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Published on: September 12, 2019
Prognostic and Therapeutic Potentials of OncomiRs Modulating mTOR Pathways in Virus-Associated Hepatocellular
Neeti Nadda1, Shashi Bala Paul2, Dawesh P Yadav1
1Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India.
Background:
Dysregulated oncomiRs are attributed to hepatocellular carcinoma (HCC) through targeting mTOR signaling pathway responsible for cell growth and proliferation. The potential of these oncomiRs as biomarker for tumor response or as target for therapy needs to be evaluated.
Aim:
Tumor response assessment by OncomiR changes following locoregional therapy (LRT) and targeting of these oncomiRs modulating pathway.
Methods:
All consecutive viral-HCC patients of BCLC stage-A/B undergoing LRT were included. OncomiRs (miR-21, -221, and -16) change in circulation and AFP-ratio at 1-month post-LRT to baseline was estimated to differentiate various categories of response as per mRECIST criteria. OncomiR modulating mTOR pathway was studied by generating miR-21 and miR-221 overexpressing Huh7 stable cell lines.
Results:
Post-LRT tumor response was assessed in 90 viral-HCC patients (CR, 40%; PR, 31%, and PD, 29%). Significant increase of miRNA-21 and -221 expression was observed in PD (p = 0.040, 0.047) and PR patients (miR-21, p = 0.045). Fold changes of miR-21 can differentiate response in group (CR from PR+PD) at AUROC 0.718 (95% CI, 0.572-0.799) and CR from PD at AUROC 0.734 (95% CI, 0.595-0.873). Overexpression of miR-21 in hepatoma cell line had shown increased phosphorylation p70S6K, the downstream regulator of cell proliferation in mTOR pathway. Upregulation of AKT, mTOR, and RPS6KB1 genes were found significant (P < 0.005) and anti-miR-21 specifically reduced mTOR gene (P = 0.02) expression.
Conclusions:
The miR-21 fold change correlates well with imaging in predicting tumor response. Overexpression of miR-21 has a role in HCC through mTOR pathway activation and can be targeted.
Insights
MicroRNA-21 (miR-21) levels can predict hepatocellular carcinoma (HCC) treatment response. Targeting miR-21 may offer a new therapeutic strategy for HCC by modulating the mTOR pathway.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Dysregulated oncomiRs (oncogenic microRNAs) contribute to hepatocellular carcinoma (HCC) by targeting the mTOR signaling pathway, which controls cell growth and proliferation.
- Evaluating oncomiRs as biomarkers for tumor response and as therapeutic targets is crucial for HCC management.
Purpose of the Study:
- To assess tumor response to locoregional therapy (LRT) in HCC patients based on changes in circulating oncomiRs (miR-21, -221, -16) and AFP-ratio.
- To investigate the role of oncomiRs in modulating the mTOR pathway through experimental models.
Main Methods:
- Analysis of consecutive viral-HCC patients (BCLC stage A/B) undergoing LRT.
- Measurement of oncomiR (miR-21, -221, -16) and AFP-ratio changes at 1-month post-LRT compared to baseline.
- Generation of miR-21 and miR-221 overexpressing Huh7 cell lines to study mTOR pathway modulation.
Main Results:
- Tumor response to LRT in 90 patients: 40% complete response (CR), 31% partial response (PR), 29% progressive disease (PD).
- Significant increase in miR-21 and miR-221 expression observed in PD and PR groups post-LRT (p < 0.05).
- miR-21 fold change demonstrated predictive value for response (AUROC 0.718-0.734). Overexpression of miR-21 activated mTOR pathway components (AKT, mTOR, RPS6KB1), while anti-miR-21 reduced mTOR expression.
Conclusions:
- Circulating miR-21 fold change is a reliable predictor of HCC treatment response, correlating with imaging-based assessments.
- miR-21 plays a role in HCC progression via mTOR pathway activation and represents a potential therapeutic target.
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