The innate immune effector ISG12a promotes cancer immunity by suppressing the canonical Wnt/β-catenin signaling pathway

Deng, Rilin; Zuo, Chaohui; Li, Yongqi; Xue, Binbin; Xun, Zhen; Guo, Yanxia; Wang, Xiaohong; Xu, Yan; Tian, Renyun; Chen, Shengwen; Liu, Qian; Chen, Jinwen; Wang, Jingjing; Huang, Xiang; Li, Huiyi; Guo, Ming; Wang, Xintao; Yang, Miaomiao; Wu, Zhihui; Wang, Jinfeng; Ma, Jiahuan; Hu, Jun; Li, Guangdi; Tang, Songqing; Tu, Zhengkun; Ji, Hongbin; Zhu, Haizhen

doi:10.1038/s41423-020-00549-9

Cited by 43 publications

(42 citation statements)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Axin1 is considered to be a concentration-limiting factor for the assembly of the β-catenin destruction complex. Degradation of Axin1 enhances the Wnt/β-catenin signalling pathway and increases the expression of downstream genes [ 23 ]. We evaluated Axin1 and GSK3-β with the use of the autophagy-lysosomal early- and final-stage inhibitors 3-MA and CQ in the presence and absence of starvation.…”

Section: Resultsmentioning

confidence: 99%

Starvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming

Tong

Yin

et al. 2021

Cancer Cell Int

View full text Add to dashboard Cite

Background Aberrant autophagy and preternatural elevated glycolysis are prevalent in bladder cancer (BLCA) and are both related to malignant progression. However, the regulatory relationship between autophagy and glycolytic metabolism remains largely unknown. We imitated starvation conditions in the tumour microenvironment and found significantly increased levels of autophagy and aerobic glycolysis, which both regulated the progression of BLCA cells. We further explored the regulatory relationships and mechanisms between them. Methods We used immunoblotting, immunofluorescence and transmission electron microscopy to detect autophagy levels in BLCA cells under different treatments. Lactate and glucose concentration detection demonstrated changes in glycolysis. The expression of lactate dehydrogenase A (LDHA) was detected at the transcriptional and translational levels and was also silenced by small interfering RNA, and the effects on malignant progression were further tested. The underlying mechanisms of signalling pathways were evaluated by western blot, immunofluorescence and immunoprecipitation assays. Results Starvation induced autophagy, regulated glycolysis by upregulating the expression of LDHA and caused progressive changes in BLCA cells. Mechanistically, after starvation, the ubiquitination modification of Axin1 increased, and Axin1 combined with P62 was further degraded by the autophagy–lysosome pathway. Liberated β-catenin nuclear translocation increased, binding with LEF1/TCF4 and promoting LDHA transcriptional expression. Additionally, high expression of LDHA was observed in cancer tissues and was positively related to progression. Conclusion Our study demonstrated that starvation-induced autophagy modulates glucose metabolic reprogramming by enhancing Axin1 degradation and β-catenin nuclear translocation in BLCA, which promotes the transcriptional expression of LDHA and further malignant progression.

show abstract

Section: Resultsmentioning

confidence: 99%

Starvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming

Tong

Yin

et al. 2021

Cancer Cell Int

View full text Add to dashboard Cite

show abstract

“…Also, activation of β-catenin signaling decreased the infiltration of T cells to the tumor, whereas the chemokine CXCL10 had the opposite effect 46 . Deng identified β-catenin as a transcription factor of PD-L1 expression 47 . Consistent with the reduction of β-catenin abundance in AEG-1 silencing glioma cells, a large restraint of PD-L1 expression (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

AEG-1 silencing attenuates M2-polarization of glioma-associated microglia/macrophages and sensitizes glioma cells to temozolomide

Sun

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Glioma is the most frequent primary malignancy in the brain; temozolomide (TMZ) is the first-line chemotherapeutic agent used to combat this tumor. We showed here that astrocyte elevated gene-1 (AEG-1) was overexpressed in glioma tissues and associated with a worse subtype and a poor prognosis. CCK-8 proliferation assays and clone formation experiments presented that AEG-1 knockdown sensitizes glioma cells to TMZ. The γH2AX foci formation assays indicated that AEG-1 silencing promotes TMZ-induced DNA damage in glioma cells. Glioma-associated microglia/macrophages (GAMs), the largest subpopulation infiltrating glioma, play important roles in the tumor microenvironment. Bioinformatics analyses and functional studies demonstrated that AEG-1 silencing decreased M2-polarization of HMC3 microglia and the secretion of tumor supportive cytokines IL-6 and TGF-β1. The expression of AEG-1 was positively associated with M2 markers in glioma tissues varified by IHC staining. Based on the results of Affymetrix microarray and GSEA analyses, Western blot and Co-Immunoprecipitation assays were conducted to show that AEG-1 activates Wnt/β-catenin signaling by directly interacting with GSK-3β. The co-localization of AEG-1 and GSK-3β in the cytoplasm of glioma cells was detected through immunofluorescence staining. This study raises the possibility that targeting AEG-1 might improve the efficiency of chemotherapy and reduce immunosuppressive M2 GAMs in glioma.

show abstract

“…Insulin gene enhancer protein 1 (ISL1) promotes glycolysis and tumorigenesis in GC through transcriptional regulation of GLUT4 [ 17 ]. β-catenin can regulate the expression of PD-L1 to induce immune escape in gastric cancer [ 18 ]. These evidence indicated that transcription factors play an important role in gastric cancer.…”

Section: Discussionmentioning

confidence: 99%

Prognostic signature composed of transcription factors accurately predicts the prognosis of gastric cancer patients

Zhou

Chen

et al. 2021

Cancer Cell Int

View full text Add to dashboard Cite

Background Transcription factors (TFs) are involved in important molecular biological processes of tumor cells and play an essential role in the occurrence and development of gastric cancer (GC). Methods Combined The Cancer Genome Atlas Program and Genotype-Tissue Expression database to extract the expression of TFs in GC, analyzed the differences, and weighted gene co-expression network analysis to extract TFs related to GC. The cohort including the training and validation cohort. Univariate Cox, least absolute contraction and selection operator (LASSO) regression, and multivariate Cox analysis was used for screening hub TFs to construct the prognostic signature in the training cohort. The Kaplan–Meier (K–M) and the receiver operating characteristic curve (ROC) was drawn to evaluate the predictive ability of the prognostic signature. A nomogram combining clinical information and prognostic signatures of TFs was constructed and its prediction accuracy was evaluated through various methods. The target genes of the hub TFs was predicted and enrichment analysis was performed to understand its molecular biological mechanism. Clinical samples and public data of GC was collected to verify its expression and prognosis. 5-Ethynyl-2′-deoxyuridine and Acridine Orange/Ethidium Bromide staining, flow cytometry and Western-Blot detection were used to analyze the effects of hub-TF ELK3 on the proliferation and apoptosis of gastric cancer in vitro. Results A total of 511 misaligned TFs were obtained and 200 GC-related TFs were exposed from them. After systematic analysis, a prognostic signature composed of 4 TFs (ZNF300, ELK3, SP6, MEF2B) were constructed. The KM and ROC curves demonstrated the good predictive ability in training, verification, and complete cohort. The areas under the ROC curve are respectively 0.737, 0.705, 0.700. The calibration chart verified that the predictive ability of the nomogram constructed by combining the prognostic signature of TFs and clinical information was accurate, with a C-index of 0.714. Enriching the target genes of hub TFs showed that it plays an vital role in tumor progression, and its expression and prognostic verification were consistent with the previous analysis. Among them, ELK3 was proved in vitro, and downregulation of its expression inhibited the proliferation of gastric cancer cells, induced proliferation, and exerted anti-tumor effects. Conclusions The 4-TFs prognostic signature accurately predicted the overall survival of GC, and ELK3 may be potential therapeutic targets for GC

show abstract

The innate immune effector ISG12a promotes cancer immunity by suppressing the canonical Wnt/β-catenin signaling pathway

Cited by 43 publications

References 66 publications

Starvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming

Starvation induced autophagy promotes the progression of bladder cancer by LDHA mediated metabolic reprogramming

AEG-1 silencing attenuates M2-polarization of glioma-associated microglia/macrophages and sensitizes glioma cells to temozolomide

Prognostic signature composed of transcription factors accurately predicts the prognosis of gastric cancer patients

Contact Info

Product

Resources

About