STING signaling in tumorigenesis and cancer therapy: A friend or foe?

He, Liangmei; Xiao, Xiaomei; Yang, Xi; Zhang, Zixiang; Wu, Longhuo; Liu, Zhiping

doi:10.1016/j.canlet.2017.05.026

Cited by 51 publications

(38 citation statements)

References 112 publications

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“…Burdette et al suggested that this recognition is often mediated by STING activation [45], highlighting the important role that the cGAS-STING pathway plays in innate immune response activation during tumour progression. Even though cGAS-STING has pro-and antitumourigenic roles, depending on the context [35,46,238], this pathway has been suggested as necessary for a therapeutic response in immunotherapy. Studies performed in a syngeneic MC38 murine tumour model showed that the knockout of STING significantly reduced tumour control after single-dose ionizing radiation [237].…”

Section: Implications For Immunotherapymentioning

confidence: 99%

“…In opposition, the cGAS-STING pathway has pro-tumorigenic roles in contexts of inflammation -induced tumorigenesis [238]. For example, it has been shown that genetic inactivation of Sting in mice has an anti-tumorigenic effect in skin cancer induced by 7,12-dimethylbenz[a]anthracene (DMBA) [240] and colorectal cancer induced by azoxymethane (AOM) [241].…”

Section: Implications For Immunotherapymentioning

confidence: 99%

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Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Ragu

Matos-Rodrigues

Lopez

2020

Genes

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Complete and accurate DNA replication is essential to genome stability maintenance during cellular division. However, cells are routinely challenged by endogenous as well as exogenous agents that threaten DNA stability. DNA breaks and the activation of the DNA damage response (DDR) arising from endogenous replication stress have been observed at pre-or early stages of oncogenesis and senescence. Proper detection and signalling of DNA damage are essential for the autonomous cellular response in which the DDR regulates cell cycle progression and controls the repair machinery. In addition to this autonomous cellular response, replicative stress changes the cellular microenvironment, activating the innate immune response that enables the organism to protect itself against the proliferation of damaged cells. Thereby, the recent descriptions of the mechanisms of the pro-inflammatory response activation after replication stress, DNA damage and DDR defects constitute important conceptual novelties. Here, we review the links of replication, DNA damage and DDR defects to innate immunity activation by pro-inflammatory paracrine effects, highlighting the implications for human syndromes and immunotherapies.Genes 2020, 11, 409 2 of 26 formed when nascent transcripts re-anneal to their template DNA, displacing the non-template strand as single-stranded DNA (ssDNA) [12]. Elevated R-loop levels cause DNA damage and genome instability. The loss of RNA processing and regulatory factors increases R-loop levels, causing R-loop dependent DNA damage in eukaryotic cells [13][14][15][16].DNA breaks and activation of the DNA damage response (DDR), arising from endogenous replication stress, have been observed at early or precancerous stages, and adaptation to replication stress plays an important role in tumour development [17][18][19][20]. The DDR protects genome stability through the precise coordination of a network of pathways, ensuring faithful transmission of genetic material, including DNA replication, repair and recombination, cell cycle checkpoint and chromosome segregation. Ultimately, these autonomous cell responses induce senescence or cell death [21][22][23][24][25]. All these processes prevent the proliferation of cells bearing DNA damage and/or genetic rearrangements. In agreement, syndromes caused by mutations in DDR and/or DNA repair factors are often associated with high genetic instability, cancer predisposition and premature ageing [24,[26][27][28]. In addition to these cell-autonomous responses, protective process(es) also act at the organism level. Such mechanism(s) involve the modification of the cellular microenvironment and ultimately the activation of innate immunity.The inflammatory response is a universal cell-intrinsic response to infections or tissue damage. Inflammation, which is triggered when innate immune cells detect infection, for example, eliminates the initial cause of cell injury, clears out necrotic cells and tissues damaged from the original insult and from the inflammatory process, and initiates ...

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Section: Implications For Immunotherapymentioning

confidence: 99%

Section: Implications For Immunotherapymentioning

confidence: 99%

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Ragu

Matos-Rodrigues

Lopez

2020

Genes

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“…In addition, STING mediates liver injury and fibrosis in mice administered CCl4 (a chemical inducer of hepatocyte death) [25]. Moreover, based on the results of several previous studies, STING is also thought to play an important role in tumor development [26]. Interestingly, STING may exert two opposite effects (tumor-suppressing and tumor-promoting effects) on tumor development under different situations.…”

Section: Discussionmentioning

confidence: 99%

High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction

Dansako

Imai

Ueda

et al. 2018

Preprint

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Hepatitis B virus (HBV) is a hepatotropic DNA virus causing hepatic diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. To study HBV, human hepatoma HepG2 cells are currently used as an HBV infectious cell culture model worldwide. HepG2 cells exhibit susceptibility to HBV by exogenously expressing sodium taurocholate cotransporting polypeptide (NTCP). We herein demonstrated that human immortalized hepatocyte NKNT‐3 cells exhibited susceptibility to HBV by exogenously expressing NTCP (NKNT‐3/NTCP cells). By comparing cyclic GMP‐AMP synthetase (cGAS)‐stimulator of interferon genes (STING) signaling pathway in several NKNT‐3/NTCP cell‐derived cell clones, we found that STING was highly expressed in cell clones exhibiting resistance but not susceptibility to HBV. High‐level expression of STING was implicated in HBV‐triggered induction of type III IFN and a pro‐inflammatory cytokine, IL‐6. In contrast, RNAi‐mediated knockdown of STING inhibited type III IFN induction and restored the levels of HBV total transcript in an HBV‐infected cell clone exhibiting resistance to HBV. These results suggest that STING regulates susceptibility to HBV by its expression levels. STING may thus be a novel target for anti‐HBV strategies.

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“…Furthermore, the whole STING signaling pathway is implicated in a number of inflammatory diseases and tumors, where it exhibits both pro-and anticancer functions. The topic has been reviewed in detail by He et al [127]. Nevertheless, the involvement of DDX41 in the context of STING signaling pathway has not been reported in pathogenesis of these diseases, but it should be considered in future studies.…”

Section: Roles Of Dead/deah-box Helicases In Innate Immunity and Disementioning

confidence: 99%

Diverse Roles of DEAD/DEAH-Box Helicases in Innate Immunity and Diseases

Perčulija

Ouyang

2019

Helicases From All Domains of Life

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STING signaling in tumorigenesis and cancer therapy: A friend or foe?

Cited by 51 publications

References 112 publications

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction

Diverse Roles of DEAD/DEAH-Box Helicases in Innate Immunity and Diseases

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