Nadda Neeti, Paul Shashi Bala, Yadav Dawesh P, Kumar Sonu, Sreenivas Vishnubhatla, Saraya Anoop, Gamanagatti Shivanand, Acharya Subrat Kumar, Nayak Baibaswata
Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India.
Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India.
Front Oncol. 2021 Feb 4;10:604540. doi: 10.3389/fonc.2020.604540. eCollection 2020.
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.
Tumor response assessment by OncomiR changes following locoregional therapy (LRT) and targeting of these oncomiRs modulating pathway.
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.
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.
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.
失调的致癌miRNA通过靶向负责细胞生长和增殖的mTOR信号通路导致肝细胞癌（HCC）。这些致癌miRNA作为肿瘤反应生物标志物或治疗靶点的潜力需要评估。
通过局部区域治疗（LRT）后致癌miRNA的变化评估肿瘤反应，并靶向调节这些致癌miRNA的信号通路。
纳入所有连续接受LRT的BCLC A/B期病毒性HCC患者。估计LRT后1个月循环中致癌miRNA（miR-21、-221和-16）的变化以及AFP比值相对于基线的变化，以根据mRECIST标准区分不同类型的反应。通过构建miR-21和miR-221过表达的Huh7稳定细胞系研究调节mTOR通路的致癌miRNA。
对90例病毒性HCC患者进行了LRT后肿瘤反应评估（完全缓解，40%；部分缓解，31%，疾病进展，29%）。在疾病进展患者（p = 0.040，0.047）和部分缓解患者（miR-21，p = 0.045）中观察到miRNA-21和-221表达显著增加。miR-21的倍数变化在曲线下面积为0.718（95%可信区间，0.572-0.799）时可区分完全缓解组与部分缓解+疾病进展组的反应，在曲线下面积为0.734（95%可信区间，0.595-0.873）时可区分完全缓解与疾病进展。肝癌细胞系中miR-21的过表达显示mTOR通路中细胞增殖的下游调节因子p70S6K磷酸化增加。发现AKT、mTOR和RPS6KB1基因上调显著（P < 0.005），抗miR-21特异性降低mTOR基因（P = 0.02）表达。
miR-21倍数变化与预测肿瘤反应的影像学检查相关性良好。miR-21的过表达通过激活mTOR通路在HCC中起作用，并且可以作为靶点。
