Pancreatic cancer-derived exosomes suppress the production of GIP and GLP-1 from STC-1 cells in vitro by down-regulating the PCSK1/3

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 o...

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Veröffentlicht in:Cancer letters 2018-09, Vol.431, p.190-200
Hauptverfasser: Zhang, Yuefeng, Huang, Shifei, Li, Pengping, Chen, Qing, Li, Yongzhou, Zhou, Yizhao, Wang, Lantian, Kang, Muxing, Zhang, Bo, Yang, Bin, Dong, Xin, Wu, Yulian
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container_end_page 200
container_issue
container_start_page 190
container_title Cancer letters
container_volume 431
creator Zhang, Yuefeng
Huang, Shifei
Li, Pengping
Chen, Qing
Li, Yongzhou
Zhou, Yizhao
Wang, Lantian
Kang, Muxing
Zhang, Bo
Yang, Bin
Dong, Xin
Wu, Yulian
description 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 cells in vitro in a concentration- and time-dependent manner. Moreover, Exo-Mia increased the levels of the Gip and proglucagon mRNAs and decreased the expression of proprotein convertase subtilisin/kexin type 1/3 (PCSK1/3), which is responsible for the post-translational processing of Gip and proglucagon. Furthermore, differentially expressed exosomal miRNAs (miR-6796-3p, miR-6763-5p, miR-4750-3p and miR-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 cells in vitro by 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. •Experimental evidences for that PC-derived exosomes are attributable for the decreased level of incretins in PC-DM.•Exosomes derived from MIA PaCa-2 cells suppress the production of GIP and GLP-1 from STC-1 cells in vitro..•We hypothesized that pancreatic juice transports pancreatic cancer-derived exosomes to K and L cells in the gut.
doi_str_mv 10.1016/j.canlet.2018.05.027
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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 cells in vitro in a concentration- and time-dependent manner. Moreover, Exo-Mia increased the levels of the Gip and proglucagon mRNAs and decreased the expression of proprotein convertase subtilisin/kexin type 1/3 (PCSK1/3), which is responsible for the post-translational processing of Gip and proglucagon. Furthermore, differentially expressed exosomal miRNAs (miR-6796-3p, miR-6763-5p, miR-4750-3p and miR-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 cells in vitro by 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. •Experimental evidences for that PC-derived exosomes are attributable for the decreased level of incretins in PC-DM.•Exosomes derived from MIA PaCa-2 cells suppress the production of GIP and GLP-1 from STC-1 cells in vitro..•We hypothesized that pancreatic juice transports pancreatic cancer-derived exosomes to K and L cells in the gut.</description><identifier>ISSN: 0304-3835</identifier><identifier>EISSN: 1872-7980</identifier><identifier>DOI: 10.1016/j.canlet.2018.05.027</identifier><identifier>PMID: 29800682</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Diabetes ; Diabetes mellitus ; Epithelium ; Exosomes ; GIP and GLP-1 ; Glucagon ; Glucagon-like peptide 1 ; Immunoglobulins ; Insulin resistance ; Intestine ; Kexin ; L cells ; Pancreatic cancer ; Pancreatic cancer-associated diabetes ; Pancreatic juice ; PCSK1/3 ; Post-translation ; Proprotein convertases ; Proteins ; Subtilisin</subject><ispartof>Cancer letters, 2018-09, Vol.431, p.190-200</ispartof><rights>2018 Elsevier B.V.</rights><rights>Copyright © 2018 Elsevier B.V. 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Elsevier B.V.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c456t-67f9fbe94c9e185fc75d8010960f93672ba6f9bc6e6c0ee94525f9b17aef28743</citedby><cites>FETCH-LOGICAL-c456t-67f9fbe94c9e185fc75d8010960f93672ba6f9bc6e6c0ee94525f9b17aef28743</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0304383518303604$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29800682$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Yuefeng</creatorcontrib><creatorcontrib>Huang, Shifei</creatorcontrib><creatorcontrib>Li, Pengping</creatorcontrib><creatorcontrib>Chen, Qing</creatorcontrib><creatorcontrib>Li, Yongzhou</creatorcontrib><creatorcontrib>Zhou, Yizhao</creatorcontrib><creatorcontrib>Wang, Lantian</creatorcontrib><creatorcontrib>Kang, Muxing</creatorcontrib><creatorcontrib>Zhang, Bo</creatorcontrib><creatorcontrib>Yang, Bin</creatorcontrib><creatorcontrib>Dong, Xin</creatorcontrib><creatorcontrib>Wu, Yulian</creatorcontrib><title>Pancreatic cancer-derived exosomes suppress the production of GIP and GLP-1 from STC-1 cells in vitro by down-regulating the PCSK1/3</title><title>Cancer letters</title><addtitle>Cancer Lett</addtitle><description>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 cells in vitro in a concentration- and time-dependent manner. Moreover, Exo-Mia increased the levels of the Gip and proglucagon mRNAs and decreased the expression of proprotein convertase subtilisin/kexin type 1/3 (PCSK1/3), which is responsible for the post-translational processing of Gip and proglucagon. Furthermore, differentially expressed exosomal miRNAs (miR-6796-3p, miR-6763-5p, miR-4750-3p and miR-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 cells in vitro by down-regulating the PCSK1/3. 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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 cells in vitro in a concentration- and time-dependent manner. Moreover, Exo-Mia increased the levels of the Gip and proglucagon mRNAs and decreased the expression of proprotein convertase subtilisin/kexin type 1/3 (PCSK1/3), which is responsible for the post-translational processing of Gip and proglucagon. Furthermore, differentially expressed exosomal miRNAs (miR-6796-3p, miR-6763-5p, miR-4750-3p and miR-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 cells in vitro by 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. •Experimental evidences for that PC-derived exosomes are attributable for the decreased level of incretins in PC-DM.•Exosomes derived from MIA PaCa-2 cells suppress the production of GIP and GLP-1 from STC-1 cells in vitro..•We hypothesized that pancreatic juice transports pancreatic cancer-derived exosomes to K and L cells in the gut.</abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>29800682</pmid><doi>10.1016/j.canlet.2018.05.027</doi><tpages>11</tpages></addata></record>
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identifier ISSN: 0304-3835
ispartof Cancer letters, 2018-09, Vol.431, p.190-200
issn 0304-3835
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language eng
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source Elsevier ScienceDirect Journals
subjects Diabetes
Diabetes mellitus
Epithelium
Exosomes
GIP and GLP-1
Glucagon
Glucagon-like peptide 1
Immunoglobulins
Insulin resistance
Intestine
Kexin
L cells
Pancreatic cancer
Pancreatic cancer-associated diabetes
Pancreatic juice
PCSK1/3
Post-translation
Proprotein convertases
Proteins
Subtilisin
title Pancreatic cancer-derived exosomes suppress the production of GIP and GLP-1 from STC-1 cells in vitro by down-regulating the PCSK1/3
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