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Cell‑cycle reactivation and hepatocyte identity loss in hepatocellular carcinoma: Transcriptomic hallmarks and validation strategies (Review)

  • Authors:
    • Jichen Hou
    • Bing Zhu
    • Lu Liang
  • View Affiliations / Copyright

    Affiliations: Department of Hepatobiliary Surgery, Affiliated Baotou Clinical College of Inner Mongolia Medical University, Baotou Central Hospital, Baotou, Inner Mongolia 014040, P.R. China, Translational Medicine Center, Baotou Central Hospital, Baotou, Inner Mongolia 014040, P.R. China
    Copyright: © Hou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 403
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    Published online on: July 9, 2026
       https://doi.org/10.3892/ol.2026.15758
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Abstract

Hepatocellular carcinoma (HCC) is molecularly diverse, but repeated transcriptomic surveys point to a useful recurring contrast: Cell‑cycle and DNA‑replication programs become prominent while differentiated hepatocyte transport, as well as metabolic and innate‑defense functions decline. In the present study, this paired change was used as a practical lens for reading HCC transcriptomes. Rather than treating individual proliferation‑, transporter‑ or metabolism‑related genes as isolated markers, the review asks what cellular state these modules represent and what evidence is needed before they are discussed as mechanisms or therapeutic vulnerabilities. The present review outlines how proliferation‑identity imbalance can guide model choice, RT‑qPCR or RNA‑seq panels, protein and pathway readouts and pharmacological testing. The current review also includes a worked example showing how a published HCC transcriptomic signal can be interpreted through this framework. The framework is deliberately conservative: Transcriptomic modules can nominate states and experiments, but they do not by themselves establish target dependency, mechanisms or therapeutic efficacy.
View Figures

Figure 1

Conceptual summary of
proliferation-identity imbalance in HCC. The schematic illustrates
a recurrent transcriptomic pattern in HCC in which cell-cycle
progression and DNA-replication programs increase, whereas
hepatocyte-associated metabolic and transporter programs decline.
The lower interpretation panel emphasizes that this paired pattern
is intended as a cell-state hypothesis that can guide module-level
interpretation, model selection and validation planning, rather
than as direct evidence of a specific mechanism or therapeutic
efficacy. HCC, hepatocellular carcinoma.

Figure 2

Module-aware model selection
framework for HCC transcriptomic programs. The schematic presents
the high-level relationship between transcriptomic modules and
state-matched model-selection principles. Module-specific
hypotheses, useful model features and claim boundaries are detailed
in Table II, whereas assay
categories and validation evidence are detailed in Table III. HCC, hepatocellular
carcinoma.

Figure 3

Stepwise validation ladder for HCC
transcriptomic modules. The figure displays only the sequence of
five validation levels from phenotype screening to model extension.
Detailed assay categories, evidentiary support and remaining
limitations are provided in Table
III. HCC, hepatocellular carcinoma; IF, immunofluorescence;
PDX, patient-derived xenograft; RNA-seq, RNA sequencing; RT-qPCR,
reverse transcription-quantitative PCR.
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Copy and paste a formatted citation
Spandidos Publications style
Hou J, Zhu B and Liang L: Cell‑cycle reactivation and hepatocyte identity loss in hepatocellular carcinoma: Transcriptomic hallmarks and validation strategies (Review). Oncol Lett 32: 403, 2026.
APA
Hou, J., Zhu, B., & Liang, L. (2026). Cell‑cycle reactivation and hepatocyte identity loss in hepatocellular carcinoma: Transcriptomic hallmarks and validation strategies (Review). Oncology Letters, 32, 403. https://doi.org/10.3892/ol.2026.15758
MLA
Hou, J., Zhu, B., Liang, L."Cell‑cycle reactivation and hepatocyte identity loss in hepatocellular carcinoma: Transcriptomic hallmarks and validation strategies (Review)". Oncology Letters 32.3 (2026): 403.
Chicago
Hou, J., Zhu, B., Liang, L."Cell‑cycle reactivation and hepatocyte identity loss in hepatocellular carcinoma: Transcriptomic hallmarks and validation strategies (Review)". Oncology Letters 32, no. 3 (2026): 403. https://doi.org/10.3892/ol.2026.15758
Copy and paste a formatted citation
x
Spandidos Publications style
Hou J, Zhu B and Liang L: Cell‑cycle reactivation and hepatocyte identity loss in hepatocellular carcinoma: Transcriptomic hallmarks and validation strategies (Review). Oncol Lett 32: 403, 2026.
APA
Hou, J., Zhu, B., & Liang, L. (2026). Cell‑cycle reactivation and hepatocyte identity loss in hepatocellular carcinoma: Transcriptomic hallmarks and validation strategies (Review). Oncology Letters, 32, 403. https://doi.org/10.3892/ol.2026.15758
MLA
Hou, J., Zhu, B., Liang, L."Cell‑cycle reactivation and hepatocyte identity loss in hepatocellular carcinoma: Transcriptomic hallmarks and validation strategies (Review)". Oncology Letters 32.3 (2026): 403.
Chicago
Hou, J., Zhu, B., Liang, L."Cell‑cycle reactivation and hepatocyte identity loss in hepatocellular carcinoma: Transcriptomic hallmarks and validation strategies (Review)". Oncology Letters 32, no. 3 (2026): 403. https://doi.org/10.3892/ol.2026.15758
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