Multi-Omics Immune Interaction Networks in Lung Cancer Tumorigenesis, Proliferation, and Survival
Abstract
:1. Introduction
2. Results
2.1. Further Validation of the Seven-Gene Signature in Prognosis for NSCLC
2.2. Diagnostic Implication of the Seven-Gene Signature in NSCLC
2.3. ZNF71 Expression and Selected Immune Cells in NSCLC Prognosis
2.4. Overexpression of ZNF71 KRAB, KRAB-Less Isoforms Suppresses Innate Immune Response
2.5. Gene Association Networks of ZNF71 and Intracellular Innate Response Genes
2.6. Identification of Genes Associated with Drug Response
2.7. Functional Pathways Associated with the ZNF71 Co-Expression Networks and Discovery of Therapeutic Targets
2.8. Potential Oncogenes and Tumor Suppressor Genes
3. Discussion
4. Materials and Methods
4.1. Non-Small Cell Lung Cancer (NSCLC) Patient Cohorts
4.2. xCell
4.3. Weka
4.4. Cell Lines
4.5. Vector Construction and Lentiviral Transduction
4.6. Western Blot
4.7. Boolean Implication Network
4.8. CRISPR-Cas9 Knockout Assays
4.9. RNAi Knockdown Assays
4.10. Pathway Enrichment Analysis Using ToppGene
4.11. Cancer Cell Line Encyclopedia (CCLE)
4.12. Drug Sensitivity in CCLE
4.13. Drug Repurposing Using Connectivity Map (CMap)
4.14. Statistical Methods
5. Conclusions
6. Patents
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Drug | Systemic/Targeted Therapy | Pan-Sensitive Genes | Pan-Resistant Genes |
---|---|---|---|
afatinib | EGFR Exon 19 Deletion or L858R/EGFR S768I, L861Q, and/or G719X | CDT1, INCENP | IL4I1, LRP1, FAM156B, DCUN1D4, ESPN, PTPRJ, NMNAT2 |
alectinib | ALK Rearrangement Positive | CSNK2A3, DYNC1H1, PSME1 | UCP3, CDC45, THSD7A, ANKRD52, EIF2A, FAM156B, KRT8, CFAP44 |
brigatinib | ALK Rearrangement Positive | MYOF, ABHD10, TMTC4 | |
cabozantinib | RET Rearrangement Positive | CSNK2A3 | RNASEL, TMTC4, SMC2, ASB7, CFAP44, IL17RA, ZXDA, THSD7A |
carboplatin | Systemic | ASB7, RAB1A | |
cisplatin | Systemic | ZNF507, CSNK2A3, WDR17 | ARHGAP12, CDC45, ESPN, EIF2A, IL17RA, MYOF, TMTC4, NMNAT2, PTPRJ, KRT8 |
crizotinib | ALK Rearrangement Positive/ROS1 Rearrangement Positive/MET Exon 14 Skipping Mutation | RFC4, CSNK2A3, MCM2, MDN1, CDT1, INCENP | LRP1, IL17RA |
dabrafenib | BRAF V600E Mutation Positive | FBLN7, MAP2, CTNNB1, RNF128, CSNK2A3, WDR17, ZNF507 | FAM156B, SLC39A8, SMC2, KRT8, NMNAT2 |
dacomitinib | EGFR Exon 19 Deletion or L858R/EGFR S768I, L861Q, and/or G719X | CDT1 | MAP3K7, DCUN1D4, LRP1, THOC5, FAM156B, ANKRD52, THSD7A |
docetaxel | Systemic | RFC4, ABCC5, FBLN7, MAP2 | SLC39A8, IL17RA, KRT8, RAB1A, THSD7A, DCUN1D4, MYOF, NMNAT2 |
erlotinib | EGFR Exon 19 Deletion or L858R/EGFR S768I, L861Q, and/or G719X | CSNK2A3, PSMB6, TGFB2 | FAM156B, ASB7, TMTC4, NMNAT2 |
etoposide | Systemic | PSMB3, CDT1, DYNC1H1, ZNF507 | ESPN, NMNAT2, ZNF324B, IL17RA |
gefitinib | EGFR Exon 19 Deletion or L858R/EGFR S768I, L861Q, and/or G719X | BRMS1L, CCNA2, CDT1, INCENP | IL4I1, ABHD10, FAM156B, MAP3K7, DCUN1D4, NMNAT2, PTPRJ, KRT8 |
gemcitabine | Systemic | MDGA1, MDN1, ZNF507, WDR17 | KRT8, ANKRD52, ASB7, RAB1A, FAM156B, IL17RA, DCUN1D4, IL4I1, LRP1, NMNAT2 |
lorlatinib | ALK Rearrangement Positive/ROS1 Rearrangement Positive | MDN1, PSMB6 | ANKRD52, ESPN, RAB1A |
osimertinib | EGFR Exon 19 Deletion or L858R/EGFR S768I, L861Q, and/or G719X | ABCC5, MDGA1, TCF20, MAP2, PSMB6 | ASB7, DCUN1D4, THSD7A |
paclitaxel | Systemic | INCENP, CDT1, MCM2, TCF20 | RAB1A, THOC5, ASB7, IL17RA, NMNAT2, KRT8, LRP1, SLC39A8, THSD7A, UCP3 |
pemetrexed | Systemic | MCM2, CCNA2 | EIF2A, IL17RA, MYOF, THSD7A, ZXDA, ARHGAP12, LRP1 |
trametinib | BRAF V600E Mutation Positive | CTNNB1 | RNASEL, IL17RA, ANKRD52, FAM156B, AP2S1, ARHGAP12, SRRM2, UCP3, ZXDA, TMTC4, DCUN1D4, NCOR1, RAB1A |
vemurafenib | BRAF V600E Mutation Positive | RNASE L, IL17RA | |
vinorelbine | Systemic | ABCC5, DYNC1H1, IRX1, TCF20 | RAB1A, SLC39A8, KRT8, DCUN1D4, PTPRJ, IL17RA, MYOF, NMNAT2 |
Drug | Systemic/Targeted Therapy | Pan-Sensitive Genes | Pan-Resistant Genes |
---|---|---|---|
afatinib | EGFR Exon 19 Deletion or L858R/EGFR S768I, L861Q, and/or G719X | DDX42, RFX7, FAT1, CREBBP | IL4I1, KRT8, CDCA4, DIXDC1 |
alectinib | ALK Rearrangement Positive | DDX42, ZNF507 | CCNA2, KIF14, CDK1, DAG1, ANKRD52, MAP3K7 |
brigatinib | ALK Rearrangement Positive | FAT1, PTPRJ, PSME1 | TEN1, MAP3K7, FBLN7, CDK1 |
cabozantinib | RET Rearrangement Positive | KANSL1, CHL1, TGFB2 | TJP1_G3V1L9, BPTF_E9PE19, NSD1, SYNE2_Q8WXH0_5, RDX, ANKRD52 |
carboplatin | Systemic | TJP1_G3V1L9 | |
cisplatin | Systemic | MYCL, DDX42, BRMS1L, KANSL1, ZNF507 | BPTF_E9PE19, FBLN7, DIP2B, MYOF, CDK1 |
crizotinib | ALK Rearrangement Positive/ROS1 Rearrangement Positive/MET Exon 14 Skipping Mutation | FAM208A, TOMM7, KANSL1 | DAG1 |
dabrafenib | BRAF V600E Mutation Positive | BRMS1L, RBBP4, ZNF507, DDX42, KANSL1 | RDX, ANKRD52, DIP2B, CDK1, DAG1, IL17RA |
dacomitinib | EGFR Exon 19 Deletion or L858R/EGFR S768I, L861Q, and/or G719X | PSME1, DDX42, GREB1, RBBP4 | MAP2_P11137_4, KRT8, CDC45, CDCA4, IL4I1 |
docetaxel | Systemic | TOMM7, CREBBP, TCF20, DDX42, FAM208A, THOC5, ZNF507 | DYNC1H1, MYOF |
erlotinib | EGFR Exon 19 Deletion or L858R/EGFR S768I, L861Q, and/or G719X | RFX7, THOC5, CREBBP | KIF14, CDCA4 |
etoposide | Systemic | CHL1, FAT1 | |
gefitinib | EGFR Exon 19 Deletion or L858R/EGFR S768I, L861Q, and/or G719X | DDX42, CREBBP, TCF20, CHL1 | CDCA4, IL4I1 |
gemcitabine | Systemic | DDX42, CREBBP, ZNF507, RBBP4, TOMM7 | DIP2B, ANKRD52, CDK1, MAP2_P11137_4, IL17RA, SLC39A8 |
lorlatinib | ALK Rearrangement Positive/ROS1 Rearrangement Positive | ASB7, PSME1, PIR | CCNA2, MYOF, CDK1, CDC45 |
osimertinib | EGFR Exon 19 Deletion or L858R/EGFR S768I, L861Q, and/or G719X | CDCA4, EIF4G3_B1AN89, IL4I1, ADARB1, CDC45 | |
paclitaxel | Systemic | CHL1, THOC5, ZNF507, UCHL3 | SLC39A8, DIXDC1, DIP2B, MYOF, IL17RA |
pemetrexed | Systemic | THOC5 | BPTF_E9PE19, RDX, DYNC1H1 |
trametinib | BRAF V600E Mutation Positive | CHL1, PSME1, TMTC4, JOSD2, PTPRJ, RPS19 | RDX, DAG1, IL17RA, MAP3K7 |
vemurafenib | BRAF V600E Mutation Positive | FAM208A | KRT8 |
vinorelbine | Systemic | TCF20, UCHL3, RBBP4, THOC5, ZNF507 | TJP1_G3V1L9 |
Src_Set_Id | Compound | Average of IC50 | Count of IC50 (Count of IC50 Outliers) | Average of EC50 | Count of EC50 (Count of EC50 Outliers) |
---|---|---|---|---|---|
CP_MEK_INHIBITOR | PD-0325901 | 0.748 | 64 (0) | 0.386 | 88 (0) |
CP_SRC_INHIBITOR | dasatinib | 0.555 | 92 (0) | 0.504 | 155 (4) |
MAP_KINASE_INHIBITOR | PD-98059 | 4.977 | 4 (0) | 0.607 | 56 (3) |
LEUCINE_RICH_REPEAT_KINASE_INHIBITOR | indirubin | 3.548 | 23 (0) | 0.630 | 160 (7) |
CP_MEK_INHIBITOR | selumetinib | 2.214 | 35 (0) | 0.647 | 165 (7) |
CP_MEK_INHIBITOR | AS-703026 | 1.514 | 100 (2) | 0.940 | 164 (8) |
CP_SRC_INHIBITOR | saracatinib | 1.733 | 103 (0) | 0.983 | 170 (6) |
CP_IGF_1_INHIBITOR | BMS-754807 | 1.744 | 97 (0) | 1.022 | 168 (8) |
CP_SRC_INHIBITOR | ZM-306416 | 2.626 | 28 (0) | 1.081 | 87 (1) |
CP_SRC_INHIBITOR | bosutinib | 3.162 | 46 (0) | 1.587 | 87 (0) |
CP_MEK_INHIBITOR | U-0126 | 4.533 | 77 (0) | 1.868 | 177 (3) |
CP_MEK_INHIBITOR | PD-198306 | 3.164 | 67 (1) | 2.034 | 92 (0) |
CP_SRC_INHIBITOR | PP-1 | 3.408 | 51 (0) | 2.079 | 87 (0) |
CP_IGF_1_INHIBITOR | linsitinib | 4.251 | 64 (1) | 2.088 | 146 (9) |
CP_MEK_INHIBITOR | PD-184352 | 3.988 | 47 (1) | 2.190 | 89 (0) |
CP_MEK_INHIBITOR | MEK1-2-inhibitor | 4.197 | 44 (7) | 2.200 | 84 (1) |
IGF-1_INHIBITOR | PQ-401 | 5.344 | 30 (0) | 2.204 | 79 (1) |
CP_SRC_INHIBITOR | PP-2 | 3.187 | 64 (0) | 2.484 | 79 (1) |
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Ye, Q.; Hickey, J.; Summers, K.; Falatovich, B.; Gencheva, M.; Eubank, T.D.; Ivanov, A.V.; Guo, N.L. Multi-Omics Immune Interaction Networks in Lung Cancer Tumorigenesis, Proliferation, and Survival. Int. J. Mol. Sci. 2022, 23, 14978. https://doi.org/10.3390/ijms232314978
Ye Q, Hickey J, Summers K, Falatovich B, Gencheva M, Eubank TD, Ivanov AV, Guo NL. Multi-Omics Immune Interaction Networks in Lung Cancer Tumorigenesis, Proliferation, and Survival. International Journal of Molecular Sciences. 2022; 23(23):14978. https://doi.org/10.3390/ijms232314978
Chicago/Turabian StyleYe, Qing, Justin Hickey, Kathleen Summers, Brianne Falatovich, Marieta Gencheva, Timothy D. Eubank, Alexey V. Ivanov, and Nancy Lan Guo. 2022. "Multi-Omics Immune Interaction Networks in Lung Cancer Tumorigenesis, Proliferation, and Survival" International Journal of Molecular Sciences 23, no. 23: 14978. https://doi.org/10.3390/ijms232314978