SERPING1 Reduces Cell Migration via ERK‐MMP2‐MMP‐9 Cascade in Sorafenib‐ Resistant Hepatocellular Carcinoma
ABSTRACT Hepatocellular carcinoma (HCC) is the most common primary hepatic malignant tumor, and it ranks 2nd in terms of mortality rate among all malignancies in Taiwan. Sorafenib is a multiple tyrosine kinase inhibitor that suppresses tumor cell proliferation and angiogenesis around tumors via diff...
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| Veröffentlicht in: | Environmental toxicology 2025-02, Vol.40 (2), p.318-327 |
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| creator | Hsieh, Ching‐Chuan Wu, Yuh‐Harn Chen, Yi‐Li Wang, Chun‐I Li, Chao‐Jen Liu, I‐Hsiu Chou, Chen‐Wei Lin, Yang‐Hsiang Huang, Po‐Shuan Huang, Te‐Chia Chen, Cheng‐Yi |
| description | ABSTRACT
Hepatocellular carcinoma (HCC) is the most common primary hepatic malignant tumor, and it ranks 2nd in terms of mortality rate among all malignancies in Taiwan. Sorafenib is a multiple tyrosine kinase inhibitor that suppresses tumor cell proliferation and angiogenesis around tumors via different pathways. However, the survival outcome of advanced HCC patients treated with sorafenib is still unsatisfactory. Unfortunately, there are no clinically applicable biomarkers to predict sorafenib therapeutic efficiency in HCC thus far. We found that serpin peptidase inhibitor, clade G, member 1 (SERPING1) is highly associated with overall and recurrence‐free survival rates in HCC patients and is also highly correlated with several clinical parameters. SERPING1 expression was increased with sorafenib in both the HCC cell extract and conditioned medium, which was also observed in sorafenib‐resistant HepG2 and Huh7 cells. Sorafenib decreased cell viability and migration, which was similar to the effect of SERPING1 in HCC progression. Moreover, sorafenib inhibited both MMP‐2 and MMP‐9 activity and enhanced the expression of p‐ERK in HCC cells. In summary, sorafenib reduces HCC cancer progression might through the p‐ERK‐MMP‐2‐MMP‐9 cascade via upregulation of SERPING1. In the present study, the roles and molecular mechanisms of SERPING1 and its value as a marker for predicting sorafenib resistance and progression in HCC patients were examined. The results of the present study provide a deep understanding of the roles of SERPING1 in HCC sorafenib resistance, which can be applied to develop early diagnosis and prognosis evaluation methods and establish novel therapeutic targets for specifically treating HCC. |
| doi_str_mv | 10.1002/tox.24434 |
| format | Article |
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Hepatocellular carcinoma (HCC) is the most common primary hepatic malignant tumor, and it ranks 2nd in terms of mortality rate among all malignancies in Taiwan. Sorafenib is a multiple tyrosine kinase inhibitor that suppresses tumor cell proliferation and angiogenesis around tumors via different pathways. However, the survival outcome of advanced HCC patients treated with sorafenib is still unsatisfactory. Unfortunately, there are no clinically applicable biomarkers to predict sorafenib therapeutic efficiency in HCC thus far. We found that serpin peptidase inhibitor, clade G, member 1 (SERPING1) is highly associated with overall and recurrence‐free survival rates in HCC patients and is also highly correlated with several clinical parameters. SERPING1 expression was increased with sorafenib in both the HCC cell extract and conditioned medium, which was also observed in sorafenib‐resistant HepG2 and Huh7 cells. Sorafenib decreased cell viability and migration, which was similar to the effect of SERPING1 in HCC progression. Moreover, sorafenib inhibited both MMP‐2 and MMP‐9 activity and enhanced the expression of p‐ERK in HCC cells. In summary, sorafenib reduces HCC cancer progression might through the p‐ERK‐MMP‐2‐MMP‐9 cascade via upregulation of SERPING1. In the present study, the roles and molecular mechanisms of SERPING1 and its value as a marker for predicting sorafenib resistance and progression in HCC patients were examined. The results of the present study provide a deep understanding of the roles of SERPING1 in HCC sorafenib resistance, which can be applied to develop early diagnosis and prognosis evaluation methods and establish novel therapeutic targets for specifically treating HCC.</description><identifier>ISSN: 1520-4081</identifier><identifier>ISSN: 1522-7278</identifier><identifier>EISSN: 1522-7278</identifier><identifier>DOI: 10.1002/tox.24434</identifier><identifier>PMID: 39474998</identifier><language>eng</language><publisher>Hoboken, USA: John Wiley & Sons, Inc</publisher><subject>Angiogenesis inhibitors ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Biomarkers ; Cancer ; cancer progression ; Carcinoma, Hepatocellular - drug therapy ; Carcinoma, Hepatocellular - pathology ; Cell Line, Tumor ; Cell migration ; Cell Movement - drug effects ; Cell proliferation ; Cell survival ; Cell viability ; drug resistance ; Drug Resistance, Neoplasm ; Extracellular signal-regulated kinase ; Gelatinase A ; Hep G2 Cells ; Hepatocellular carcinoma ; Humans ; Inhibitor drugs ; Inhibitors ; Kinases ; Liver cancer ; Liver Neoplasms - drug therapy ; Liver Neoplasms - pathology ; Malignancy ; MAP Kinase Signaling System - drug effects ; Matrix Metalloproteinase 2 - genetics ; Matrix Metalloproteinase 2 - metabolism ; Matrix Metalloproteinase 9 - genetics ; Matrix Metalloproteinase 9 - metabolism ; Medical prognosis ; Molecular modelling ; Neoplasms ; Patients ; SERPING1 ; Serpins - metabolism ; sorafenib ; Sorafenib - pharmacology ; Sorafenib - therapeutic use ; Survival ; Targeted cancer therapy ; Therapeutic targets ; Tumors ; Tyrosine</subject><ispartof>Environmental toxicology, 2025-02, Vol.40 (2), p.318-327</ispartof><rights>2024 The Author(s). published by Wiley Periodicals LLC.</rights><rights>2024 The Author(s). Environmental Toxicology published by Wiley Periodicals LLC.</rights><rights>2024. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c2494-ec567141ec1e1c287d46cb218ca1b270c4356b694bf567f7f2a9fb2dc1442c4b3</cites><orcidid>0000-0001-9397-4792</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Ftox.24434$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Ftox.24434$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39474998$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hsieh, Ching‐Chuan</creatorcontrib><creatorcontrib>Wu, Yuh‐Harn</creatorcontrib><creatorcontrib>Chen, Yi‐Li</creatorcontrib><creatorcontrib>Wang, Chun‐I</creatorcontrib><creatorcontrib>Li, Chao‐Jen</creatorcontrib><creatorcontrib>Liu, I‐Hsiu</creatorcontrib><creatorcontrib>Chou, Chen‐Wei</creatorcontrib><creatorcontrib>Lin, Yang‐Hsiang</creatorcontrib><creatorcontrib>Huang, Po‐Shuan</creatorcontrib><creatorcontrib>Huang, Te‐Chia</creatorcontrib><creatorcontrib>Chen, Cheng‐Yi</creatorcontrib><title>SERPING1 Reduces Cell Migration via ERK‐MMP2‐MMP‐9 Cascade in Sorafenib‐ Resistant Hepatocellular Carcinoma</title><title>Environmental toxicology</title><addtitle>Environ Toxicol</addtitle><description>ABSTRACT
Hepatocellular carcinoma (HCC) is the most common primary hepatic malignant tumor, and it ranks 2nd in terms of mortality rate among all malignancies in Taiwan. Sorafenib is a multiple tyrosine kinase inhibitor that suppresses tumor cell proliferation and angiogenesis around tumors via different pathways. However, the survival outcome of advanced HCC patients treated with sorafenib is still unsatisfactory. Unfortunately, there are no clinically applicable biomarkers to predict sorafenib therapeutic efficiency in HCC thus far. We found that serpin peptidase inhibitor, clade G, member 1 (SERPING1) is highly associated with overall and recurrence‐free survival rates in HCC patients and is also highly correlated with several clinical parameters. SERPING1 expression was increased with sorafenib in both the HCC cell extract and conditioned medium, which was also observed in sorafenib‐resistant HepG2 and Huh7 cells. Sorafenib decreased cell viability and migration, which was similar to the effect of SERPING1 in HCC progression. Moreover, sorafenib inhibited both MMP‐2 and MMP‐9 activity and enhanced the expression of p‐ERK in HCC cells. In summary, sorafenib reduces HCC cancer progression might through the p‐ERK‐MMP‐2‐MMP‐9 cascade via upregulation of SERPING1. In the present study, the roles and molecular mechanisms of SERPING1 and its value as a marker for predicting sorafenib resistance and progression in HCC patients were examined. The results of the present study provide a deep understanding of the roles of SERPING1 in HCC sorafenib resistance, which can be applied to develop early diagnosis and prognosis evaluation methods and establish novel therapeutic targets for specifically treating HCC.</description><subject>Angiogenesis inhibitors</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biomarkers</subject><subject>Cancer</subject><subject>cancer progression</subject><subject>Carcinoma, Hepatocellular - drug therapy</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell Movement - drug effects</subject><subject>Cell proliferation</subject><subject>Cell survival</subject><subject>Cell viability</subject><subject>drug resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>Extracellular signal-regulated kinase</subject><subject>Gelatinase A</subject><subject>Hep G2 Cells</subject><subject>Hepatocellular carcinoma</subject><subject>Humans</subject><subject>Inhibitor drugs</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - drug therapy</subject><subject>Liver Neoplasms - pathology</subject><subject>Malignancy</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Matrix Metalloproteinase 2 - genetics</subject><subject>Matrix Metalloproteinase 2 - metabolism</subject><subject>Matrix Metalloproteinase 9 - genetics</subject><subject>Matrix Metalloproteinase 9 - metabolism</subject><subject>Medical prognosis</subject><subject>Molecular modelling</subject><subject>Neoplasms</subject><subject>Patients</subject><subject>SERPING1</subject><subject>Serpins - metabolism</subject><subject>sorafenib</subject><subject>Sorafenib - pharmacology</subject><subject>Sorafenib - therapeutic use</subject><subject>Survival</subject><subject>Targeted cancer therapy</subject><subject>Therapeutic targets</subject><subject>Tumors</subject><subject>Tyrosine</subject><issn>1520-4081</issn><issn>1522-7278</issn><issn>1522-7278</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNp1kc9u1DAQhy0EoqX0wAsgS1zKIa1n4jjJCaHV9o_o0mpbJG6W4zjFVdZe7KTQG4_AM_IkeJu2AiQuHkvz-fOMfoS8ArYPjOHB4L_vI-c5f0K2oUDMSiyrp3d3lnFWwRZ5EeM1Y6wWhXhOtvKal7yuq20SL-bL85OPR0CXph21iXRm-p4u7FVQg_WO3lhF58sPv378XCzOcSrprOlMRa1aQ62jFz6ozjjbpEbyRBsH5QZ6bNZq8Dr5xl6F9CBo6_xKvSTPOtVHs3tfd8inw_nl7Dg7PTs6mb0_zTTymmdGF6IEDkaDAY1V2XKhG4RKK2iwZJrnhWhEzZsugV3Zoaq7BlsNnKPmTb5D3k3e9disTKuNG4Lq5TrYlQq30isr_-44-0Ve-RsJUKJIPyTD3r0h-K-jiYNc2bhZSDnjxyhzQBR5kWOR0Df_oNd-DC7tl6iCCyFAbIRvJ0oHH2Mw3eM0wOQmS5mylHdZJvb1n-M_kg_hJeBgAr7Z3tz-3yQvzz5Pyt-T9aux</recordid><startdate>202502</startdate><enddate>202502</enddate><creator>Hsieh, Ching‐Chuan</creator><creator>Wu, Yuh‐Harn</creator><creator>Chen, Yi‐Li</creator><creator>Wang, Chun‐I</creator><creator>Li, Chao‐Jen</creator><creator>Liu, I‐Hsiu</creator><creator>Chou, Chen‐Wei</creator><creator>Lin, Yang‐Hsiang</creator><creator>Huang, Po‐Shuan</creator><creator>Huang, Te‐Chia</creator><creator>Chen, Cheng‐Yi</creator><general>John Wiley & Sons, Inc</general><general>Wiley Subscription Services, Inc</general><scope>24P</scope><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>7QH</scope><scope>7ST</scope><scope>7TN</scope><scope>7U7</scope><scope>7UA</scope><scope>C1K</scope><scope>F1W</scope><scope>H97</scope><scope>K9.</scope><scope>L.G</scope><scope>M7N</scope><scope>SOI</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9397-4792</orcidid></search><sort><creationdate>202502</creationdate><title>SERPING1 Reduces Cell Migration via ERK‐MMP2‐MMP‐9 Cascade in Sorafenib‐ Resistant Hepatocellular Carcinoma</title><author>Hsieh, Ching‐Chuan ; Wu, Yuh‐Harn ; Chen, Yi‐Li ; Wang, Chun‐I ; Li, Chao‐Jen ; Liu, I‐Hsiu ; Chou, Chen‐Wei ; Lin, Yang‐Hsiang ; Huang, Po‐Shuan ; Huang, Te‐Chia ; Chen, Cheng‐Yi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c2494-ec567141ec1e1c287d46cb218ca1b270c4356b694bf567f7f2a9fb2dc1442c4b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>Angiogenesis inhibitors</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biomarkers</topic><topic>Cancer</topic><topic>cancer progression</topic><topic>Carcinoma, Hepatocellular - drug therapy</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell migration</topic><topic>Cell Movement - drug effects</topic><topic>Cell proliferation</topic><topic>Cell survival</topic><topic>Cell viability</topic><topic>drug resistance</topic><topic>Drug Resistance, Neoplasm</topic><topic>Extracellular signal-regulated kinase</topic><topic>Gelatinase A</topic><topic>Hep G2 Cells</topic><topic>Hepatocellular carcinoma</topic><topic>Humans</topic><topic>Inhibitor drugs</topic><topic>Inhibitors</topic><topic>Kinases</topic><topic>Liver cancer</topic><topic>Liver Neoplasms - drug therapy</topic><topic>Liver Neoplasms - pathology</topic><topic>Malignancy</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Matrix Metalloproteinase 2 - genetics</topic><topic>Matrix Metalloproteinase 2 - metabolism</topic><topic>Matrix Metalloproteinase 9 - genetics</topic><topic>Matrix Metalloproteinase 9 - metabolism</topic><topic>Medical prognosis</topic><topic>Molecular modelling</topic><topic>Neoplasms</topic><topic>Patients</topic><topic>SERPING1</topic><topic>Serpins - metabolism</topic><topic>sorafenib</topic><topic>Sorafenib - pharmacology</topic><topic>Sorafenib - therapeutic use</topic><topic>Survival</topic><topic>Targeted cancer therapy</topic><topic>Therapeutic targets</topic><topic>Tumors</topic><topic>Tyrosine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hsieh, Ching‐Chuan</creatorcontrib><creatorcontrib>Wu, Yuh‐Harn</creatorcontrib><creatorcontrib>Chen, Yi‐Li</creatorcontrib><creatorcontrib>Wang, Chun‐I</creatorcontrib><creatorcontrib>Li, Chao‐Jen</creatorcontrib><creatorcontrib>Liu, I‐Hsiu</creatorcontrib><creatorcontrib>Chou, Chen‐Wei</creatorcontrib><creatorcontrib>Lin, Yang‐Hsiang</creatorcontrib><creatorcontrib>Huang, Po‐Shuan</creatorcontrib><creatorcontrib>Huang, Te‐Chia</creatorcontrib><creatorcontrib>Chen, Cheng‐Yi</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Aqualine</collection><collection>Environment Abstracts</collection><collection>Oceanic Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Water Resources Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ASFA: Aquatic Sciences and Fisheries Abstracts</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) 3: Aquatic Pollution & Environmental Quality</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) Professional</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Environment Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Environmental toxicology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hsieh, Ching‐Chuan</au><au>Wu, Yuh‐Harn</au><au>Chen, Yi‐Li</au><au>Wang, Chun‐I</au><au>Li, Chao‐Jen</au><au>Liu, I‐Hsiu</au><au>Chou, Chen‐Wei</au><au>Lin, Yang‐Hsiang</au><au>Huang, Po‐Shuan</au><au>Huang, Te‐Chia</au><au>Chen, Cheng‐Yi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SERPING1 Reduces Cell Migration via ERK‐MMP2‐MMP‐9 Cascade in Sorafenib‐ Resistant Hepatocellular Carcinoma</atitle><jtitle>Environmental toxicology</jtitle><addtitle>Environ Toxicol</addtitle><date>2025-02</date><risdate>2025</risdate><volume>40</volume><issue>2</issue><spage>318</spage><epage>327</epage><pages>318-327</pages><issn>1520-4081</issn><issn>1522-7278</issn><eissn>1522-7278</eissn><abstract>ABSTRACT
Hepatocellular carcinoma (HCC) is the most common primary hepatic malignant tumor, and it ranks 2nd in terms of mortality rate among all malignancies in Taiwan. Sorafenib is a multiple tyrosine kinase inhibitor that suppresses tumor cell proliferation and angiogenesis around tumors via different pathways. However, the survival outcome of advanced HCC patients treated with sorafenib is still unsatisfactory. Unfortunately, there are no clinically applicable biomarkers to predict sorafenib therapeutic efficiency in HCC thus far. We found that serpin peptidase inhibitor, clade G, member 1 (SERPING1) is highly associated with overall and recurrence‐free survival rates in HCC patients and is also highly correlated with several clinical parameters. SERPING1 expression was increased with sorafenib in both the HCC cell extract and conditioned medium, which was also observed in sorafenib‐resistant HepG2 and Huh7 cells. Sorafenib decreased cell viability and migration, which was similar to the effect of SERPING1 in HCC progression. Moreover, sorafenib inhibited both MMP‐2 and MMP‐9 activity and enhanced the expression of p‐ERK in HCC cells. In summary, sorafenib reduces HCC cancer progression might through the p‐ERK‐MMP‐2‐MMP‐9 cascade via upregulation of SERPING1. In the present study, the roles and molecular mechanisms of SERPING1 and its value as a marker for predicting sorafenib resistance and progression in HCC patients were examined. The results of the present study provide a deep understanding of the roles of SERPING1 in HCC sorafenib resistance, which can be applied to develop early diagnosis and prognosis evaluation methods and establish novel therapeutic targets for specifically treating HCC.</abstract><cop>Hoboken, USA</cop><pub>John Wiley & Sons, Inc</pub><pmid>39474998</pmid><doi>10.1002/tox.24434</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0001-9397-4792</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Angiogenesis inhibitors Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Biomarkers Cancer cancer progression Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - pathology Cell Line, Tumor Cell migration Cell Movement - drug effects Cell proliferation Cell survival Cell viability drug resistance Drug Resistance, Neoplasm Extracellular signal-regulated kinase Gelatinase A Hep G2 Cells Hepatocellular carcinoma Humans Inhibitor drugs Inhibitors Kinases Liver cancer Liver Neoplasms - drug therapy Liver Neoplasms - pathology Malignancy MAP Kinase Signaling System - drug effects Matrix Metalloproteinase 2 - genetics Matrix Metalloproteinase 2 - metabolism Matrix Metalloproteinase 9 - genetics Matrix Metalloproteinase 9 - metabolism Medical prognosis Molecular modelling Neoplasms Patients SERPING1 Serpins - metabolism sorafenib Sorafenib - pharmacology Sorafenib - therapeutic use Survival Targeted cancer therapy Therapeutic targets Tumors Tyrosine |
| title | SERPING1 Reduces Cell Migration via ERK‐MMP2‐MMP‐9 Cascade in Sorafenib‐ Resistant Hepatocellular Carcinoma |
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