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Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models
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Novel Cross-Cancer Hub Genes in Doxorubicin Resistance Identified by Transcriptional Mapping

Arseny D Moralev1, Oleg V Markov1, Marina A Zenkova1

  • 1Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia.

Biomedicines
|October 29, 2025
PubMed

Insights

Chemoresistance to Doxorubicin (DOX) involves common gene expression changes across cancers, including cytoskeletal alterations and pathway dysregulation. Key genes like GJA1 and ZYX are identified as potential biomarkers for predicting treatment outcomes.

Area of Science:

  • Genomics and Bioinformatics
  • Cancer Biology
  • Chemotherapy Resistance

Background:

  • Doxorubicin (DOX) is a vital chemotherapy drug, yet cancer cells frequently develop resistance, limiting its clinical effectiveness.
  • The global transcriptomic changes driving DOX resistance across diverse cancer types are not fully understood.
  • Identifying common resistance mechanisms is crucial for developing strategies to overcome treatment failure.

Purpose of the Study:

  • To investigate if a shared transcriptional response to DOX desensitization exists across different tumor origins.
  • To identify the core genes and pathways involved in this conserved DOX resistance signature.
  • To evaluate the potential of identified genes as predictive biomarkers and therapeutic targets.

Main Methods:

  • Integrated bioinformatics analysis of independent transcriptomic datasets from DOX-resistant and sensitive cells (neuroblastoma, breast, cervical carcinoma).
  • Functional annotation, gene network reconstruction, text mining, and survival analysis.
  • In vitro validation, RT-PCR, and analysis of public cancer databases (Cancer Therapeutics Response Portal, The Cancer Genome Atlas).

Main Results:

  • DOX resistance is linked to cytoskeletal reorganization, altered cell adhesion, cholesterol biosynthesis changes, and dysregulated mTORC1, Wnt, and Gβγ signaling.
  • A conserved network of 37 resistance-associated genes was identified, with GJA1, SEH1L, TCF3, TUBA4A, and ZYX as central hubs.
  • Experimental validation confirmed enhanced cell adhesion and reduced cholesterol in resistant cells; hub genes correlate with poor patient outcomes.

Conclusions:

  • Conserved transcriptomic signatures define Doxorubicin resistance across various cancer types.
  • Hub genes GJA1, SEH1L, TCF3, TUBA4A, and ZYX are promising predictive biomarkers and potential therapeutic targets.
  • Targeting these identified pathways could enhance chemotherapy efficacy and improve patient outcomes.
Keywords:
MDRcancerchemoresistancedoxorubicingene networkhub generegulometranscriptomics

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