Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathway

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

doi:10.1080/2162402X.2018.1527650

Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE₂ pathway

Oncoimmunology. 2018 Oct 10;8(2):e1527650. doi: 10.1080/2162402X.2018.1527650. eCollection 2019.

Authors

Junru Li¹, Huifang Li¹, Yu Yu¹, Yan Liu¹, Yunzhi Liu¹, Qiang Ma², Liyun Zhang¹, Xiao Lu¹, Xiang-Yang Wang³, Zhengliang Chen^{1

4}, Daming Zuo^{1

4

5

6}, Jia Zhou¹

Affiliations

¹ Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
² Department of Biopharmaceutics, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China.
³ Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, USA.
⁴ Guangdong Provincial Key Laboratory of Proteomics, Southern Medical University, Guangzhou, Guangdong, China.
⁵ Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangdong, China.
⁶ Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangdong, China.

Abstract

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.

Keywords: ERK/COX-2/PGE2 pathway; Mannan binding lectin; hepatic stellate cells; hepatocellular carcinoma.

Publication types

Research Support, Non-U.S. Gov't

Grants and funding

This work was supported in part by National Natural Science Foundation of China (31100627, 81671568, 81571608, and 81771771), Guangdong Natural Science Foundation 2017A030313542 and the Open Project of Guangdong Provincial Key Laboratory of Proteomics (NO. P201801).