SREBP1 promotes the invasion of colorectal cancer accompanied upregulation of MMP7 expression and NF-κB pathway activation
SREBP1 promotes the invasion of colorectal cancer accompanied upregulation of MMP7 expression and NF-κB pathway activation
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DOI：
10.1186/s12885-019-5904-x
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发表时间：
2019-07-12
期刊：
影响因子：
3.8
通讯作者：
Liu, Shulin
中科院分区：
文献类型：
--
作者：
Gao, Yuyan;Nan, Xianxiu;Liu, Shulin
背景甾醇调节元件结合蛋白1（SREBP1）是一种位于内质网的细胞内胆固醇传感器，通过Insig-Srebp-Scap途径调节细胞内胆固醇。 SREBP1的过度表达可导致血脂异常。 SREBP1可以调节代谢途径，进而促进肿瘤细胞的增殖。然而，在结直肠癌(CRC)领域还没有相关的转移和侵袭研究。方法通过转染含有SREBP1基因的质粒或通过shRNA在低和高水平SREBP1表达的CRC细胞系中操纵SREBP1的表达。测定了SREBP1对细胞迁移的影响。 Western blot检测SREBP1、p65、MMP7的表达。人脐静脉内皮细胞加入HT29和SW620培养上清液检测血管生成。通过二氢乙锭（DHE）染色检测活性氧（ROS）水平。采用NF-kappa B抑制剂SN50检测SREBP1、NF-kappa B通路与MMP7的关系。结果我们发现结肠腺癌中SREBP1的表达显着高于非癌组织，特别是在包括肿瘤出芽在内的侵袭性肿瘤前沿。在体外，结肠癌细胞系 HT29 中过表达的 SREBP1 促进内皮细胞血管生成、增加 ROS 水平、NF-κ B-p65 磷酸化并增加 MMP7 表达。 NF-κB抑制剂SN50处理后，SREBP1对MMP7表达的影响消失。结论我们的研究结果表明，SREBP1可以通过促进p65磷酸化相关的MMP7表达来促进CRC细胞的侵袭和转移。
BackgroundSterol-regulatory element binding protein 1 (SREBP1), an intracellular cholesterol sensor located in the endoplasmic reticulum, regulates the intracellular cholesterol by the Insig-Srebp-Scap pathway. Over-expression of SREBP1 can cause dyslipidemia. SREBP1 can regulate the metabolic pathway, and then promote the proliferation of tumor cells. However, there is no relevant research of metastasis and invasion in the field of colorectal cancer (CRC).MethodsExpression of SREBP1 was manipulated in CRC cell lines with low and high level SREBP1 expression by transfectiong with plasmids containing the SREBP1 gene, or by shRNA. The effect of SREBP1 on cell migration was assayed. The expression of SREBP1, p65 and MMP7 were detected by western blot. Human umbilical vein endothelial cell was used for detection of angiogenesis by adding the culture supernatant from HT29 and SW620. The level of reactive oxygen species (ROS) was detected by Dihydroethidium (DHE) staining. NF-kappa B inhibitor SN50 was used to test the relationship of SREBP1, NF-kappa B pathway and MMP7.ResultsWe found that the expression of SREBP1 in colon adenocarcinoma was significantly higher than that in noncancerous tissues, especially in the invasive tumor front including tumor budding. In vitro, SREBP1 over-expressed in colon cancer cell lines HT29 promoted angiogenesis in endothelial cells, increased ROS levels, phosphorylation of NF-kappa B-p65 and increases MMP7 expression. The effect of SREBP1 on expression of MMP7 was lost following treatment with the NF-kappa B inhibitor SN50.ConclusionOur results suggest that SREBP1 can promote the invasion and metastasis of CRC cells by means of promoting the expression of MMP7 related to phosphorylation of p65.