A Noncoding Regulatory RNAs Network Driven byCirc-CDYL Acts Specifically in the Early Stages Hepatocellular Carcinoma.

Wei Y^1,2,3, Chen X^1,2, Liang C^1,2, Ling Y^1,2, Yang X⁴, Ye X⁵, Zhang H⁶, Yang P⁴, Cui X^1,2, Ren Y^1,2, Xin X⁴, Li H⁶, Wang R⁴, Wang W⁷, Jiang F⁸, Liu S⁴, Ding J^1,2, Zhang B⁴, Li L^1,2, Wang H^1,2,9.

Hepatology.（IF：14.079）Pub date: 2019-5-30

  DOI:10.1002/hep.30795

Abstract

Hepatocellularcarcinoma (HCC) is the fastest-rising cause of cancer-related death worldwide,but its deficiency of specific biomarkers and therapeutic targets in the earlystages lead to severe inadequacy in the early diagnosis and treatment of HCC.Covalently closed circular RNA, which was once considered an aberrant splicingbyproduct, is now drawing new interest in cancer research due to its remarkablefunctionality. Beneath the surface of the dominant functional proteins events,a hidden circRNA-centric noncoding regulatory RNAs network active in the veryearly stage of HCC is here revealed by a genome-wide analysis of mRNA, circRNAand microRNA expression profiles. Circ-CDYL is specifically upregulated in theearly stages of HCC and therefore contributes to the properties ofEPCAM-positive liver tumor-initiating cells. Circ-CDYL interacts with mRNAsencoding hepatoma-derived growth factor (HDGF) and hypoxia inducible factorasparagine hydroxylase (HIF1AN) by acts as the sponge of miR-892a and miR-328-3p,respectively. Subsequently, activation of the PI3K-AKT-mTORC1/尾-catenin and NOTCH2 pathways, which promote the expression ofthe effect proteins baculoviral IAP repeat containing 5 (BIRC5 or SURVIVIN) andMYC proto-oncogene, is influenced by Circ-CDYL. A treatment incorporatingCirc-CDYL interference and traditional enzyme inhibitors targeting PI3K andHIF1AN demonstrated highly effective inhibition of stem-like characteristicsand tumor growth in HCC. Finally, we demonstrated that the Circ-CDYL expressionor which combined with HDGF and HIF1AN are both independent marker fordiscrimination of early stages HCC with the odds ratio (OR) of 1.09 (95% CI:1.02-1.17) and 124.58 (95% CI: 13.26-1170.56), respectively. CONCLUSION: Thesefindings uncover a circRNA-centric noncoding regulatory RNAs network in theearly stages HCC and thus provide a possibility for surveillance and treatmentof HCC early. This article is protected by copyright. All rights reserved.

推薦理由：

1.肝細(xì)胞癌（HCC）是全球癌癥相關(guān)死亡增加最快的原因,，但其在早期階段缺乏特異性生物標(biāo)志物和治療靶點(diǎn)導(dǎo)致HCC早期診斷和治療的嚴(yán)重不足,。

2.在顯性功能蛋白事件的表面下，通過對mRNA,，circRNA和microRNA表達(dá)譜的全基因組分析揭示了在HCC的早期階段活躍的隱藏的以circRNA為中心的非編碼調(diào)控RNA網(wǎng)絡(luò),。

3.實(shí)驗(yàn)思路和方法值得學(xué)習(xí)。