Platelet microRNAs inhibit primary tumor growth via broad modulation of tumor cell mRNA expression in ectopic pancreatic cancer in mice.
Platelet microRNAs inhibit primary tumor growth via broad modulation of tumor cell mRNA expression in ectopic pancreatic cancer in mice.
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DOI：
10.1371/journal.pone.0261633
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Goldfinger LE
中科院分区：
文献类型：
--
作者：
Wurtzel JGT;Lazar S;Sikder S;Cai KQ;Astsaturov I;Weyrich AS;Rowley JW;Goldfinger LE
我们使用小鼠模型研究了血小板microRNAs（miRNAs）对原发性异位肿瘤生长速率和基因表达调控的贡献。我们先前鉴定了血小板在实体瘤生长中的抑制作用，其由富含血小板衍生的miRNA的血小板微泡（微粒）的肿瘤浸润介导。为了研究血小板miRNAs在肿瘤生长模型中的特定作用，我们将胰腺导管腺癌细胞作为团块植入小鼠体内，巨核细胞/血小板特异性耗尽成熟miRNAs。我们观察到，与对照组相比，这些小鼠中异位原发性肿瘤的生长速率增加了约50%，包括在早期阶段，与肿瘤中的细胞凋亡减少有关，特别是与血小板微泡相关的肿瘤细胞，这些微泡耗尽了富含血小板的miRNAs，这表明血小板miRNAs在调节原发性肿瘤生长中具有特定作用。从晚期原发性肿瘤中分离的肿瘤细胞的差异表达RNA测序揭示了作为宿主血小板miRNA的功能在肿瘤细胞中调节的广泛的mRNA群组。改变的基因包括548个上调的转录本和43个下调的转录本，大部分mRNA共同跨越各种生长信号通路，特别是与上皮间质转化相关的通路，与对照小鼠相比，在血小板miRNA缺失小鼠的肿瘤细胞中。血小板miRNA缺失小鼠的肿瘤表现出更多的肉瘤样生长和更晚期的肿瘤分级，表明宿主血小板miRNA在肿瘤可塑性中的作用。我们进一步验证了由于宿主动物中血小板miRNA耗竭而导致的与肿瘤中同源mRNA增加相关的选定基因的蛋白质表达增加，从而提供了血小板miRNA对体内原发性肿瘤中肿瘤细胞功能基因表达的广泛影响的原理证据。总之，这些数据表明，血小板衍生的miRNA通过肿瘤细胞转录组的广谱重组来调节体内实体瘤生长。
We investigated the contributions of platelet microRNAs (miRNAs) to the rate of growth and regulation of gene expression in primary ectopic tumors using mouse models. We previously identified an inhibitory role for platelets in solid tumor growth, mediated by tumor infiltration of platelet microvesicles (microparticles) which are enriched in platelet-derived miRNAs. To investigate the specific roles of platelet miRNAs in tumor growth models, we implanted pancreatic ductal adenocarcinoma cells as a bolus into mice with megakaryocyte-/platelet-specific depletion of mature miRNAs. We observed an ~50% increase in the rate of growth of ectopic primary tumors in these mice compared to controls including at early stages, associated with reduced apoptosis in the tumors, in particular in tumor cells associated with platelet microvesicles—which were depleted of platelet-enriched miRNAs—demonstrating a specific role for platelet miRNAs in modulation of primary tumor growth. Differential expression RNA sequencing of tumor cells isolated from advanced primary tumors revealed a broad cohort of mRNAs modulated in the tumor cells as a function of host platelet miRNAs. Altered genes comprised 548 up-regulated transcripts and 43 down-regulated transcripts, mostly mRNAs altogether spanning a variety of growth signaling pathways–notably pathways related to epithelial-mesenchymal transition—in tumor cells from platelet miRNA-deleted mice compared with those from control mice. Tumors in platelet miRNA-depleted mice showed more sarcomatoid growth and more advanced tumor grade, indicating roles for host platelet miRNAs in tumor plasticity. We further validated increased protein expression of selected genes associated with increased cognate mRNAs in the tumors due to platelet miRNA depletion in the host animals, providing proof of principle of widespread effects of platelet miRNAs on tumor cell functional gene expression in primary tumors in vivo. Together, these data demonstrate that platelet-derived miRNAs modulate solid tumor growth in vivo by broad-spectrum restructuring of the tumor cell transcriptome.
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影响因子：
--
作者：
Bobrov E;Skobeleva N;Restifo D;Beglyarova N;Cai KQ;Handorf E;Campbell K;Proia DA;Khazak V;Golemis EA;Astsaturov I
通讯作者：
Astsaturov I
DOI：
10.1073/pnas.61.1.46
发表时间：
1968-01-01
影响因子：
11.1
作者：
GASIC, GJ;GASIC, TB;STEWART, CC
通讯作者：
STEWART, CC
影响因子：
3.7
作者：
Mironova N;Patutina O;Brenner E;Kurilshikov A;Vlassov V;Zenkova M
通讯作者：
Zenkova M
DOI：
10.4137/cmo.s18991
发表时间：
2014
期刊：
Clinical Medicine Insights. Oncology
影响因子：
--
作者：
Elyamany G;Alzahrani AM;Bukhary E
通讯作者：
Bukhary E
影响因子：
7.5
作者：
Bucciarelli, Paolo;Martinelli, Ida;Mannucci, Pier Mannuccio
通讯作者：
Mannucci, Pier Mannuccio