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

ABSTRACT: 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-1? 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.

SUBMITTER: Zhang L 

PROVIDER: S-EPMC6763460 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature