Effects Of STING On The Development Of Colorectal Cancer Via AMPK-mTOR Signaling Pathway

[Background]Colorectal cancer(CRC)is one of the most common gastrointestinal cancer.A proportion of patients are initially diagnosed at the advanced stage,with the treatment armamentarium currently remain limited.Cancer cells in rapid proliferation have strong demand for nutrition and energy,where the AMPK-mTOR pathway might play a role in the cellular energy metabolism process.Meanwhile,recent studies have shown that the AMPK-mTOR pathway is involved in drug resistance of cancer cells.Recently,some findings suggested that stimulator of interferon genes involved in the innate imunology-STING is associated with oncogenesis in several cancer types and can play a role in the regulation of AMPK and mTOR.However,it remains unclear that if the effect of STING on oncogenesis is AMPK-mTOR signaling dependent.Therefore,mechanistic study on the potential crosstalk between STING and AMPK-mTOR signaling as a possible therapeutic target for this lethal disease is needed.[Objective]We aim to investigate the differential expression of STING between normal and cancer tissues in colorectal cancer and to reveal the potential correlation of STING expression with clinical indicators of colorectal cancer patients.Furthermore,we explore the downstream mechanism of STING regulation by GSEA gene function enrichment analysis,functional and molecular experiments,to validate the potential value of STING as the therapeutic biomarker.[Methods]CRC Cell lines of HCT116 and SW480,as well as 32 paired colorectal cancer specimens were chosen for this study.STING expressions in tissues were examined by Western blotting and immunohistochemistry to evaluate the correlation with clinicopathological factors.Western blotting was used to determine STING and other protein expression as well as the underlying mechanism in colorectal cancer cell lines.Transwell assay was employed to evaluate cell migration.CCK-8 and clone formation assay were used for assessing the change of cell proliferation.Drug sensitive test and glucose uptake analysis were involved to evaluate the potential therapeutic value of STING pathway.[Results]In the 32 paired colorectal cancer and adjacent normal tissues,we found a significant difference in STING expression with immunohistochemical staining(IHC),which was correlated with the TNM stage of patients.Meanwhile,GESA enrichment analysis indicated a remarkable change in mTOR signaling following STING regulation.We found STING as an upstream regulator of AMPK-mTOR signaling by genetic manipulations and its influence on cell viability,cell invasion and drug sensitivity to 5-fluorouracil of colorectal cancer cell lines in vitro.Finally,we observed the decrease of glucose uptake following STING downregulation.[Conclusions]STING is found to promote cell proliferation,invasion ability,drug sensitivity and regulated glucose uptake mediating AMPK-mTOR signaling in colorectal cancer.STING could be a promising target for the sensitization of chemotherapy and the inhibition of tumor progression in colorectal cancer.