Inhibition of TMPRSS2 by HAI-2 reduces prostate cancer cell invasion and metastasis
TMPRSS2 is an important membrane-anchored serine protease involved in human prostate cancer progression and metastasis. A serine protease physiologically often comes together with a cognate inhibitor for execution of proteolytically biologic function; however, TMPRSS2’s cognate inhibitor is still el...
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| Veröffentlicht in: | Oncogene 2020-09, Vol.39 (37), p.5950-5963 |
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| creator | Ko, Chun-Jung Hsu, Ting-Wei Wu, Shang-Ru Lan, Shao-Wei Hsiao, Ting-Feng Lin, Hsin-Ying Lin, Hsin-Hsien Tu, Hsin-Fang Lee, Cheng-Fan Huang, Cheng-Chung Chen, Mei-Ju May Hsiao, Pei-Wen Huang, Hsiang-Po Lee, Ming-Shyue |
| description | TMPRSS2 is an important membrane-anchored serine protease involved in human prostate cancer progression and metastasis. A serine protease physiologically often comes together with a cognate inhibitor for execution of proteolytically biologic function; however, TMPRSS2’s cognate inhibitor is still elusive. To identify the cognate inhibitor of TMPRSS2, in this study, we applied co-immunoprecipitation and LC/MS/MS analysis and isolated hepatocyte growth factor activator inhibitors (HAIs) to be potential inhibitor candidates for TMPRSS2. Moreover, the recombinant HAI-2 proteins exhibited a better inhibitory effect on TMPRSS2 proteolytic activity than HAI-1, and recombinant HAI-2 proteins had a high affinity to form a complex with TMPRSS2. The immunofluorescence images further showed that TMPRSS2 was co-localized to HAI-2. Both KD1 and KD2 domain of HAI-2 showed comparable inhibitory effects on TMPRSS2 proteolytic activity. In addition, HAI-2 overexpression could suppress the induction effect of TMPRSS2 on pro-HGF activation, extracellular matrix degradation and prostate cancer cell invasion. We further determined that the expression levels of TMPRSS2 were inversely correlated with HAI-2 levels during prostate cancer progression. In orthotopic xenograft animal model, TMPRSS2 overexpression promoted prostate cancer metastasis, and HAI-2 overexpression efficiently blocked TMPRSS2-induced metastasis. In summary, the results together indicate that HAI-2 can function as a cognate inhibitor for TMPRSS2 in human prostate cancer cells and may serve as a potential factor to suppress TMPRSS2-mediated malignancy. |
| doi_str_mv | 10.1038/s41388-020-01413-w |
| format | Article |
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A serine protease physiologically often comes together with a cognate inhibitor for execution of proteolytically biologic function; however, TMPRSS2’s cognate inhibitor is still elusive. To identify the cognate inhibitor of TMPRSS2, in this study, we applied co-immunoprecipitation and LC/MS/MS analysis and isolated hepatocyte growth factor activator inhibitors (HAIs) to be potential inhibitor candidates for TMPRSS2. Moreover, the recombinant HAI-2 proteins exhibited a better inhibitory effect on TMPRSS2 proteolytic activity than HAI-1, and recombinant HAI-2 proteins had a high affinity to form a complex with TMPRSS2. The immunofluorescence images further showed that TMPRSS2 was co-localized to HAI-2. Both KD1 and KD2 domain of HAI-2 showed comparable inhibitory effects on TMPRSS2 proteolytic activity. In addition, HAI-2 overexpression could suppress the induction effect of TMPRSS2 on pro-HGF activation, extracellular matrix degradation and prostate cancer cell invasion. We further determined that the expression levels of TMPRSS2 were inversely correlated with HAI-2 levels during prostate cancer progression. In orthotopic xenograft animal model, TMPRSS2 overexpression promoted prostate cancer metastasis, and HAI-2 overexpression efficiently blocked TMPRSS2-induced metastasis. In summary, the results together indicate that HAI-2 can function as a cognate inhibitor for TMPRSS2 in human prostate cancer cells and may serve as a potential factor to suppress TMPRSS2-mediated malignancy.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-020-01413-w</identifier><identifier>PMID: 32778768</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/105 ; 13/51 ; 14/19 ; 38/109 ; 38/70 ; 38/77 ; 59/5 ; 631/337/474 ; 631/67/322 ; 631/67/589/466 ; 64/60 ; 82/47 ; 82/58 ; 96/1 ; 96/95 ; Analysis ; Animal models ; Animals ; Apoptosis ; Carrier Proteins - metabolism ; Cell Biology ; Cell Line, Tumor ; Disease Models, Animal ; Extracellular matrix ; Hepatocyte growth factor ; Heterografts ; Human Genetics ; Humans ; Immunofluorescence ; Immunoprecipitation ; Internal Medicine ; Male ; Malignancy ; Medicine ; Medicine & Public Health ; Membrane Glycoproteins - chemistry ; Membrane Glycoproteins - metabolism ; Metastases ; Metastasis ; Neoplasm Invasiveness ; Oncology ; Prostate cancer ; Prostatic Neoplasms - etiology ; Prostatic Neoplasms - metabolism ; Prostatic Neoplasms - pathology ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Interaction Mapping ; Proteinase Inhibitory Proteins, Secretory - metabolism ; Proteins ; Proteolysis ; Serine ; Serine Endopeptidases - metabolism ; Serine proteinase ; Thrombin ; Xenografts</subject><ispartof>Oncogene, 2020-09, Vol.39 (37), p.5950-5963</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020</rights><rights>COPYRIGHT 2020 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c635t-e6d762de1c68069242945dc7cf0e38231f440dd05ea1180db29183340d079eac3</citedby><cites>FETCH-LOGICAL-c635t-e6d762de1c68069242945dc7cf0e38231f440dd05ea1180db29183340d079eac3</cites><orcidid>0000-0002-8673-5088 ; 0000-0002-3589-6754 ; 0000-0002-3382-305X ; 0000-0001-6565-7060</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41388-020-01413-w$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41388-020-01413-w$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32778768$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ko, Chun-Jung</creatorcontrib><creatorcontrib>Hsu, Ting-Wei</creatorcontrib><creatorcontrib>Wu, Shang-Ru</creatorcontrib><creatorcontrib>Lan, Shao-Wei</creatorcontrib><creatorcontrib>Hsiao, Ting-Feng</creatorcontrib><creatorcontrib>Lin, Hsin-Ying</creatorcontrib><creatorcontrib>Lin, Hsin-Hsien</creatorcontrib><creatorcontrib>Tu, Hsin-Fang</creatorcontrib><creatorcontrib>Lee, Cheng-Fan</creatorcontrib><creatorcontrib>Huang, Cheng-Chung</creatorcontrib><creatorcontrib>Chen, Mei-Ju May</creatorcontrib><creatorcontrib>Hsiao, Pei-Wen</creatorcontrib><creatorcontrib>Huang, Hsiang-Po</creatorcontrib><creatorcontrib>Lee, Ming-Shyue</creatorcontrib><title>Inhibition of TMPRSS2 by HAI-2 reduces prostate cancer cell invasion and metastasis</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>TMPRSS2 is an important membrane-anchored serine protease involved in human prostate cancer progression and metastasis. A serine protease physiologically often comes together with a cognate inhibitor for execution of proteolytically biologic function; however, TMPRSS2’s cognate inhibitor is still elusive. To identify the cognate inhibitor of TMPRSS2, in this study, we applied co-immunoprecipitation and LC/MS/MS analysis and isolated hepatocyte growth factor activator inhibitors (HAIs) to be potential inhibitor candidates for TMPRSS2. Moreover, the recombinant HAI-2 proteins exhibited a better inhibitory effect on TMPRSS2 proteolytic activity than HAI-1, and recombinant HAI-2 proteins had a high affinity to form a complex with TMPRSS2. The immunofluorescence images further showed that TMPRSS2 was co-localized to HAI-2. Both KD1 and KD2 domain of HAI-2 showed comparable inhibitory effects on TMPRSS2 proteolytic activity. In addition, HAI-2 overexpression could suppress the induction effect of TMPRSS2 on pro-HGF activation, extracellular matrix degradation and prostate cancer cell invasion. We further determined that the expression levels of TMPRSS2 were inversely correlated with HAI-2 levels during prostate cancer progression. In orthotopic xenograft animal model, TMPRSS2 overexpression promoted prostate cancer metastasis, and HAI-2 overexpression efficiently blocked TMPRSS2-induced metastasis. In summary, the results together indicate that HAI-2 can function as a cognate inhibitor for TMPRSS2 in human prostate cancer cells and may serve as a potential factor to suppress TMPRSS2-mediated malignancy.</description><subject>13</subject><subject>13/105</subject><subject>13/51</subject><subject>14/19</subject><subject>38/109</subject><subject>38/70</subject><subject>38/77</subject><subject>59/5</subject><subject>631/337/474</subject><subject>631/67/322</subject><subject>631/67/589/466</subject><subject>64/60</subject><subject>82/47</subject><subject>82/58</subject><subject>96/1</subject><subject>96/95</subject><subject>Analysis</subject><subject>Animal models</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Disease Models, Animal</subject><subject>Extracellular matrix</subject><subject>Hepatocyte growth factor</subject><subject>Heterografts</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Immunofluorescence</subject><subject>Immunoprecipitation</subject><subject>Internal Medicine</subject><subject>Male</subject><subject>Malignancy</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Membrane Glycoproteins - chemistry</subject><subject>Membrane Glycoproteins - metabolism</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Neoplasm Invasiveness</subject><subject>Oncology</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms - etiology</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Protein Binding</subject><subject>Protein Interaction Domains and Motifs</subject><subject>Protein Interaction Mapping</subject><subject>Proteinase Inhibitory Proteins, Secretory - metabolism</subject><subject>Proteins</subject><subject>Proteolysis</subject><subject>Serine</subject><subject>Serine Endopeptidases - metabolism</subject><subject>Serine proteinase</subject><subject>Thrombin</subject><subject>Xenografts</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkk1v1DAQhi0EotvCH-CAInHhkuJvOxekVQXtSkUgtpwtrz3ZukqcxU5a9d_jsKWlCIF8sDXzvGPP-EXoFcHHBDP9LnPCtK4xxTUm5VzfPEELwpWshWj4U7TAjcB1Qxk9QIc5X2GMVYPpc3TAqFJaSb1A61W8DJswhiFWQ1tdfPrydb2m1ea2Oluualol8JODXO3SkEc7QuVsdJAqB11XhXht86y00Vc9jLYgOeQX6Flruwwv7_Yj9O3jh4uTs_r88-nqZHleO8nEWIP0SlIPxEmNZUM5bbjwTrkWA9OUkZZz7D0WYAnR2G9oQzRjJVbaAOvYEXq_r7ubNj14B3FMtjO7FHqbbs1gg3mcieHSbIdroziRmshS4O1dgTR8nyCPpg957sxGGKZsKGdUC6GJKOibP9CrYUqxtFcoJRXTiv2Hmn-LC8YfqK3twITYDuV1br7aLMtkCJOCqUId_4Uqy0Mf3BChDSX-SED3Alf-Kido7ydBsJkNY_aGMcUw5qdhzE0Rvf59hveSXw4pANsDuaTiFtJDS_8o-wNRzMhu</recordid><startdate>20200910</startdate><enddate>20200910</enddate><creator>Ko, Chun-Jung</creator><creator>Hsu, Ting-Wei</creator><creator>Wu, Shang-Ru</creator><creator>Lan, Shao-Wei</creator><creator>Hsiao, Ting-Feng</creator><creator>Lin, Hsin-Ying</creator><creator>Lin, Hsin-Hsien</creator><creator>Tu, Hsin-Fang</creator><creator>Lee, Cheng-Fan</creator><creator>Huang, Cheng-Chung</creator><creator>Chen, Mei-Ju May</creator><creator>Hsiao, Pei-Wen</creator><creator>Huang, Hsiang-Po</creator><creator>Lee, Ming-Shyue</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8673-5088</orcidid><orcidid>https://orcid.org/0000-0002-3589-6754</orcidid><orcidid>https://orcid.org/0000-0002-3382-305X</orcidid><orcidid>https://orcid.org/0000-0001-6565-7060</orcidid></search><sort><creationdate>20200910</creationdate><title>Inhibition of TMPRSS2 by HAI-2 reduces prostate cancer cell invasion and metastasis</title><author>Ko, Chun-Jung ; Hsu, Ting-Wei ; Wu, Shang-Ru ; Lan, Shao-Wei ; Hsiao, Ting-Feng ; Lin, Hsin-Ying ; Lin, Hsin-Hsien ; Tu, Hsin-Fang ; Lee, Cheng-Fan ; Huang, Cheng-Chung ; Chen, Mei-Ju May ; Hsiao, Pei-Wen ; Huang, Hsiang-Po ; Lee, Ming-Shyue</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c635t-e6d762de1c68069242945dc7cf0e38231f440dd05ea1180db29183340d079eac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>13</topic><topic>13/105</topic><topic>13/51</topic><topic>14/19</topic><topic>38/109</topic><topic>38/70</topic><topic>38/77</topic><topic>59/5</topic><topic>631/337/474</topic><topic>631/67/322</topic><topic>631/67/589/466</topic><topic>64/60</topic><topic>82/47</topic><topic>82/58</topic><topic>96/1</topic><topic>96/95</topic><topic>Analysis</topic><topic>Animal models</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Carrier Proteins - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ko, Chun-Jung</au><au>Hsu, Ting-Wei</au><au>Wu, Shang-Ru</au><au>Lan, Shao-Wei</au><au>Hsiao, Ting-Feng</au><au>Lin, Hsin-Ying</au><au>Lin, Hsin-Hsien</au><au>Tu, Hsin-Fang</au><au>Lee, Cheng-Fan</au><au>Huang, Cheng-Chung</au><au>Chen, Mei-Ju May</au><au>Hsiao, Pei-Wen</au><au>Huang, Hsiang-Po</au><au>Lee, Ming-Shyue</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of TMPRSS2 by HAI-2 reduces prostate cancer cell invasion and metastasis</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2020-09-10</date><risdate>2020</risdate><volume>39</volume><issue>37</issue><spage>5950</spage><epage>5963</epage><pages>5950-5963</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>TMPRSS2 is an important membrane-anchored serine protease involved in human prostate cancer progression and metastasis. A serine protease physiologically often comes together with a cognate inhibitor for execution of proteolytically biologic function; however, TMPRSS2’s cognate inhibitor is still elusive. To identify the cognate inhibitor of TMPRSS2, in this study, we applied co-immunoprecipitation and LC/MS/MS analysis and isolated hepatocyte growth factor activator inhibitors (HAIs) to be potential inhibitor candidates for TMPRSS2. Moreover, the recombinant HAI-2 proteins exhibited a better inhibitory effect on TMPRSS2 proteolytic activity than HAI-1, and recombinant HAI-2 proteins had a high affinity to form a complex with TMPRSS2. The immunofluorescence images further showed that TMPRSS2 was co-localized to HAI-2. Both KD1 and KD2 domain of HAI-2 showed comparable inhibitory effects on TMPRSS2 proteolytic activity. In addition, HAI-2 overexpression could suppress the induction effect of TMPRSS2 on pro-HGF activation, extracellular matrix degradation and prostate cancer cell invasion. We further determined that the expression levels of TMPRSS2 were inversely correlated with HAI-2 levels during prostate cancer progression. In orthotopic xenograft animal model, TMPRSS2 overexpression promoted prostate cancer metastasis, and HAI-2 overexpression efficiently blocked TMPRSS2-induced metastasis. In summary, the results together indicate that HAI-2 can function as a cognate inhibitor for TMPRSS2 in human prostate cancer cells and may serve as a potential factor to suppress TMPRSS2-mediated malignancy.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32778768</pmid><doi>10.1038/s41388-020-01413-w</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-8673-5088</orcidid><orcidid>https://orcid.org/0000-0002-3589-6754</orcidid><orcidid>https://orcid.org/0000-0002-3382-305X</orcidid><orcidid>https://orcid.org/0000-0001-6565-7060</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Oncogene, 2020-09, Vol.39 (37), p.5950-5963 |
| issn | 0950-9232 1476-5594 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7416816 |
| source | MEDLINE; Springer Online Journals Complete |
| subjects | 13 13/105 13/51 14/19 38/109 38/70 38/77 59/5 631/337/474 631/67/322 631/67/589/466 64/60 82/47 82/58 96/1 96/95 Analysis Animal models Animals Apoptosis Carrier Proteins - metabolism Cell Biology Cell Line, Tumor Disease Models, Animal Extracellular matrix Hepatocyte growth factor Heterografts Human Genetics Humans Immunofluorescence Immunoprecipitation Internal Medicine Male Malignancy Medicine Medicine & Public Health Membrane Glycoproteins - chemistry Membrane Glycoproteins - metabolism Metastases Metastasis Neoplasm Invasiveness Oncology Prostate cancer Prostatic Neoplasms - etiology Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Protein Binding Protein Interaction Domains and Motifs Protein Interaction Mapping Proteinase Inhibitory Proteins, Secretory - metabolism Proteins Proteolysis Serine Serine Endopeptidases - metabolism Serine proteinase Thrombin Xenografts |
| title | Inhibition of TMPRSS2 by HAI-2 reduces prostate cancer cell invasion and metastasis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T21%3A05%3A50IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Inhibition%20of%20TMPRSS2%20by%20HAI-2%20reduces%20prostate%20cancer%20cell%20invasion%20and%20metastasis&rft.jtitle=Oncogene&rft.au=Ko,%20Chun-Jung&rft.date=2020-09-10&rft.volume=39&rft.issue=37&rft.spage=5950&rft.epage=5963&rft.pages=5950-5963&rft.issn=0950-9232&rft.eissn=1476-5594&rft_id=info:doi/10.1038/s41388-020-01413-w&rft_dat=%3Cgale_pubme%3EA635136537%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2441384534&rft_id=info:pmid/32778768&rft_galeid=A635136537&rfr_iscdi=true |