Pancreatic cancer-derived exosomes suppress the production of GIP and GLP-1 from STC-1cells in vitro by down-regulating the PCSK1/3.
Pancreatic cancer-derived exosomes suppress the production of GIP and GLP-1 from STC-1cells in vitro by down-regulating the PCSK1/3.
复制标题
胰腺癌来源的外泌体通过下调 PCSK1/3 在体外抑制 STC-1 细胞 GIP 和 GLP-1 的产生
DOI：
10.1016/j.canlet.2018.05.027
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发表时间：
2018
期刊：
影响因子：
9.7
通讯作者：
Wu Yulian
中科院分区：
文献类型：
--
作者：
Zhang Yuefeng;Huang Shifei;Li Pengping;Chen Qing;Li Yongzhou;Zhou Yizhao;Wang Lantian;Kang Muxing;Zhang Bo;Yang Bin;Dong Xin;Wu Yulian
胰腺癌(PC)的一个特点是胰腺癌相关糖尿病(PC-DM)的高发病率，但其发病机制尚不清楚。最近发现，被诊断为新发糖尿病/糖尿病前期的PC患者，其主要由肠内分泌细胞分泌的葡萄糖依赖型胰岛素样多肽(GIP)水平显著降低。我们假设PC衍生的外切体是导致PC-DM患者胰岛素水平降低的原因。本研究成功地从PANC-1、MIA Paca-2和SW620 细胞中分离到外切体，并对其进行了鉴定。只有MIA Paca-2 细胞的外切体(Exo-Mia)在体外以浓度和时间依赖的方式抑制 细胞GIP和GLP-1的产生。此外，Exo-Mia还上调了GipRNA和GipproGlygonmRNAs的水平，并降低了参与Gip和原胰高血糖素翻译后加工的原蛋白转换酶枯草杆菌/kexin 1/3(PCSK1/3)的表达。此外，还鉴定了差异表达的外体miRNAs(miR-6796-3p、miR-6763-5p、miR-4750-3andmiR-197-3p)，并被认为与抑制GIP和GLP-1的产生有关。为了进一步确定癌症来源的外切体到达肠内分泌细胞的途径，我们分析了动物模型中外切体的摄取和分布。观察到，注入肠腔的外切体比注入血液的外切体更容易被肠上皮所内化。综上所述，胰腺癌外切体通过下调 1/3的表达，在体外抑制STC-1细胞合成GIP和GLP-1。此外，可能是胰液将癌源性外切体输送到肠道靶细胞(K细胞和L细胞)。
One hallmark of pancreatic cancer (PC) is the high prevalence of pancreatic cancer-associated diabetes mellitus (PC-DM), but the mechanisms remain to be elucidated. Patients with PC who are diagnosed with new-onset diabetes/prediabetes have recently been shown to display significantly lower levels of glucose-dependent insulinotropic peptide (GIP) secreted mainly by enteroendocrine cells. We hypothesized that PC-derived exosomes are responsible for the decreased levels of incretins in patients with PC-DM. In this study, exosomes were successfully isolated from PANC-1, MIA PaCa-2 and SW620 cells and characterized. Only the exosomes from MIA PaCa-2 cells (Exo-Mia) reduce the production of GIP and glucagon-like peptide-1 (GLP-1) from STC-1 cellsin vitroin a concentration- and time-dependent manner. Moreover, Exo-Mia increased the levels of theGipandproglucagonmRNAs and decreased the expression of proprotein convertase subtilisin/kexin type 1/3 (PCSK1/3), which is responsible for the post-translational processing ofGipandproglucagon. Furthermore, differentially expressed exosomal miRNAs (miR-6796-3p,miR-6763-5p,miR-4750-3pandmiR-197-3p) were identified and considered to be responsible for the inhibitory effects on GIP and GLP-1 production. To further determine the approach of cancer-derived exosomes reaching enteroendocrine cells, we analyzed the uptake and distribution of exosomes in animal model. It was observed that exosomes infused into the intestinal cavity were more easily internalized by the intestinal epithelium than exosomes injected into blood. In conclusion, pancreatic cancer-derived exosomes (Exo-Mia) suppress the synthesis of GIP and GLP-1 from STC-1 cellsin vitroby down-regulating the PCSK1/3. Moreover, it may be the pancreatic juice that transport cancer-derived exosomes to target cells (K and L cells) in the gut.