Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathway
Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathway
复制标题
甘露聚糖结合凝集素通过 ERK/COX-2/PGE(2) 途径调节肝星状细胞活化，抑制肝细胞癌的生长
DOI：
10.1080/2162402x.2018.1527650
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发表时间：
2019-01-01
期刊：
影响因子：
7.2
通讯作者：
Zhou, Jia
中科院分区：
文献类型：
--
作者：
Li, Junru;Li, Huifang;Zhou, Jia
甘露聚糖结合凝集素（MBL），最初已知激活补体凝集素途径并防御感染，最近被证明可能参与几种类型癌症的发展；然而，其在癌症中的确切作用，特别是对肿瘤微环境的影响在很大程度上仍不清楚。通过小鼠肝细胞癌（HCC）模型，我们发现MBL是肝脏微环境的一个组成部分，与野生型（WT）小鼠相比，MBL缺失（MBL-/-）小鼠表现出更强的肿瘤生长。这种现象与MBL-/-小鼠肿瘤组织中髓源性抑制细胞（MDSCs）的升高有关。MBL缺乏还导致活化的肝星状细胞（hsc）增加，其表现为环氧化酶-2 （COX-2）表达增强和前列腺素E2 （PGE(2)）产生增强。体内COX-2的药物抑制部分消除了MBL缺陷，促进了肿瘤生长和MDSC积累。机制研究表明，MBL可通过下调细胞外信号调节激酶(ERK)/COX-2/PGE(2)信号通路，直接与hsc相互作用，抑制hcc诱导的hsc活化。此外，通过给药表达MBL的肝脏特异性腺相关病毒（AAV），证实了MBL介导的HCC抑制作用，该病毒可显著抑制MBL-/-小鼠的HCC进展。综上所述，这些数据表明MBL可能通过与局部基质细胞的相互作用来塑造肿瘤微环境，从而影响肿瘤的发展，并且还表明其在HCC治疗中的潜在治疗用途。
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 (PGE(2)) 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/PGE(2) 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.