Evidence map›Paper›PMID 25537274›Full record

ArticleJournal of medical genetics2015

Novel role for non-homologous end joining in the formation of double minutes in methotrexate-resistant colon cancer cells.

Xiangning Meng, Xiuying Qi, Huanhuan Guo, Mengdi Cai, Chunxiang Li, Jing Zhu, Feng Chen, Huan Guo, Jie Li, Yuzhen Zhao and 12 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of medical genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
57citing papers in PubMed, 1 pooled it
0.4field-weighted citation impact, top 37% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

57 citing papers in PubMed, 1 synthesis or guideline pooled it, 82 citations in OpenAlex.

  1. Pooled it
  2. Article
  3. Targeting extrachromosomal DNA in human cancers.Nature reviews. Drug discovery · 2026
    Review
  4. Review
  5. Article
  6. Article
  7. Review
  8. Extrachromosomal DNA and cancer: function, formation, and clinical implications.Journal of experimental & clinical cancer research : CR · 2026
    Review
  9. Article
  10. EccDNA-Driven VPS41 Amplification Alleviates Genotoxic Stress via Lysosomal KAI1 Degradation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025
    Article
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  12. Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

22 authors at 3 institutions in 3 countries.

Xiangning MengLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Xiuying QiLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Huanhuan GuoLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Mengdi CaiLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Chunxiang LiLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Jing ZhuLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Feng ChenLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Huan GuoLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Jie LiLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Yuzhen ZhaoLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Peng LiuLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Xueyuan JiaLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Jingcui YuLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Chunyu ZhangLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Wenjing SunLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Yang YuLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Yan JinLaboratory of Medical Genetics, Harbin Medical University, Harbin, China Key Laboratory of Medical Genetics (Harbin Medical University), Heilongjiang Higher Education Institutions, Harbin, China.
Jing BaiLaboratory of Medical Genetics, Harbin Medical University, Harbin, China.
Mingrong WangState Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Jesusa RosalesDepartments of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
Ki-Young LeeCell Biology & Anatomy, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Songbin FuLaboratory of Medical Genetics, Harbin Medical University, Harbin, China Key Laboratory of Medical Genetics (Harbin Medical University), Heilongjiang Higher Education Institutions, Harbin, China.
Harbin Medical University · CNUniversity of Calgary · CAPeking Union Medical College Hospital · CN

Funding

Canadian Institutes of Health Research
6 · The paper itself

Abstract

backgroundGene amplification is a frequent manifestation of genomic instability that plays a role in tumour progression and development of drug resistance. It is manifested cytogenetically as extrachromosomal double minutes (DMs) or intrachromosomal homogeneously staining regions (HSRs). To better understand the molecular mechanism by which HSRs and DMs are formed and how they relate to the development of methotrexate (MTX) resistance, we used two model systems of MTX-resistant HT-29 colon cancer cell lines harbouring amplified DHFR primarily in (i) HSRs and (ii) DMs.

resultsIn DM-containing cells, we found increased expression of non-homologous end joining (NHEJ) proteins. Depletion or inhibition of DNA-PKcs, a key NHEJ protein, caused decreased DHFR amplification, disappearance of DMs, increased formation of micronuclei or nuclear buds, which correlated with the elimination of DHFR, and increased sensitivity to MTX. These findings indicate for the first time that NHEJ plays a specific role in DM formation, and that increased MTX sensitivity of DM-containing cells depleted of DNA-PKcs results from DHFR elimination. Conversely, in HSR-containing cells, we found no significant change in the expression of NHEJ proteins. Depletion of DNA-PKcs had no effect on DHFR amplification and resulted in only a modest increase in sensitivity to MTX. Interestingly, both DM-containing and HSR-containing cells exhibited decreased proliferation upon DNA-PKcs depletion.

conclusionsWe demonstrate a novel specific role for NHEJ in the formation of DMs, but not HSRs, in MTX-resistant cells, and that NHEJ may be targeted for the treatment of MTX-resistant colon cancer.

Indexed as

Cell ProliferationColonic NeoplasmsDNA Breaks, Double-StrandedDNA End-Joining RepairDrug Resistance, NeoplasmGene AmplificationHT29 CellsHumansMethotrexateStaining and LabelingMethotrexateCancer: colonGeneticsMolecular geneticsOncology

Identifiers

PMID25537274
PMCPMC4316941
OpenAlexW1995204735

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.