Expression of CDCA3 Is a Prognostic Biomarker and Potential Therapeutic Target in Non–Small Cell Lung Cancer

Adams, Mark N.; Burgess, Joshua T.; He, Yaowu; Gately, Kathy; Snell, Cameron; Zhang, Shudong; Hooper, John D.; Richard, Derek J.; O’Byrne, Kenneth J.

doi:10.1016/j.jtho.2017.04.018

Cited by 63 publications

(89 citation statements)

References 30 publications

(43 reference statements)

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“…For example, the gene H19 (cg21926276 locate) is related with both lung cancer and tumor growth, methylation of which has been thought as a sensitive marker of tobacco history [40,41]. The gene CDCA3 (cg27042065 located) is also associated with lung cancer and survival of cancer patients [42][43][44], and Song and Yang (2018) have reported that gene LOC338797 (cg26387355 located) is related with progression of tumor in lung cancer patients [45]. Besides confirming the previously reported genes, the three CpGs (cg21926276, cg27042065 and cg26387355) are also identified as novel markers for the survival of lung cancer patients.…”

Section: Plos Computational Biologymentioning

confidence: 99%

High-dimensional mediation analysis in survival models

Luo

Yan

et al. 2020

PLoS Comput Biol

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Mediation analysis with high-dimensional DNA methylation markers is important in identifying epigenetic pathways between environmental exposures and health outcomes. There have been some methodology developments of mediation analysis with high-dimensional mediators. However, high-dimensional mediation analysis methods for time-to-event outcome data are still yet to be developed. To address these challenges, we propose a new high-dimensional mediation analysis procedure for survival models by incorporating sure independent screening and minimax concave penalty techniques for variable selection, with the Sobel and the joint method for significance test of indirect effect. The simulation studies show good performance in identifying correct biomarkers, false discovery rate control, and minimum estimation bias of the proposed procedure. We also apply this approach to study the causal pathway from smoking to overall survival among lung cancer patients potentially mediated by 365,307 DNA methylations in the TCGA lung cancer cohort. Mediation analysis using a Cox proportional hazards model estimates that patients who have serious smoking history increase the risk of lung cancer through methylation markers including cg21926276,

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Section: Plos Computational Biologymentioning

confidence: 99%

High-dimensional mediation analysis in survival models

Luo

Yan

et al. 2020

PLoS Comput Biol

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“…13 CDCA3 is regulated transcriptionally in the whole cell cycle and on the translational level in the G1 phase. 15 As a candidate driver involved in cancer progression, we focus here on demonstrating that CDCA3 can be methylation-silenced and that its methylation contributes to epigenetic field cancerization in GCs. 17,18,39 If CDCA3 is deleted, cells cannot pass through the G2 phase to the M phase, while p21 is upregulated without dependence on p53 and cell aging is induced.…”

Section: Introductionmentioning

confidence: 99%

DNA hypomethylation promotes invasion and metastasis of gastric cancer cells by regulating the binding of SP1 to the CDCA3 promoter

Hua

Zhang

et al. 2019

J of Cellular Biochemistry

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Background Cell division cycle associated protein‐3 (CDCA3) has been reported frequently upregulated in various cancers. It has been progressively realized that changed DNA methylations occur in diverse carcinomas. However, the concrete involvement of CDCA3 and DNA methylation in gastric cancer (GC) still needs to be further elucidated. Methods In this study, quantitative reverse‐transcription polymerase chain reaction (PCR) was utilized to determine the relative expressions of CDCA3 in GC and normal tissue samples. The methylation condition of CDCA3 was determined by bisulfite‐sequencing PCR (BSP) and methylation‐specific PCR (MSP). A chromatin immunoprecipitation (ChIP) assay and luciferase activity assay was used for the interaction between transcription factors and promoters and binding site determination, respectively. The effects of knockdown or overexpression of specificity protein 1 (SP1) or CDCA3 on GC cells in vitro were further assessed via wound healing assay, colony formation assay, and matrigel invasion assay. Results In comparison to paired normal tissues, CDCA3 expressions were significantly increased in the GC tissues. The CDCA3 expression was regulated by DNA methylation, with the CpG island hypomethylation responsible for CDCA3 upregulation of GC. ChIP assays verified that the activity of SP1 binding to the CDCA3 promoter was dramatically increased. When the CDCA3 expression was downregulated in MKN45 cells by knockdown SP1, the proliferation ability, healing ability, and invasive ability were significantly suppressed. Conclusion The process by which SP1 bound to the nearest promoter region was expedited in GC cells, by which DNA was hypomethylated and CDCA3 expression was promoted. The effect on cell proliferation and invasion by CDCA3 was under the regulation of SP1 and also affected by hypomethylation of DNA.

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“…SCF E3 ligases regulate numerous short- acting proteins, such as cell cycle regulators, and mediate several biological processes, including cancer cellular activities ( 12 ). An increasing number of reports have demonstrated that CDCA3 expression is increased in liver cancer ( 13 ), oral squamous cell carcinoma tissue ( 14 ), non-small cell lung cancer ( 15 ) and prostate cancer cells ( 16 ), and may be associated to malignant diseases. However, the role of CDCA3 in CRC remains unclear.…”

Section: Introductionmentioning

confidence: 99%

CDCA3 mediates p21-dependent proliferation by regulating E2F1 expression in colorectal cancer

et al. 2018

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Dysregulated cell cycle progression serves a crucial role in tumor development. Cell division cycle- associated 3 (CDCA3) is considered a trigger of mitotic entry; it is an important part of the S phase kinase-associated protein 1/Cullin/F-box ubiquitin ligase complex and mediates the destruction of mitosis-inhibitory kinase wee1. However, little is known about the role of CDCA3 in cancer, particularly colorectal cancer (CRC). The present study aimed to explore the biological and clinical significance of CDCA3 in CRC growth and progression. CDCA3 expression was significantly associated with tumor progression and poor survival. Overexpression of CDCA3 increased proliferation in LoVo CRC cells, whereas CDCA3 knockdown in SW480 CRC cells led to decreased proliferation, in vitro and in vivo. Further mechanistic investigations demonstrated that reduced CDCA3 expression resulted in G1/S phase transition arrest, which was attributed to a significant accumulation of p21 in SW480 cells; conversely, increased CDCA3 expression promoted G1/S phase transition through decreased p21 accumulation in LoVo cells. It was also demonstrated that CDCA3 was able to regulate the expression of transcription factor E2F1, thereby repressing p21 expression. Taken together, these results suggested that overexpression of CDCA3 may serve a crucial role in tumor malignant potential and that CDCA3 may be used as a prognostic factor and a potential therapeutic target in CRC.

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Expression of CDCA3 Is a Prognostic Biomarker and Potential Therapeutic Target in Non–Small Cell Lung Cancer

Abstract: Our findings highlight CDCA3 as a prognostic factor and potential novel therapeutic target in NSCLC through inhibition of tumor growth and promotion of tumor senescence.

Cited by 63 publications

References 30 publications

High-dimensional mediation analysis in survival models

High-dimensional mediation analysis in survival models

DNA hypomethylation promotes invasion and metastasis of gastric cancer cells by regulating the binding of SP1 to the CDCA3 promoter

CDCA3 mediates p21-dependent proliferation by regulating E2F1 expression in colorectal cancer

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