Multiomic analysis of microRNA-mediated regulation reveals a proliferative axis involving miR-10b in fibrolamellar carcinoma.
Multiomic analysis of microRNA-mediated regulation reveals a proliferative axis involving miR-10b in fibrolamellar carcinoma.
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DOI：
10.1172/jci.insight.154743
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发表时间：
2022-06-08
期刊：
影响因子：
8
通讯作者：
Sethupathy, Praveen
中科院分区：
文献类型：
--
作者：
Francisco, Adam B.;Kanke, Matt;Massa, Andrew P.;Dinh, Timothy A.;Sritharan, Ramja;Vakili, Khashayar;Bardeesy, Nabeel;Sethupathy, Praveen
纤维板层癌（FLC）是一种侵袭性肝癌，主要累及青少年和年轻人。大多数FLC患者在19号染色体上存在杂合性缺失，导致致癌基因融合DNAJB 1-PRKACA。目前还没有有效的FLC治疗方法。为了解决这个问题，关键是要获得更深入的机制洞察FLC发病机制。我们组装了一个大的FLC和非恶性肝脏组织样本集（n = 52）并进行了综合多组学分析。具体来说，我们进行了小RNA测序，以确定肿瘤样本中改变的microRNA表达模式，然后将此分析与RNA测序和染色质连续测序数据相结合，以确定FLC中基因表达的候选主microRNA调节因子。我们还评估了DNAJB 1-PRKACA和几种人类和小鼠细胞模型中的microRNA之间的关系。最后，我们在从患者来源的异种移植物（PDX）模型建立的细胞中对特定microRNA进行了功能丧失实验。我们将miR-10 b-5 p鉴定为FLC中最佳候选促增殖microRNA。在多种人类细胞模型中，DNAJB 1-PRKACA的过表达导致miR-10 b-5 p的显著上调。在PDX衍生的细胞中抑制miR-10 b增加了几种潜在的新靶基因的表达，伴随着代谢活性、增殖和锚定非依赖性生长的显著降低。这项研究突出了一个潜在的新的增殖轴在FLC，并提供了丰富的资源，为进一步调查FLC的病因。
Fibrolamellar carcinoma (FLC) is an aggressive liver cancer primarily afflicting adolescents and young adults. Most patients with FLC harbor a heterozygous deletion on chromosome 19 that leads to the oncogenic gene fusion, DNAJB1-PRKACA. There are currently no effective therapeutics for FLC. To address that, it is critical to gain deeper mechanistic insight into FLC pathogenesis. We assembled a large sample set of FLC and nonmalignant liver tissue (n = 52) and performed integrative multiomic analysis. Specifically, we carried out small RNA sequencing to define altered microRNA expression patterns in tumor samples and then coupled this analysis with RNA sequencing and chromatin run-on sequencing data to identify candidate master microRNA regulators of gene expression in FLC. We also evaluated the relationship between DNAJB1-PRKACA and microRNAs of interest in several human and mouse cell models. Finally, we performed loss-of-function experiments for a specific microRNA in cells established from a patient-derived xenograft (PDX) model. We identified miR-10b-5p as the top candidate pro-proliferative microRNA in FLC. In multiple human cell models, overexpression of DNAJB1-PRKACA led to significant upregulation of miR-10b-5p. Inhibition of miR-10b in PDX-derived cells increased the expression of several potentially novel target genes, concomitant with a significant reduction in metabolic activity, proliferation, and anchorage-independent growth. This study highlights a potentially novel proliferative axis in FLC and provides a rich resource for further investigation of FLC etiology.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
4.6
作者：
Dinh TA;Vitucci EC;Wauthier E;Graham RP;Pitman WA;Oikawa T;Chen M;Silva GO;Greene KG;Torbenson MS;Reid LM;Sethupathy P
通讯作者：
Sethupathy P
影响因子：
29.4
作者：
Hu T;Shukla SK;Vernucci E;He C;Wang D;King RJ;Jha K;Siddhanta K;Mullen NJ;Attri KS;Murthy D;Chaika NV;Thakur R;Mulder SE;Pacheco CG;Fu X;High RR;Yu F;Lazenby A;Steegborn C;Lan P;Mehla K;Rotili D;Chaudhary S;Valente S;Tafani M;Mai A;Auwerx J;Verdin E;Tuveson D;Singh PK
通讯作者：
Singh PK
影响因子：
11.4
作者：
Hirano, S;Yamamoto, K;Takata, M
通讯作者：
Takata, M
影响因子：
5.2
作者：
Abba, Mohammed;Patil, Nitin;Allgayer, Heike
通讯作者：
Allgayer, Heike