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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

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

Zhang Lirong L Shi Hui H Chen Hongbo H Gong Aihua A Liu Yanfang Y Song Lian L Xu Xuewen X You Tao T Fan Xin X Wang Dongqing D Cheng Fang F Zhu Haitao H

Cell death & disease 20190926 10

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<sup>-</sup> pancreatic cancer cells dedifferentiation following radiotherapy. We firstly confirmed that X-ray irradiation induced differentiation of CD133<sup>-</sup> pancreatic cancer cells, from either sorted from patient samples or established cell lines, into ...[more]

PMID: 31558702

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Project description:Background: The management of aggressive and progressive metastatic papillary thyroid cancer (PTC) is very difficult. An inverse relationship between radioiodine and F-18 fluorodeoxyglucose (FDG) uptake (''flip-flop'' phenomenon) is described for invasive PTC during dedifferentiation. However, no satisfactory biologic explanation for this phenomenon. Hypoxia is an important microenvironmental factor that promotes cancer progression and glycolysis. The Hippo-YAP is a highly conserved tumor suppressor pathway and contributes to cancer metabolic reprogramming. Thus, we investigated the underlying molecular mechanisms of glucose/iodine metabolic reprogramming in PTC, focusing on the tumor hypoxia microenvironment and Hippo-YAP signaling. Methods: Immunohistochemistry staining was conducted to evaluate the expressions of hypoxia-inducible factor 1α (HIF-1α), yes-associated protein (YAP), glucose transporters 1 (GLUT1) and sodium iodine symporter (NIS) in matched PTC and the adjacent noncancerous tissues. PTC cell lines were cultured under normoxic (20% O2) and hypoxic (1% O2) conditions and the glycolysis level and NIS expression were measured. Further, we characterized the molecular mechanism of glucose/iodine metabolic reprogramming in PTC cell. Finally, we validated the results in vivo by establishing subcutaneous xenografts in nude mice. Results: The expression levels of HIF1-α, YAP and GLUT1 were upregulated in PTC tissues and YAP expression was positively associated with HIF-1α, GLUT1 and TNM stages. Meanwhile, the expression of NIS was negatively correlated with YAP. Further, in vitro studies indicated that hypoxia-induced YAP activation was critical for accelerating glycolysis and reducing NIS expression in PTC cells. Inhibition of YAP had the opposite effects in vitro and tumorigenicity in vivo. Hypoxia inhibited the Hippo signaling pathway resulting in the inactivation of YAP phosphorylation, further promoting the nuclear localization of YAP in PTC cells. The mechanism is that hypoxic stress promoted YAP binding to HIF-1α in the nucleus and maintained HIF-1α protein stability. The YAP/HIF-1α complex bound and directly activated the GLUT1 transcription to accelerate glycolysis. Meanwhile, HIF-1α/YAP signaling might indirectly reduce the expression of NIS by promoting the output of MAPK signaling. In vivo studies confirmed the YAP-mediated reprogramming of glucose/iodine metabolism promoted PTC progression. Conclusions: Collectively, our data revealed a novel regulatory mechanism of the glucose/iodine metabolic program rewritten by HIF-1α/YAP signaling in PTC. Inhibition of HIF-1α/YAP signaling alone or in combination with other potential markers may effectively combat aggressive PTC.

Dataset Information

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

Publications

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

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