vivo. In addition, chloroquine was introduced to determine the role of autophagy in UBL4A-related tumor proliferation and metastasis. Ultimately, coimmunoprecipitation was used to confirm the interaction between UBL4A and lysosome associated membrane protein-1 (LAMP1), and western blotting was performed to explore the UBL4A mechanism.</p>
</sec>
<sec><title>Results</title>
<p id="Par3">We found that UBL4A was decreased in PDAC and that high levels of UBL4A correlated with a favorable prognosis. We observed that UBL4A inhibited tumor proliferation and metastasis through suppression of autophagy, a critical intracellular catabolic process that reportedly protects cells from nutrient starvation and other stress conditions. UBL4A caused impaired autophagic degradation in vitro, a crucial process in autophagy, by disturbing the function of lysosomes and contributing to autophagosome accumulation. We found a positive correlation between UBL4A and LAMP1. Furthermore, UBL4A caused lysosomal dysfunction by directly interacting with LAMP1, and LAMP1 overexpression reversed the antitumor effects of UBL4A in pancreatic cancer. In addition, we demonstrated that UBL4A suppressed tumor growth and metastasis in a pancreatic orthotopic tumor model.</p>
</sec>
<sec><title>Conclusions</title>
<p id="Par4">These findings suggest that UBL4A exerts an antitumor effect on autophagy-related proliferation and metastasis in PDAC by directly targeting LAMP1. Herein, we describe a novel mechanism of UBL4A that suppresses the progression of pancreatic cancer. UBL4A might be a promising target for the treatment and prognostication of PDAC.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (10.1186/s13046-019-1278-9) contains supplementary material, which is available to authorized users.</p>
</sec>
</div>
</front>
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<author><name sortKey="Zhou, B" uniqKey="Zhou B">B Zhou</name>
</author>
<author><name sortKey="Huang, N" uniqKey="Huang N">N Huang</name>
</author>
<author><name sortKey="Farfel Becker, T" uniqKey="Farfel Becker T">T Farfel-Becker</name>
</author>
<author><name sortKey="Sheng, Zh" uniqKey="Sheng Z">ZH Sheng</name>
</author>
</analytic>
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</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Exp Clin Cancer Res</journal-id>
<journal-id journal-id-type="iso-abbrev">J. Exp. Clin. Cancer Res</journal-id>
<journal-title-group><journal-title>Journal of Experimental & Clinical Cancer Research : CR</journal-title>
</journal-title-group>
<issn pub-type="ppub">0392-9078</issn>
<issn pub-type="epub">1756-9966</issn>
<publisher><publisher-name>BioMed Central</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31288830</article-id>
<article-id pub-id-type="pmc">6617940</article-id>
<article-id pub-id-type="publisher-id">1278</article-id>
<article-id pub-id-type="doi">10.1186/s13046-019-1278-9</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research</subject>
</subj-group>
</article-categories>
<title-group><article-title>UBL4A inhibits autophagy-mediated proliferation and metastasis of pancreatic ductal adenocarcinoma via targeting LAMP1</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Hongze</given-names>
</name>
<address><email>chenhongze0428@163.com</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Li</surname>
<given-names>Le</given-names>
</name>
<address><email>lile@outlook.com.cn</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hu</surname>
<given-names>Jisheng</given-names>
</name>
<address><email>hujisheng0816@126.com</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhao</surname>
<given-names>Zhongjie</given-names>
</name>
<address><email>zhaozhongjie1990@163.com</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ji</surname>
<given-names>Liang</given-names>
</name>
<address><email>aeropippo@sina.com</email>
</address>
<xref ref-type="aff" rid="Aff2">2</xref>
<xref ref-type="aff" rid="Aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cheng</surname>
<given-names>Chundong</given-names>
</name>
<address><email>chengchundong1989@126.com</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Zhang</surname>
<given-names>Guangquan</given-names>
</name>
<address><email>surgeon_zhang@hotmail.com</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>zhang</surname>
<given-names>Tao</given-names>
</name>
<address><email>taiyizhangtao@163.com</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Li</surname>
<given-names>Yilong</given-names>
</name>
<address><email>liyi6565091@163.com</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Hua</given-names>
</name>
<address><email>chenhuahyd@126.com</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pan</surname>
<given-names>Shangha</given-names>
</name>
<address><email>576531070@qq.com</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
<xref ref-type="aff" rid="Aff2">2</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><name><surname>Sun</surname>
<given-names>Bei</given-names>
</name>
<address><phone>+86 451 85555734</phone>
<email>sunbei70@tom.com</email>
</address>
<xref ref-type="aff" rid="Aff1">1</xref>
</contrib>
<aff id="Aff1"><label>1</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Pancreatic and Biliary Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, 23 Youzheng Street, Nangang District, Harbin, 150001 Heilongjiang Province China</aff>
<aff id="Aff2"><label>2</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0369 313X</institution-id>
<institution-id institution-id-type="GRID">grid.419897.a</institution-id>
<institution>Key Laboratory of Hepatosplenic Surgery,</institution>
<institution>Ministry of Education,</institution>
</institution-wrap>
Harbin, Heilongjiang China</aff>
<aff id="Aff3"><label>3</label>
<institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1797 9737</institution-id>
<institution-id institution-id-type="GRID">grid.412596.d</institution-id>
<institution>Department of Breast Surgery,</institution>
<institution>The First Affiliated Hospital of Harbin Medical University,</institution>
</institution-wrap>
Harbin, Heilongjiang China</aff>
</contrib-group>
<pub-date pub-type="epub"><day>9</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>9</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><year>2019</year>
</pub-date>
<volume>38</volume>
<elocation-id>297</elocation-id>
<history><date date-type="received"><day>21</day>
<month>4</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>13</day>
<month>6</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© The Author(s). 2019</copyright-statement>
<license license-type="OpenAccess"><license-p><bold>Open Access</bold>
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
), 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 (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>
) applies to the data made available in this article, unless otherwise stated.</license-p>
</license>
</permissions>
<abstract id="Abs1"><sec><title>Background</title>
<p id="Par1">Ubiquitin-like protein 4A (UBL4A) plays a significant role in protein metabolism and the maintenance of cellular homeostasis. In cancer, UBL4A represses tumorigenesis and is involved in various signaling pathways. Pancreatic ductal adenocarcinoma (PDAC) is still a major cause of cancer-related death and the underlying molecular mechanism of UBL4A and PDAC remains unknown.</p>
</sec>
<sec><title>Methods</title>
<p id="Par2">First, the prognostic role of UBL4A and its expression in human PDAC patients and in pancreatic cancer cell lines were detected by survival analysis and qRT-PCR, western blotting, and immunohistochemistry. Next, the effects of UBL4A on proliferation and metastasis in pancreatic cancer were evaluated by functional assays in vitro and in vivo. In addition, chloroquine was introduced to determine the role of autophagy in UBL4A-related tumor proliferation and metastasis. Ultimately, coimmunoprecipitation was used to confirm the interaction between UBL4A and lysosome associated membrane protein-1 (LAMP1), and western blotting was performed to explore the UBL4A mechanism.</p>
</sec>
<sec><title>Results</title>
<p id="Par3">We found that UBL4A was decreased in PDAC and that high levels of UBL4A correlated with a favorable prognosis. We observed that UBL4A inhibited tumor proliferation and metastasis through suppression of autophagy, a critical intracellular catabolic process that reportedly protects cells from nutrient starvation and other stress conditions. UBL4A caused impaired autophagic degradation in vitro, a crucial process in autophagy, by disturbing the function of lysosomes and contributing to autophagosome accumulation. We found a positive correlation between UBL4A and LAMP1. Furthermore, UBL4A caused lysosomal dysfunction by directly interacting with LAMP1, and LAMP1 overexpression reversed the antitumor effects of UBL4A in pancreatic cancer. In addition, we demonstrated that UBL4A suppressed tumor growth and metastasis in a pancreatic orthotopic tumor model.</p>
</sec>
<sec><title>Conclusions</title>
<p id="Par4">These findings suggest that UBL4A exerts an antitumor effect on autophagy-related proliferation and metastasis in PDAC by directly targeting LAMP1. Herein, we describe a novel mechanism of UBL4A that suppresses the progression of pancreatic cancer. UBL4A might be a promising target for the treatment and prognostication of PDAC.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (10.1186/s13046-019-1278-9) contains supplementary material, which is available to authorized users.</p>
</sec>
</abstract>
<kwd-group xml:lang="en"><title>Keywords</title>
<kwd>Ubiquitin-like protein 4A, UBL4A</kwd>
<kwd>Lysosome associated membrane protein-1, LAMP1</kwd>
<kwd>Autophagy</kwd>
<kwd>Lysosome dysfunction</kwd>
<kwd>Pancreatic ductal adenocarcinoma, PDAC</kwd>
<kwd>Proliferation and metastasis</kwd>
</kwd-group>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100001809</institution-id>
<institution>National Natural Science Foundation of China</institution>
</institution-wrap>
</funding-source>
<award-id>81372613</award-id>
<award-id>81670583</award-id>
<award-id>81800572</award-id>
<principal-award-recipient><name><surname>Li</surname>
<given-names>Le</given-names>
</name>
<name><surname>Sun</surname>
<given-names>Bei</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/501100002858</institution-id>
<institution>China Postdoctoral Science Foundation</institution>
</institution-wrap>
</funding-source>
<award-id>2017M621300</award-id>
<award-id>2018T110316</award-id>
<principal-award-recipient><name><surname>Li</surname>
<given-names>Le</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">http://dx.doi.org/10.13039/100012548</institution-id>
<institution>Heilongjiang Postdoctoral Science Foundation</institution>
</institution-wrap>
</funding-source>
<award-id>LBH-Z17179</award-id>
<award-id>LBH-TZ17</award-id>
<principal-award-recipient><name><surname>Li</surname>
<given-names>Le</given-names>
</name>
</principal-award-recipient>
</award-group>
</funding-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2019</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
</record>
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