A positive feedback loop consisting of C12orf59/NF-κB/CDH11 promotes gastric cancer invasion and metastasis

Abstract Background: Hypoxia and inflammation tumor microenvironment (TME) play a crucial role in tumor development and progression. Although increased understanding of TME contributed to gastric cancer (GC) progression and prognosis, the direct interaction between macrophage and GC cells was not fully understood.Methods: Hypoxia and normoxia macrophage microarrays of GEO database was analyzed. The peripheral blood mononuclear cell acquired from the healthy volunteers. The expression of CXCL8 in GC tissues and cell lines was detected by quantitative reverse transcription PCR (qRT-PCR), western-blot, Elisa and immunofluorescence. Cell proliferation, migration, and invasion were evaluated by cell counting kit 8 (CCK8), colony formation, real-time imaging of cell migration and transwell. Luciferase reporter assays and chromatin immunoprecipitation were used to identify the interaction between transcription factor and target gene. Especially, a series of truncated and mutation reporter genes were applied to identify precise binding sites.The corresponding functions were verified in the complementation test and in vivo animal experiment.Results: Our results revealed that Hypoxia triggered macrophage secreted C-X-C Motif Chemokine Ligand 8 (CXCL8), which induced GC invasion and proliferation. This macrophage-induced GC progression was CXCL8 activated C-X-C Motif Chemokine Receptor 1/2 (CXCR1/2) on the GC cell membrane subsequently hyperactivated Janus kinase 1/ Signal transducer and activator of transcription 1 (JAK/STAT1) signaling pathway. Then, the transcription factor STAT1 directly led to the overexpression and secretion of Interleukin 10 (IL-10). Correspondingly, IL-10 induced the M2-type polarization of macrophages through the Nuclear Factor kappa B (NF-κB) pathway-dependent mechanism and continued to increase the expression and secretion of CXCL8 through the transcription factor Nuclear Factor Kappa B Subunit 1 (NFKB1, p50). It suggested a positive feedback loop between macrophage and GC. In clinical GC samples, increased CXCL8 predicted a patient's pessimistic outcome.Conclusion: Our work identified a positive feedback loop governing cancer cells and macrophage in GC that contributed to tumor progression and patient outcome.

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SIRT1 inhibits chemoresistance and cancer stemness of gastric cancer by initiating an AMPK/FOXO3 positive feedback loop

Cell Death and Disease ◽

10.1038/s41419-020-2308-4 ◽

2020 ◽

Vol 11 (2) ◽

Cited By ~ 5

Author(s):

Yifei An ◽

Bo Wang ◽

Xin Wang ◽

Guoying Dong ◽

Jihui Jia ◽

...

Keyword(s):

Gastric Cancer ◽

Positive Feedback ◽

Feedback Loop ◽

Cancer Stemness ◽

Positive Feedback Loop

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Positive feedback loop of HMGB1 and tumor-associated macrophages plays a key role in osteosarcoma metastasis

10.21203/rs.3.rs-1185816/v1 ◽

2021 ◽

Author(s):

Changhe Hou ◽

Ming Lu ◽

Zixiong Lei ◽

Shuangwu Dai ◽

Wei Chen ◽

...

Keyword(s):

Positive Feedback ◽

Feedback Loop ◽

Macrophage Polarization ◽

Migration And Invasion ◽

M2 Macrophages ◽

Osteosarcoma Cells ◽

Invasion And Metastasis ◽

Tumor Associated Macrophages ◽

Positive Feedback Loop ◽

Hmgb1 Expression

Abstract Background Numerous studies have demonstrated the important roles of tumor-associated macrophages (TAMs) in osteosarcoma metastasis. In osteosarcoma, higher levels of HMGB1 correlate with osteosarcoma progression. However, whether HMGB1 is involved in the polarization of M2 macrophages into M1 macrophages in osteosarcoma still remains largely unknown. Methods HMGB1 and CD206 mRNA expression was measured by qRT-PCR in osteosarcoma tissues and cells. HMGB1 and RAGE protein expression was measured by western blotting. Osteosarcoma migration was measured using a Transwell and wound-healing assay. Osteosarcoma invasion was measured using a Transwell assay. Macrophage subtypes were detected using flow cytometry. Results HMGB1 is aberrantly overexpressed in osteosarcoma, and positively correlates with the TNM III & IV stages, lymph node metastasis, and distant metastasis. Silencing HMGB1 inhibits migration, invasion, and metastasis-related proteins in osteosarcoma cells. Furthermore, the reduced HMGB1 expression in the conditioned media derived from osteosarcoma cells also induces the polarization of M2 TAMs to M1 TAMs. In addition, silencing HMGB1 inhibits the liver and lung metastases of osteosarcoma and reduces the expression of HMGB1, CD163, and CD206 in vivo experiments. HMGB1 regulates macrophage polarization through RAGE. Interestingly, the polarized M2 macrophages could induce osteosarcoma migration and invasion, which in turn results in activation of HMGB1 expression in osteosarcoma cells to form a positive feedback loop. Conclusions HMGB1 and M2 macrophages enhance osteosarcoma migration, invasion, and metastasis capability through positive feedback regulation. These findings reveal the significance of tumor cell and TAM interaction in the metastatic microenvironment.

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