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.

中文翻译：

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甘露聚糖结合凝集素通过通过ERK / COX-2 / PGE2途径调节肝星状细胞的活化来抑制肝细胞癌的生长。

甘露聚糖结合凝集素（MBL），最初已知是激活补体凝集素途径并防御感染，最近被证明可能参与多种类型癌症的发展。然而，其在癌症中的确切作用，特别是对肿瘤微环境的作用仍然未知。在这里，使用鼠类肝细胞癌（HCC）模型，我们显示MBL是肝脏微环境的组成部分，与野生型（WT）小鼠相比，MBL缺陷（MBL-/-）小鼠表现出增强的肿瘤生长。此现象与MBL-/-小鼠肿瘤组织中髓样来源的抑制细胞（MDSC）升高有关。MBL缺乏还导致活化的肝星状细胞（HSC）增多，这表明环氧合酶2（COX-2）表达增强和前列腺素E2（PGE2）产生。体内COX-2的药理抑制作用部分废除了MBL缺乏促进的肿瘤生长和MDSC积累。机理研究表明，MBL可以通过下调细胞外信号调节激酶（ERK）/ COX-2 / PGE2信号通路直接与HSC相互作用并抑制HCC诱导的HSC活化。此外，通过施用表达MBL的肝特异性腺相关病毒（AAV）可证实MBL介导的肝癌抑制作用，该病毒显着抑制了MBL-/-小鼠的肝癌进展。综上所述，这些数据表明，MBL可能通过与局部基质细胞相互作用来塑造肿瘤微环境，从而影响肿瘤的发展，并且还暗示了MBL在治疗HCC中的潜在治疗用途。