Cargando…

TMED3 promotes the development of malignant melanoma by targeting CDCA8 and regulating PI3K/Akt pathway

BACKGROUND: Transmembrane emp24 domain containing (TMED) proteins are known to play pivotal roles in normal development, but have been reported to be implicated in pancreatic disease, immune system disorders, and cancers. As far as TMED3 is concerned, its roles in cancers are controversial. However,...

Descripción completa

Detalles Bibliográficos
Autores principales: Guo, Xianling, Yin, Xiaolan, Xu, Yu, Li, Liang, Yuan, Min, Zhao, Huaxin, Jiang, Yuxiong, Shi, Xiujuan, Bi, Hongda, Liu, Yeqiang, Chen, Yong, Xu, Qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053972/
https://www.ncbi.nlm.nih.gov/pubmed/36991473
http://dx.doi.org/10.1186/s13578-023-01006-6
_version_ 1785015541158641664
author Guo, Xianling
Yin, Xiaolan
Xu, Yu
Li, Liang
Yuan, Min
Zhao, Huaxin
Jiang, Yuxiong
Shi, Xiujuan
Bi, Hongda
Liu, Yeqiang
Chen, Yong
Xu, Qing
author_facet Guo, Xianling
Yin, Xiaolan
Xu, Yu
Li, Liang
Yuan, Min
Zhao, Huaxin
Jiang, Yuxiong
Shi, Xiujuan
Bi, Hongda
Liu, Yeqiang
Chen, Yong
Xu, Qing
author_sort Guo, Xianling
collection PubMed
description BACKGROUND: Transmembrane emp24 domain containing (TMED) proteins are known to play pivotal roles in normal development, but have been reported to be implicated in pancreatic disease, immune system disorders, and cancers. As far as TMED3 is concerned, its roles in cancers are controversial. However, evidence describing TMED3 in the context of malignant melanoma (MM) is scarce. RESULTS: In this study, we characterized the functional significance of TMED3 in MM and identified TMED3 as a tumor-promoting factor in MM development. Depletion of TMED3 arrested the development of MM in vitro and in vivo. Mechanistically, we found that TMED3 could interact with Cell division cycle associated 8 (CDCA8). Knocking down CDCA8 suppressed cell events associated with MM development. On the contrary, elevating CDCA8 augmented cell viability and motility and even reversed the inhibitory effects of TMED3 knockdown on MM development. On the other hand, we found that the levels of P-Akt and P-PI3K were decreased in response to TMED3 downregulation, which was partially abolished following SC79 treatment. Thus, our suspicion was that TMED3 exacerbates MM progression via PI3K/Akt pathway. More notably, previously decreased P-Akt and P-PI3K in TMED3-depleted cells were rescued after overexpressing CDCA8. Also, previously impaired cell events due to CDCA8 depletion were ameliorated after SC79 addition, implying that TMED3 regulates PI3K-AKT pathway via CDCA8, thereby promoting MM development. CONCLUSIONS: Collectively, this study established the link between TMED3 and MM, and provides a potential therapeutic intervention for patients with MM harboring abundant TMED3. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01006-6.
format Online
Article
Text
id pubmed-10053972
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-100539722023-03-30 TMED3 promotes the development of malignant melanoma by targeting CDCA8 and regulating PI3K/Akt pathway Guo, Xianling Yin, Xiaolan Xu, Yu Li, Liang Yuan, Min Zhao, Huaxin Jiang, Yuxiong Shi, Xiujuan Bi, Hongda Liu, Yeqiang Chen, Yong Xu, Qing Cell Biosci Research BACKGROUND: Transmembrane emp24 domain containing (TMED) proteins are known to play pivotal roles in normal development, but have been reported to be implicated in pancreatic disease, immune system disorders, and cancers. As far as TMED3 is concerned, its roles in cancers are controversial. However, evidence describing TMED3 in the context of malignant melanoma (MM) is scarce. RESULTS: In this study, we characterized the functional significance of TMED3 in MM and identified TMED3 as a tumor-promoting factor in MM development. Depletion of TMED3 arrested the development of MM in vitro and in vivo. Mechanistically, we found that TMED3 could interact with Cell division cycle associated 8 (CDCA8). Knocking down CDCA8 suppressed cell events associated with MM development. On the contrary, elevating CDCA8 augmented cell viability and motility and even reversed the inhibitory effects of TMED3 knockdown on MM development. On the other hand, we found that the levels of P-Akt and P-PI3K were decreased in response to TMED3 downregulation, which was partially abolished following SC79 treatment. Thus, our suspicion was that TMED3 exacerbates MM progression via PI3K/Akt pathway. More notably, previously decreased P-Akt and P-PI3K in TMED3-depleted cells were rescued after overexpressing CDCA8. Also, previously impaired cell events due to CDCA8 depletion were ameliorated after SC79 addition, implying that TMED3 regulates PI3K-AKT pathway via CDCA8, thereby promoting MM development. CONCLUSIONS: Collectively, this study established the link between TMED3 and MM, and provides a potential therapeutic intervention for patients with MM harboring abundant TMED3. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01006-6. BioMed Central 2023-03-29 /pmc/articles/PMC10053972/ /pubmed/36991473 http://dx.doi.org/10.1186/s13578-023-01006-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Guo, Xianling
Yin, Xiaolan
Xu, Yu
Li, Liang
Yuan, Min
Zhao, Huaxin
Jiang, Yuxiong
Shi, Xiujuan
Bi, Hongda
Liu, Yeqiang
Chen, Yong
Xu, Qing
TMED3 promotes the development of malignant melanoma by targeting CDCA8 and regulating PI3K/Akt pathway
title TMED3 promotes the development of malignant melanoma by targeting CDCA8 and regulating PI3K/Akt pathway
title_full TMED3 promotes the development of malignant melanoma by targeting CDCA8 and regulating PI3K/Akt pathway
title_fullStr TMED3 promotes the development of malignant melanoma by targeting CDCA8 and regulating PI3K/Akt pathway
title_full_unstemmed TMED3 promotes the development of malignant melanoma by targeting CDCA8 and regulating PI3K/Akt pathway
title_short TMED3 promotes the development of malignant melanoma by targeting CDCA8 and regulating PI3K/Akt pathway
title_sort tmed3 promotes the development of malignant melanoma by targeting cdca8 and regulating pi3k/akt pathway
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10053972/
https://www.ncbi.nlm.nih.gov/pubmed/36991473
http://dx.doi.org/10.1186/s13578-023-01006-6
work_keys_str_mv AT guoxianling tmed3promotesthedevelopmentofmalignantmelanomabytargetingcdca8andregulatingpi3kaktpathway
AT yinxiaolan tmed3promotesthedevelopmentofmalignantmelanomabytargetingcdca8andregulatingpi3kaktpathway
AT xuyu tmed3promotesthedevelopmentofmalignantmelanomabytargetingcdca8andregulatingpi3kaktpathway
AT liliang tmed3promotesthedevelopmentofmalignantmelanomabytargetingcdca8andregulatingpi3kaktpathway
AT yuanmin tmed3promotesthedevelopmentofmalignantmelanomabytargetingcdca8andregulatingpi3kaktpathway
AT zhaohuaxin tmed3promotesthedevelopmentofmalignantmelanomabytargetingcdca8andregulatingpi3kaktpathway
AT jiangyuxiong tmed3promotesthedevelopmentofmalignantmelanomabytargetingcdca8andregulatingpi3kaktpathway
AT shixiujuan tmed3promotesthedevelopmentofmalignantmelanomabytargetingcdca8andregulatingpi3kaktpathway
AT bihongda tmed3promotesthedevelopmentofmalignantmelanomabytargetingcdca8andregulatingpi3kaktpathway
AT liuyeqiang tmed3promotesthedevelopmentofmalignantmelanomabytargetingcdca8andregulatingpi3kaktpathway
AT chenyong tmed3promotesthedevelopmentofmalignantmelanomabytargetingcdca8andregulatingpi3kaktpathway
AT xuqing tmed3promotesthedevelopmentofmalignantmelanomabytargetingcdca8andregulatingpi3kaktpathway