cGAMP inhibits tumor growth in colorectal cancer metastasis through the STING/STAT3 axis in a zebrafish xenograft model

Xiao-feng, Jiang; Liu, Guangping; Hu, Zhiyi; Chen, Guiqian; Lv, Zhengbing

doi:10.1016/j.fsi.2019.09.075

Cited by 28 publications

(20 citation statements)

References 27 publications

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“…After sensing the tumor-derived DNA in the cytoplasm, the cytoplasmic nucleotide transferase cGAS in dendritic cells (DCs) catalyzes cyclic GmP-AmP (GAmP) formation to bind and activate STING, which successively stimulates the type I IFN response to initiate antitumor responses (9). Emerging studies have shown that STING was involved in tumorigenesis and treatment resistance, and could serve as a promising treatment target for CRC patients (10)(11)(12)(13)(14)(15). For example, Xia et al revealed recurrently suppressed STING signaling in CRC, and the loss of STING signaling impaired the DNA damage response (13).…”

Section: Introductionmentioning

confidence: 99%

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A STING-related prognostic score predicts high-risk patients of colorectal cancer and provides insights into immunotherapy

Chen¹,

Chen²,

Wu³

et al. 2021

Ann Transl Med

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Background: Targeted therapeutic strategies for advanced colorectal cancer (CRC) have been limited.STING is crucial to the antitumor immunotherapy, for it stimulates IFN signaling to mediate the crosstalk between innate and adaptive immune responses. Emerging evidence suggests that STING also contributes to the prognosis of CRC. However, prognostic models relating to STING have not yet been explored.Methods: A total of 431 CRC samples from the TCGA database were analyzed to explore the prognostic value of STING-related genes. We trained prognostic models using the multivariate Cox regression. A STING-related prognostic score (SPS) was calculated as the gene expression multiplied by the corresponding coefficients of the final model. A backward stepAIC strategy was adopted to select the optimal model. A nomogram was used to personalize medical decisions for CRC.Results: The expression level of STING was upregulated in the CMS1 subtype (P=0.036). Among STING-related genes, DHX9 (HR =0.72, P=0.01), IRF2 (HR =1.34, P=0.022), and POLR1D (HR =1.23, P=0.038) showed significant prognostic value. The SPS was proven to be an independent risk factor (training: HR =2.9, P=0.00013; validation: HR =3.02, P=0.01), and outperformed random classifiers in identifying high-risk CRC. The high SPS group was characterized by less genomic aberrations, upregulated IL6-JAK-STAT3 and IL2-STAT5 signaling pathways, increased expression of TIM-3, increased infiltration of regulatory T (Treg) cells and T helper 17 (Th17) cells, and decreased infiltration of M0 macrophages.Finally, the nomogram based on the SPS and clinical factors showed good performance in CRC.Conclusions: SPS is an independent risk factor that could identify high-risk CRC. While ICBs may benefit patients of the CMS1 subtype, for the CMS2, CMS3, and CMS4 subtypes in the high SPS group, STING agonists and immunotherapies targeting the Th17 axis may be beneficial. Finally, the SPS-based nomogram could help advance personalized medical decisions for CRC.

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Section: Introductionmentioning

confidence: 99%

“…Chon et al also elucidated the independent prognostic value of STING, which could be harnessed as a potential therapeutic target to enhance anticancer immune responses in CRC (15). Moreover, STING has also been associated with tumor progression, metastasis, and radiotherapy resistance in CRC (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

A STING-related prognostic score predicts high-risk patients of colorectal cancer and provides insights into immunotherapy

Chen¹,

Chen²,

Wu³

et al. 2021

Ann Transl Med

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“…Consistently, it is acknowledged that STING activation can synergize with the VEGFR blockade 10 . Previous studies have also suggested that STING can affect angiogenesis in various ways, including the STING/STAT3/VEGFA axis 22–24 or STING/IRF3 axis 25 …”

Section: Discussionmentioning

confidence: 80%

“…Consistently, it is acknowledged that STING activation can synergize with the VEGFR blockade. 10 Previous studies have also suggested that STING can affect angiogenesis in various ways, including the STING/ STAT3/VEGFA axis [22][23][24] or STING/IRF3 axis. 25 Meanwhile, a high level of H-151 had an inhibitory effect on tubular structure formation, consistent with the qRT-PCR results.…”

Section: Sting Inhibition Promoted Angiogenesis In Vitromentioning

confidence: 99%

STING inhibition accelerates the bone healing process while enhancing type H vessel formation

Chen

Sun

et al. 2021

The FASEB Journal

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The stimulator of interferon genes (STING), one of the critical factors of innate immunity, is indicated to be closely related to angiogenesis. This study examined STING's role in angiogenesis and the formation of type H vessels, a specific subtype of bone vessels that regulates bone healing. Different concentrations of 2′,3′-cGAMP, and H-151 or C-176 were applied to activate or inhibit STING, respectively. Human umbilical vein endothelial cells were used to examine the effect of STING on angiogenesis in vitro; cell viability, cell migration, and quantitative real-time polymerase chain reactions were performed. Also, the metatarsal experiment was applied as ex vivo proof. Bone fracture or defect mice models were used to examine the effect of STING in vivo; the bone healing process was evaluated by radiography weekly and by μCT on the 14th day after surgery. The formation of type H vessels (CD31 hi Emcn hi endothelial cells) and osteogenesis (OCN-positive cells) was assessed using the cryosection and paraffin section.STING activation inhibited angiogenesis both in vitro and ex vivo and slowed down the bone healing process in vivo. Histological analysis showed an increased callus formation, fewer type H vessels, and almost no callus mineralization in the STING activation group compared to the control group. By contrast, H-151 (a hsSTING inhibitor) promoted angiogenesis at a low dose. Moreover, inhibition of mmSTING by C-176 enhanced type H vessels' formation, implying osteogenesis promotion in bone healing (higher bone volume density and more OCN-positive cells). Our data suggested that STING inhibition accelerates the bone healing process while enhancing type H vessel formation.

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“…Recently，study suggests the potential roles of STING as an independent prognostic biomarker and potential target to improve anticancer immunity in CRC [6]. Although the STING pathway in CRC has not been elucidated fully, multiple studies suggest that it mediates carcinogenesis [7,8]. The rapid proliferation of cancer cells imposes a high energy demand.…”

Section: Introductionmentioning

confidence: 99%

STING promotes proliferation and induces drug resistance in colorectal cancer by regulating the AMPK mTOR pathway

Yao

Wang

Zhou

et al. 2022

Preprint

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Background: Despite a rapidly growing body of pertinent literature, what role the protein stimulator of interferon genes (STING) plays in colorectal cancer (CRC) remains unclear. We are committed to exploring whether STING can be adopted as an effective target and biomarker for CRC. Methods: STING expression was examined by immunohistochemistry to evaluate its association with clinicopathological factors. In addition, the effects of STING on various biological characteristics of CRC cells, such as proliferation, migration, invasiveness and drug resistance, were also studied. Gene set enrichment analysis was an indispensable tool to study the downstream mechanism of STING. Meanwhile, we explored the effect of STING on glucose uptake. Results: Our study suggested that the expression of STING was not only up-regulated in CRC, but also correlated with TNM stage and poor prognosis. Moreover, STING regulates cell migration, proliferation, invasiveness and drug resistance via mediating AMPK-mTOR pathway. Finally, we confirmed that STING regulates energy metabolism in CRC cells. Conclusions: STING may be a promising biomarker and a target for chemosensitization and inhibition of CRC progression.

show abstract

cGAMP inhibits tumor growth in colorectal cancer metastasis through the STING/STAT3 axis in a zebrafish xenograft model

Cited by 28 publications

References 27 publications

A STING-related prognostic score predicts high-risk patients of colorectal cancer and provides insights into immunotherapy

A STING-related prognostic score predicts high-risk patients of colorectal cancer and provides insights into immunotherapy

STING inhibition accelerates the bone healing process while enhancing type H vessel formation

STING promotes proliferation and induces drug resistance in colorectal cancer by regulating the AMPK mTOR pathway

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