Iron-dependent CDK1 activity promotes lung carcinogenesis via activation of the GP130/STAT3 signaling pathway

Kuang, Yanbin; Guo, Wenzheng; Jing, Ling; Xu, Danfeng; Liao, Yueling; Zhao, Hui; Du, Xiaohui; Wang, Han; Xu, Mingxin; Song, Hui; Wang, Tong; Jing, Bo; Li, Kaimi; Hu, Min; Wu, Wenjuan; Deng, Jiong; Wang, Qi

doi:10.1038/s41419-019-1528-y

Cited by 46 publications

(36 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, CDK1 upregulation is associated with poor prognosis 38 . However, the molecular mechanism and potential application of CDK1 in lung cancer have not been determined 39 . PLK1 is indispensable for finely regulating cell division and maintenance of genomic stability in mitosis, spindle assembly, and DNA damage response 40 .…”

Section: Discussionmentioning

confidence: 99%

Independent prognostic implications of RRM2 in lung adenocarcinoma

Luo

Cao

et al. 2020

J. Cancer

View full text Add to dashboard Cite

Background: Ribonucleoside-diphosphate reductase subunit M2 ( RRM2 ) is the catalytic subunit of ribonucleotide reductase and modulates the enzymatic activity, which is essential for DNA replication and repair. However, the role of RRM2 in lung adenocarcinoma (LUAD) remains unclear. Methods: In this study, we explored the expression pattern and prognostic value of RRM2 in LUAD across TCGA, GEO, Oncomine, UALCAN, PrognoScan, and Kaplan-Meier Plotter, and confirmed its independent prognostic value via Cox analyses. LinkedOmics and GEPIA2 were applied to investigate co-expression and functional networks associated with RRM2 . Besides, we used TIMER to assess the correlation between RRM2 and the main six types of tumor-infiltrating immune cells. Lastly, the correlations between immune signatures of immunomodulators, chemokines, and 28 tumor-infiltrating lymphocytes (TILs) and RRM2 were examined by tumor purity-corrected partial Spearman's rank correlation coefficient through TIMER portal. Results: RRM2 was found upregulated in tumor tissues in TCGA-LUAD, and validated in multiple independent cohorts. Moreover, whether in TCGA or other cohorts, high RRM2 expression was found to be associated with poor survival. Cox analyses showed that high RRM2 expression was an independent risk factor for overall survival, disease-specific survival, and progression-free survival of LUAD. Functional network analysis suggested that RRM2 regulates RNA transport, oocyte meiosis, spliceosome, ribosome biogenesis in eukaryotes, and cellular senescence signaling through pathways involving multiple cancer-related kinases and E2F family. Also, RRM2 expression correlated with infiltrating levels of B cells, CD4+ T cells, and neutrophils. Subsequent analysis found that B cells and dendritic cells could predict the outcome of LUAD. B cells were identified as an independent risk factor among six types of immune cells through Cox analyses. At last, the correlation analysis showed RRM2 correlated with 67.68% (624/922) of the immune signatures we performed. Conclusion: Our research showed that RRM2 could independently predict the prognosis of LUAD and was associated with immune infiltration. In particular, the tight relationship between RRM2 and B cell marker genes are the potential epicenter of the immune response and one of the critical factors affecting the prognosis. Our findings laid the foundation for further research on the immunomodulatory role of RRM2 in LUAD.

show abstract

Section: Discussionmentioning

confidence: 99%

Independent prognostic implications of RRM2 in lung adenocarcinoma

Luo

Cao

et al. 2020

J. Cancer

View full text Add to dashboard Cite

show abstract

“…Lung cancer tissue have faster division of cancer cells and a shorter cell cycle. CDKs protein activation is a key driver of cell cycle transition in lung cancer cells [57]. CCNB1 overexpression in NSCLC is closely related to tumor type, tumor differentiation, vascular in ltration and positive [58].…”

Section: Discussionmentioning

confidence: 99%

Uncovering the Mechanism of Shenlian Capsules in the Treatment of Non-small Cell Lung Cancer by System Pharmacology

Gong

Wei

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Shenlian Capsule is a Chinese medicine compound approved by the China Food and Drug Administration (CFDA) for the treatment of advanced non-small cell lung cancer(NSCLC). However, due to its complex constituents, cause its effective active compounds and main action mechanisms for treating diseases are still not fully clear. The purpose of this work is to explore the active ingredients and mechanisms of Shenlian Capsule treatment NSCLC through a system pharmacological approach. Methods: First, a database of Shenlian Capsule chemical composition was constructed by retrieving Chinese herbal medicine data. Absorption, distribution, metabolism and excretion (ADME) methods were used to screen potential active compounds. Predict active compound targets with a large-scale molecular network target prediction technology. Clustering of active compounds obtained through cluster analysis by MECODE plug-in, each cluster obtains the main pathways through enrichment analysis method. To get all targets related to survival in NSCLC, the survival related targets were intersected with the compounds target (C-T) network to get the survival related targets for Shenlian Capsule. Finally, a batch molecular docking technique was used to verify the effect of active compounds of Shenlian Capsule on survival-related targets.Results: The Shenlian Capsule C-T network was constructed with 117 potential compounds and 47 targets. Treatment of NSCLC with Shenlian Capsule through enrichment analysis may involve multiple pathways such as anti-inflammatory, immune regulation, regulation of cell cycle, apoptosis, antiviral, cell hypoxia, angiogenesis and so on. Shenlian Capsule has eight survival-related genes in non-small cell lung adenocarcinoma (LUAD) and two survival-related genes in non-small cell squamous cell lung carcinoma (LUSC). It is known through molecular docking that the active compound has lower energy after conformation with survival-related genes, and has lower binding energy and stable binding.Conclusion: In this study, the potential compounds of active compounds in Shenlian Capsule were first predicted using network pharmacology technology. Through the enrichment analysis, the main pathways of the role of Shenlian Capsule were outcropped. Secondly, by combining bioinformatics and network pharmacology, Shenlian Capsule can be regulated to target survival-related targets. Finally, the molecular docking technique shows the relationship between active compounds and survival-related targets after docking. This work provided a scientific basis for the clinical role of Shenlian Capsule in the treatment of NSCLC, provided a research basis for further clarifying the active ingredients and mechanism of Shenlian Capsule in the treatment of NSCLC.

show abstract

“…Numerous evidences have demonstrated that iron is associated with the initiation and development of several malignant tumors 17,19,21 . Iron overload promotes carcinogenesis and tumorigenesis in colorectal and lung cancer [17][18][19] . Moreover, several studies have also demonstrated the therapeutic effects of iron chelator in lung cancer, pancreatic cancer, multiple myeloma and colorectal cancer 15,[17][18][19]21,28 .…”

Section: Discussionmentioning

confidence: 99%

“…Iron overload promotes carcinogenesis and tumorigenesis in colorectal and lung cancer [17][18][19] . Moreover, several studies have also demonstrated the therapeutic effects of iron chelator in lung cancer, pancreatic cancer, multiple myeloma and colorectal cancer 15,[17][18][19]21,28 . In the present study, we generated a tumor-load model by injecting SAOS-2 cell line in nude mice.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrion-mediated iron accumulation promotes carcinogenesis and Warburg effect through reactive oxygen species in osteosarcoma

Kuang

Yuan

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Iron metabolism disorder is closely associated with several malignant tumors, however the mechanisms underlying iron and the carcinogenesis in osteosarcoma are not yet well understood. Methods: Cell proliferation ability of osteosarcoma cell lines was measured by CCK-8, EdU incorporation and colony formation assays. Cell cycle analysis was detected by flow cytometry. The carcinogenesis of osteosarcoma was measured by soft-agar formation, trans-well and Wound healing-scratch assay. Warburg effect was detected by Seahorse respirometry assays. Reactive oxygen species (ROS) level was measured by Dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probes. Western blotting was used to measure the expression of mitoferrin 1 (SLC25A37) and mitoferrin 2 (SLC25A28) . Iron level in vitro and vivo was detected by iron assay kit. RNAi stable cell lines was generated using shRNA. Results: Iron promoted proliferation, carcinogenesis and Warburg effect of osteosarcoma cells. Iron-induced reactive oxygen species (ROS) played an important role in these processes. Iron accumulated more in mitochondrion than in cytoplasm, suggesting mitochondrion-mediated iron accumulation was involved in the development of osteosarcoma. Moreover, iron upregulated the expression of mitoferrin 1 (SLC25A37) and mitoferrin 2 (SLC25A28) . Knock-down of mitoferrin 1 (SLC25A37) and mitoferrin 2 (SLC25A28) decreased the production of ROS. In addition, iron increased the expression of Warburg key enzymes HK2 and Glut1, and affected AMPK / mTORC1 signaling axis. Conclusions: Mitochondrion-mediated iron accumulation promotes carcinogenesis and Warburg effect of osteosarcoma cells. Meanwhile, iron deprivation might be a novel effective strategy in the treatment of osteosarcoma.

show abstract

Iron-dependent CDK1 activity promotes lung carcinogenesis via activation of the GP130/STAT3 signaling pathway

Cited by 46 publications

References 32 publications

Independent prognostic implications of RRM2 in lung adenocarcinoma

Independent prognostic implications of RRM2 in lung adenocarcinoma

Uncovering the Mechanism of Shenlian Capsules in the Treatment of Non-small Cell Lung Cancer by System Pharmacology

Mitochondrion-mediated iron accumulation promotes carcinogenesis and Warburg effect through reactive oxygen species in osteosarcoma

Contact Info

Product

Resources

About