LncRNA-MALAT1调控剪接蛋白SRSF1在炎症诱导的癌症恶病质脂肪丢失中的作用及机制研究

Fat loss is one of the most important features of cancer cachexia, which is the late stage of many cancers. Our previous studies have shown that inflammation can induce fat loss of cancer cachexia by accelerating lipolysis and white fat browning, but the underlying mechanism is not clear. LncRNA-MALAT1, screening by microarray analysis, is downregulated in subcutaneous fat of cachexic human and mouse. In addition, it was associated with inflammation and fat loss. Cell experiments suggest that inflammation reduces the expression of MALAT1, while knockdown of MALAT1 promotes lipolysis and white fat browning induced by inflammation. Bioinformatics and primary experiments confirmed SRSF1 as the target gene of MALAT1. Accordingly, we proposed a hypothesis that: MALAT1 is involved in the fat loss of inflammation induced cancer cachexia by regulating SRSF1 regulating via lipolysis and white fat browning. The purpose of this study is to systematically evaluate the function and mechanism of MALAT1 during fat loss of inflammation induced cancer cachexia in cells, animals and clinical samples using SRSF1 as a mechanic clue. This study is expected to provide new clues for understanding the mechanism of fat loss in cancer cachexia, and may provide new diagnostic and therapeutic targets.

癌症恶病质是各种癌症晚期的一种表现，脂肪丢失是其重要特征之一。我们的前期研究表明炎症可以促进脂肪分解和白色脂肪棕色化而导致癌症恶病质脂肪丢失，但机制未明。lncRNA-MALAT1是我们前期筛选发现的差异低表达于癌症恶病质皮下脂肪中的lncRNA。研究发现: MALAT1在人和小鼠癌症恶病质中均低表达，并且和炎症及脂肪丢失相关。细胞实验提示炎症下调MALAT1的表达，沉默MALAT1后促进炎症诱导的脂肪分解和白色脂肪棕色化的发生。生物信息学和初步实验验证剪接蛋白SRSF1为其靶基因。据此我们提出“MALAT1通过SRSF1调控脂肪分解和白色脂肪棕色化而参与炎症诱导的癌症恶病质脂肪丢失”的假说。本研究拟用细胞、动物和临床样本，以SRSF1为机制线索，系统评价MALAT1在炎症诱导的癌症恶病质脂肪丢失中的作用和机制。本研究有望为理解癌症恶病质脂肪丢失机制提供新线索，并可能提供新诊断和治疗靶标。

癌症恶病质是各种癌症晚期的一种表现，脂肪丢失是其重要特征之一。我们的前期研究表明炎症可以促进脂肪分解和白色脂肪棕色化而导致癌症恶病质脂肪丢失，但机制未明。lncRNA-MALAT1是我们前期筛选发现的在癌症恶病质患者皮下脂肪中低表达的lncRNA。通过预实验我们提出“MALAT1通过SRSF1调控脂肪分解和白色脂肪棕色化而参与炎症诱导的癌症恶病质脂肪丢失”的假说。本项目立项以后我们进行了以下研究：1）我们对MALAT1进行细胞定位研究和在脂肪细胞分化不同阶段的表达研究，发现MALAT1主要定位于脂肪细胞的细胞核内并且随着细胞分化水平其表达也逐渐升高。2）在C3H10细胞中敲减MALAT1的表达，研究脂肪代谢相关指标的变化，结果发现FABP4和LPL等分化指标明显降低。提示MALAT1主要通过影响细胞分化而调节恶病质脂肪丢失。3）我们在C3H10细胞中敲减MALAT1的表达，然后进行转录组测序，结果发MALAT1敲掉以后脂肪代谢相关基因和PPAR-γ通路出现显著变化。敲除MALAT1后发现PPAR-γ的表达水平也随之降低。4）临床研究中，我们发现恶病质患者皮下脂肪中MALAT1的表达显著降低， MALAT1表达水平和患者的体重丢失程度成负相关，和去脂体重指数成正相关。临床随访发现低表达MALAT1的患者预后更差。本研究系统评价MALAT1在炎症诱导的癌症恶病质脂肪丢失中的作用和机制。为理解癌症恶病质脂肪丢失机制提供新线索和新的诊断和治疗靶标。