Epigenetic–smoking interaction reveals histologically heterogeneous effects of <i>TRIM27</i> DNA methylation on overall survival among early‐stage NSCLC patients

Ji, Xinyu; Lin, Lijuan; Shen, Sipeng; Dong, Xuesi; Chen, Chao; Li, Yang; Zhu, Ying; Huang, Hui; Chen, Jia-Jin Jason; Chen, Xin; Wei, Liangmin; He, Jieyu; Duan, Weiwei; Li, Su; Jiang, Yue; Fan, Juanjuan; Guan, Jinxing; You, Dongfang; Shafer, Andrea T.; Bjaanæs, Maria Moksnes; Karlsson, Anna; Planck, Maria; Staaf, Johan; Helland, Åslaug; Esteller, Manel; Wei, Yongyue; Zhang, Ruyang; Chen, Feng; Christiani, David C.

doi:10.1002/1878-0261.12785

Cited by 14 publications

(10 citation statements)

References 63 publications

(71 reference statements)

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“…1,2 At present, there are no clear results for the cause of NSCLC in clinical practice, but it is known that environment, heredity, and bad living habits are high risk factors that cause this disease. 3,4 Radiotherapy is one of the local treatments for NSCLC, but the emergence of radioresistance greatly reduces the probability of successful radiotherapy. 5,6 Therefore, seeking effective targets to improve radiosensitivity is expected to offer a theoretical basis for improving the cure rate of NSCLC patients.…”

Section: Introductionmentioning

confidence: 99%

Circ_0007580 knockdown strengthens the radiosensitivity of non‐small cell lung cancer via the miR‐598‐dependent regulation of THBS2

Yang

Zhang

et al. 2022

Thoracic Cancer

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Background: Radioresistance is a common cause of treatment failure in many cancers, including non-small cell lung cancer (NSCLC). Circular RNA (circRNA) has been shown to be involved in the radiosensitivity of many cancers. However, the role and mechanism of circ_0007580 in the radiosensitivity of NSCLC remain unclear. Methods: The expression levels of circ_0007580, miR-598 and thrombospondin 2 (THBS2) were estimated by quantitative real-time PCR. The radiosensitivity of cells was measured using colony formation assay. Cell proliferation and apoptosis were assessed by performing cell counting kit 8 assay, colony formation assay, flow cytometry, and by detecting caspase-3 and caspase-9 activities. Protein expression was determined using western blot analysis. Results: Our data showed that circ_0007580 was highly expressed and miR-598 was lowly expressed in radioresistant NSCLC tissues. Functional experiments suggested that circ_0007580 silencing could improve the radiosensitivity of cells by suppressing cell proliferation and increasing apoptosis. MiR-598 was confirmed to be a target of circ_0007580, and its inhibitor could reverse the regulation of circ_0007580 on the radiosensitivity of NSCLC cells. MiR-598 was found to target THBS2. The suppressive effect of miR-598 on the radiosensitivity of cells could be reversed by THBS2 overexpression. Additionally, circ_0007580 could sponge miR-598 to regulate THBS2. In vivo experiments showed that knockdown of circ_0007580 enhanced the radiosensitivity of NSCLC tumors. Conclusions: Our results revealed that circ_0007580 might be a target for improving the radiosensitivity of NSCLC, which was mainly achieved by regulating the miR-598/ THBS2 axis.

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Section: Introductionmentioning

confidence: 99%

Circ_0007580 knockdown strengthens the radiosensitivity of non‐small cell lung cancer via the miR‐598‐dependent regulation of THBS2

Yang

Zhang

et al. 2022

Thoracic Cancer

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“…Cigarette smoking is one of the leading risk factors to lung cancer morbidity and mortality [20,21]. Our previous study found that a two‐way interaction between cg05293407 TRIM27 and smoking reveals the histologically heterogeneous effect of TRIM27 DNA methylation on survival among early‐stage NSCLC patients [22].…”

Section: Introductionmentioning

confidence: 99%

“…As is well known, gene–gene and gene–environment interactions provide important clues regarding biologic mechanisms of complex diseases [23] and are associated with the overall survival of NSCLC [10,11,14,22,24]. However, tumorigenesis and progression of complex diseases, such as NSCLC, often involves a multistep, multigenic, and multicausal biological process [25]; interactions between two relevant factors may only provide limited information understanding the cancer process driven by multiple factors [26].…”

Section: Introductionmentioning

confidence: 99%

Epigenome‐wide three‐way interaction study identifies a complex pattern betweenTRIM27,KIAA0226, and smoking associated with overall survival of early‐stage NSCLC

Lin

Fan

et al. 2022

Molecular Oncology

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The interaction between DNA methylation of tripartite motif containing 27 (cg05293407TRIM27) and smoking has previously been identified to reveal histologically heterogeneous effects of TRIM27 DNA methylation on early‐stage non‐small‐cell lung cancer (NSCLC) survival. However, to understand the complex mechanisms underlying NSCLC progression, we searched three‐way interactions. A two‐phase study was adopted to identify three‐way interactions in the form of pack‐year of smoking (number of cigarettes smoked per day × number of years smoked) × cg05293407TRIM27 × epigenome‐wide DNA methylation CpG probe. Two CpG probes were identified with FDR‐q ≤ 0.05 in the discovery phase and P ≤ 0.05 in the validation phase: cg00060500KIAA0226 and cg17479956EXT2. Compared to a prediction model with only clinical information, the model added 42 significant three‐way interactions using a looser criterion (discovery: FDR‐q ≤ 0.10, validation: P ≤ 0.05) had substantially improved the area under the receiver operating characteristic curve (AUC) of the prognostic prediction model for both 3‐year and 5‐year survival. Our research identified the complex interaction effects among multiple environment and epigenetic factors, and provided therapeutic target for NSCLC patients.

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“…Hsa_circ_0006168 (circ_0006168) is derived from CCR4-NOT transcription complex subunit 6 like (CNOT6L) gene and located at chr4:78,694,234–78,697,546, and it has been reported to act as an oncogene in ESCC [ 16 ]. Moreover, hsa_circ_0030998 suppressed lung cancer tumorigenesis and Taxol resistance by sponging miR‐558 [ 17 ]. In addition, hsa_circ_0002483 inhibited the progression and enhanced the Taxol sensitivity of non-small cell lung cancer via regulating miR-182-5p [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Circular RNA circ_0006168 enhances Taxol resistance in esophageal squamous cell carcinoma by regulating miR-194-5p/JMJD1C axis

Wang

et al. 2021

Cancer Cell Int

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Background Chemoresistance is one of the major obstacles for cancer therapy in the clinic. Circular RNAs (circRNAs) are involved in the pathogenesis of esophageal squamous cell carcinoma (ESCC) and chemoresistance. This study aimed to explore the role and molecular mechanism of circ_0006168 in Taxol resistance of ESCC. Methods The expression levels of circ_0006168, microRNA-194-5p (miR-194-5p) and jumonji domain containing 1C (JMJD1C) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. The half-inhibition concentration (IC50) value of Taxol was evaluated by Cell Counting Kit-8 (CCK-8) assay. Cell proliferation was evaluated by CCK-8 and colony formation assays. Cell migration and invasion were detected by transwell assay. Cell apoptosis was determined by flow cytometry. The interaction between miR-194-5p and circ_0006168 or JMJD1C was predicted by bioinformatics analysis (Circinteractome and TargetScan) and verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) and RNA pull-down assays. The mice xenograft model was established to investigate the roles of circ_0006168 in vivo. Results Circ_0006168 and JMJD1C were upregulated and miR-194-5p was downregulated in ESCC tissues, ESCC cells, and Taxol-resistant cells. Functionally, knockdown of circ_0006168 or JMJD1C increased Taxol sensitivity of ESCC in vitro via inhibiting cell proliferation, migration and invasion, and promoting apoptosis. Moreover, circ_0006168 could directly bind to miR-194-5p and JMJD1C was verified as a direct target of miR-194-5p. Mechanically, circ_0006168 was a sponge of miR-194-5p to regulate JMJD1C expression in ESCC cells. Furthermore, JMJD1C overexpression reversed the promotive effect of circ_0006168 knockdown on Taxol sensitivity. Besides, circ_0006168 silence suppressed tumor growth in vivo. Conclusion Circ_0006168 facilitated Taxol resistance in ESCC by regulating miR-194-5p/JMJD1C axis, providing a promising therapeutic target for ESCC chemotherapy.

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Epigenetic–smoking interaction reveals histologically heterogeneous effects of TRIM27 DNA methylation on overall survival among early‐stage NSCLC patients

Cited by 14 publications

References 63 publications

Circ_0007580 knockdown strengthens the radiosensitivity of non‐small cell lung cancer via the miR‐598‐dependent regulation of THBS2

Circ_0007580 knockdown strengthens the radiosensitivity of non‐small cell lung cancer via the miR‐598‐dependent regulation of THBS2

Epigenome‐wide three‐way interaction study identifies a complex pattern betweenTRIM27,KIAA0226, and smoking associated with overall survival of early‐stage NSCLC

Circular RNA circ_0006168 enhances Taxol resistance in esophageal squamous cell carcinoma by regulating miR-194-5p/JMJD1C axis

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