Monoglyceride lipase gene knockout in mice leads to increased incidence of lung adenocarcinoma.
Monoglyceride lipase gene knockout in mice leads to increased incidence of lung adenocarcinoma.
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DOI：
10.1038/s41419-017-0188-z
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发表时间：
2018-01-18
影响因子：
9
通讯作者：
Huang Y
中科院分区：
文献类型：
--
作者：
Liu R;Wang X;Curtiss C;Landas S;Rong R;Sheikh MS;Huang Y
单甘酯脂肪酶(MGL)是最近发现的一种与癌症相关的蛋白质。MGL在肿瘤发生中的作用仍有待充分阐明。我们先前已经证明，在多种人类恶性肿瘤中，MGL的表达减少或缺失，而MGL的过度表达抑制了癌细胞的生长。在这里，我们建立了MGL基因敲除小鼠，以进一步研究MGL在体内肿瘤发生中的作用。我们的结果表明，mgl缺陷(mgl+/−，mgl−/−)小鼠多器官肿瘤发生率较高，包括肺、脾、肝和淋巴组织。有趣的是，肺肿瘤是MGL缺陷小鼠中最常见的肿瘤性改变。重要的是，MGL缺乏的动物发生了癌前高度不典型增生和肺腺癌。对肺癌患者标本中MGL表达状况的调查也显示，与相应的匹配正常组织相比，大多数人原发肺癌组织中MGL的表达显著降低。此外，来自MGL缺乏动物的小鼠胚胎成纤维细胞(MEF)表现出细胞转化的特征，包括细胞增殖增加、病灶形成和锚定无关生长。我们的结果还表明，MGL缺乏与EGFR和ERK的激活有关。此外，促炎症分子COX-2和肿瘤坏死因子-α在MGL缺乏的肺组织中也被激活。因此，我们的结果为MGL作为EGFR、COX-2和肿瘤坏死因子-α的重要负性调节因子的新作用提供了新的见解。因此，表皮生长因子受体和环氧合酶-2/肿瘤坏死因子-α的激活/诱导在mgl缺乏所致的肺肿瘤中可能发挥重要作用。总之，我们的结果暗示了MGL在体内阻止肿瘤发展方面的肿瘤抑制作用，特别是在肺癌的背景下，并强调了它作为潜在的肿瘤抑制物的作用。
Monoglyceride lipase (MGL) is a recently discovered cancer-related protein. The role of MGL in tumorigenesis remains to be fully elucidated. We have previously shown that MGL expression was reduced or absent in multiple human malignancies, and overexpression of MGL inhibited cancer cell growth. Here, we have generated the MGL knockout mice to further investigate the role of MGL in tumorigenesis in vivo. Our results indicate that MGL-deficient (MGL+/−, MGL−/−) mice exhibited a higher incidence of neoplasia in multiple organs, including the lung, spleen, liver and lymphoid tissues. Interestingly, lung neoplasms were the most common neoplastic changes in the MGL-deficient mice. Importantly, MGL-deficient animals developed premalignant high-grade dysplasia and adenocarcinomas in their lungs. Investigation of the MGL expression status in lung cancer specimens from patients also revealed that MGL expression was significantly reduced in the majority of primary human lung cancers when compared to corresponding matched normal tissues. Furthermore, mouse embryonic fibroblasts (MEFs) from MGL-deficient animals showed characteristics of cellular transformation including increased cell proliferation, foci formation and anchorage-independent growth. Our results also indicate that MGL deficiency was associated with activation of EGFR and ERK. In addition, pro-inflammatory molecules COX-2 and TNF-α were also activated in the MGL-deficient lung tissues. Thus, our results provide new insights into the novel role of MGL as an important negative regulator of EGFR, COX-2 and TNF-α. Accordingly, EGFR and COX-2/TNF-α activation/induction is expected to play important roles in MGL deficiency-driven lung tumors. Collectively, our results implicate the tumor suppressive role of MGL in preventing tumor development in vivo, particularly in context to the lung cancer, and highlight its role as a potential tumor suppressor.
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影响因子：
64.5
作者：
Nomura DK;Long JZ;Niessen S;Hoover HS;Ng SW;Cravatt BF
通讯作者：
Cravatt BF
DOI：
10.1016/j.bbamcr.2014.10.022
发表时间：
2015-01
影响因子：
5.1
作者：
Krisenko, Mariya O.;Geahlen, Robert L.
通讯作者：
Geahlen, Robert L.
影响因子：
4.8
作者：
Guturi, Kiran Kumar Naidu;Mandal, Tapashi;Ghosh, Mrinal K.
通讯作者：
Ghosh, Mrinal K.
影响因子：
8
作者：
Lucchesi, C.;Sheikh, M. S.;Huang, Y.
通讯作者：
Huang, Y.
DOI：
10.1073/pnas.241500798
发表时间：
2001-11-20
影响因子：
11.1
作者：
Garber, ME;Troyanskaya, OG;Petersen, I
通讯作者：
Petersen, I