Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathway
Mannan binding lectin (MBL), initially known to activate the complement lectin pathway and defend against infection, was recently shown to be potentially involved in the development of several types of cancer; however, its exact role in cancers, especially its effect on tumor microenvironment remain...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-02-01
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| Series: | OncoImmunology |
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| Online Access: | http://dx.doi.org/10.1080/2162402X.2018.1527650 |
| _version_ | 1811210096405905408 |
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| author | Junru Li Huifang Li Yu Yu Yan Liu Yunzhi Liu Qiang Ma Liyun Zhang Xiao Lu Xiang-yang Wang Zhengliang Chen Daming Zuo Jia Zhou |
| author_facet | Junru Li Huifang Li Yu Yu Yan Liu Yunzhi Liu Qiang Ma Liyun Zhang Xiao Lu Xiang-yang Wang Zhengliang Chen Daming Zuo Jia Zhou |
| author_sort | Junru Li |
| collection | DOAJ |
| description | Mannan binding lectin (MBL), initially known to activate the complement lectin pathway and defend against infection, was recently shown to be potentially involved in the development of several types of cancer; however, its exact role in cancers, especially its effect on tumor microenvironment remain largely unknown. Here, using a murine hepatocellular carcinoma (HCC) model, we showed that MBL was a component of liver microenvironment and MBL-deficient (MBL–/–) mice exhibited an enhanced tumor growth compared with wild-type (WT) mice. This phenomenon was associated with elevation of myeloid derived suppressed cells (MDSCs) in tumor tissue of MBL–/– mice. MBL deficiency also resulted in an increase of activated hepatic stellate cells (HSCs), which showed enhanced cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production. Pharmacological inhibition of COX-2 in vivo partially abrogated the MBL deficiency-promoted tumor growth and MDSC accumulation. Mechanistic studies revealed that MBL could interact directly with HSCs and inhibit HCC-induced HSCs activation via downregulating the extracellular signal-regulated kinase (ERK)/COX-2/PGE2 signaling pathway. Furthermore, MBL-mediated suppression of HCC is validated by administration of MBL-expressing, liver-specific adeno-associated virus (AAV), which significantly inhibited HCC progression in MBL–/– mice. Taken together, these data reveal that MBL may impact on tumor development by shaping the tumor microenvironment via its interaction with the local stromal cells, and also suggests its potential therapeutic use for the treatment of HCC. |
| first_indexed | 2024-04-12T04:50:28Z |
| format | Article |
| id | doaj.art-ae36c557f58c4163ab7dbd25bbaf9eb3 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-04-12T04:50:28Z |
| publishDate | 2019-02-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-ae36c557f58c4163ab7dbd25bbaf9eb32022-12-22T03:47:20ZengTaylor & Francis GroupOncoImmunology2162-402X2019-02-018210.1080/2162402X.2018.15276501527650Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathwayJunru Li0Huifang Li1Yu Yu2Yan Liu3Yunzhi Liu4Qiang Ma5Liyun Zhang6Xiao Lu7Xiang-yang Wang8Zhengliang Chen9Daming Zuo10Jia Zhou11Southern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversityVirginia Commonwealth UniversitySouthern Medical UniversitySouthern Medical UniversitySouthern Medical UniversityMannan binding lectin (MBL), initially known to activate the complement lectin pathway and defend against infection, was recently shown to be potentially involved in the development of several types of cancer; however, its exact role in cancers, especially its effect on tumor microenvironment remain largely unknown. Here, using a murine hepatocellular carcinoma (HCC) model, we showed that MBL was a component of liver microenvironment and MBL-deficient (MBL–/–) mice exhibited an enhanced tumor growth compared with wild-type (WT) mice. This phenomenon was associated with elevation of myeloid derived suppressed cells (MDSCs) in tumor tissue of MBL–/– mice. MBL deficiency also resulted in an increase of activated hepatic stellate cells (HSCs), which showed enhanced cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production. Pharmacological inhibition of COX-2 in vivo partially abrogated the MBL deficiency-promoted tumor growth and MDSC accumulation. Mechanistic studies revealed that MBL could interact directly with HSCs and inhibit HCC-induced HSCs activation via downregulating the extracellular signal-regulated kinase (ERK)/COX-2/PGE2 signaling pathway. Furthermore, MBL-mediated suppression of HCC is validated by administration of MBL-expressing, liver-specific adeno-associated virus (AAV), which significantly inhibited HCC progression in MBL–/– mice. Taken together, these data reveal that MBL may impact on tumor development by shaping the tumor microenvironment via its interaction with the local stromal cells, and also suggests its potential therapeutic use for the treatment of HCC.http://dx.doi.org/10.1080/2162402X.2018.1527650mannan binding lectinhepatocellular carcinomahepatic stellate cellserk/cox-2/pge2 pathway |
| spellingShingle | Junru Li Huifang Li Yu Yu Yan Liu Yunzhi Liu Qiang Ma Liyun Zhang Xiao Lu Xiang-yang Wang Zhengliang Chen Daming Zuo Jia Zhou Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathway OncoImmunology mannan binding lectin hepatocellular carcinoma hepatic stellate cells erk/cox-2/pge2 pathway |
| title | Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathway |
| title_full | Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathway |
| title_fullStr | Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathway |
| title_full_unstemmed | Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathway |
| title_short | Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathway |
| title_sort | mannan binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the erk cox 2 pge2 pathway |
| topic | mannan binding lectin hepatocellular carcinoma hepatic stellate cells erk/cox-2/pge2 pathway |
| url | http://dx.doi.org/10.1080/2162402X.2018.1527650 |
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