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Dedifferentiation process driven by radiotherapy-induced HMGB1/TLR2/YAP/HIF-1α signaling enhances pancreatic cancer stemness

Dongqing Wang; Lian Song; Hui Shi; Xuewen Xu; Aihua Gong; Hongbo Chen; Tao You; Haitao Zhu; Xin Fan; Fang Cheng; Yanfang Liu; Lirong Zhang

dc.contributor.authorDongqing Wang
dc.contributor.authorLian Song
dc.contributor.authorHui Shi
dc.contributor.authorXuewen Xu
dc.contributor.authorAihua Gong
dc.contributor.authorHongbo Chen
dc.contributor.authorTao You
dc.contributor.authorHaitao Zhu
dc.contributor.authorXin Fan
dc.contributor.authorFang Cheng
dc.contributor.authorYanfang Liu
dc.contributor.authorLirong Zhang
dc.date.accessioned2022-10-28T13:52:01Z
dc.date.available2022-10-28T13:52:01Z
dc.identifier.urihttps://www.utupub.fi/handle/10024/167934
dc.description.abstract<p>Differentiated cancer cells reacquiring stem cell traits following radiotherapy may enrich cancer stem cells and accelerate tumor recurrence and metastasis. We are interested in the mechanistic role of dying cells-derived HMGB1 in CD133− pancreatic cancer cells dedifferentiation following radiotherapy. We firstly confirmed that X-ray irradiation induced differentiation of CD133− pancreatic cancer cells, from either sorted from patient samples or established cell lines, into cancer stem-like cells (iCSCs). Using an in vitro coculture model, X-ray irradiation induced dying cells to release HMGB1, which further promoted CD133− pancreatic cancer cells regaining stem cell traits, such as higher sphere forming ability and expressed higher level of stemness-related genes and proteins. Inhibiting the expression and activity of HMGB1 attenuated the dedifferentiation stimulating effect of irradiated, dying cells on C133− pancreatic cancer cells in vitro and in PDX models. Mechanistically, HMGB1 binding with TLR2 receptor functions in a paracrine manner to affect CD133− pancreatic cancer cells dedifferentiation via activating Hippo-YAP pathway and HIF-1α expression in oxygen independent manner in vitro and in vivo. We conclude that X-ray irradiation induces CD133− pancreatic cancer cell dedifferentiation into a CSC phenotype, and inhibiting HMGB1 may be a strategy to prevent CSC enrichment and further pancreatic carcinoma relapse.<br /></p>
dc.language.isoen
dc.publisherNature Publishing Group
dc.titleDedifferentiation process driven by radiotherapy-induced HMGB1/TLR2/YAP/HIF-1α signaling enhances pancreatic cancer stemness
dc.identifier.urnURN:NBN:fi-fe2021042823978
dc.relation.volume10
dc.contributor.organizationfi=biotiedekeskuksen yhteiset|en=Biotiedekeskuksen yhteiset|
dc.contributor.organization-code2609200
dc.converis.publication-id43310115
dc.converis.urlhttps://research.utu.fi/converis/portal/Publication/43310115
dc.identifier.eissn2041-4889
dc.identifier.jour-issn2041-4889
dc.okm.affiliatedauthorCheng, Fang
dc.okm.discipline3111 Biomedicineen_GB
dc.okm.discipline3111 Biolääketieteetfi_FI
dc.okm.discipline1182 Biokemia, solu- ja molekyylibiologiafi_FI
dc.okm.discipline1182 Biochemistry, cell and molecular biologyen_GB
dc.okm.internationalcopublicationinternational co-publication
dc.okm.internationalityInternational publication
dc.okm.typeJournal article
dc.publisher.countryUnited Kingdomen_GB
dc.publisher.countryBritanniafi_FI
dc.publisher.country-codeGB
dc.relation.doi10.1038/s41419-019-1956-8
dc.relation.ispartofjournalCell Death and Disease
dc.relation.issue10
dc.year.issued2019


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