Molecular Pathogenesis of Colorectal Cancer: Impact of Oncogenic Targets Regulated by Tumor Suppressive miR-139-3p.
Molecular Pathogenesis of Colorectal Cancer: Impact of Oncogenic Targets Regulated by Tumor Suppressive miR-139-3p.
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DOI：
10.3390/ijms231911616
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发表时间：
2022-10-01
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
我们最近确定了结直肠癌（CRC）基于RNA测序的microRNA （miRNA）表达特征。对该特征的分析表明，在结直肠癌组织中，pre-miR-139的两条链（miR-139-5p，引导链和miR-139-3p，乘客链）的表达均显著降低。瞬时转染实验显示，miR-139-3p的表达阻断了癌细胞的恶性转化（如细胞增殖、迁移和侵袭）。值得注意的是，miR-139-3p的表达明显阻断了结直肠癌细胞中rac - α丝氨酸/苏氨酸蛋白激酶（AKT）的磷酸化。通过对转染miR-139-3p的细胞进行计算机数据库和基因表达分析，揭示了CRC细胞中29个可能受miR-139-3p调控的靶点。使用Argonaute2 （AGO2）抗体的RNA免疫沉淀分析显示，KRT80有效地结合到RNA诱导的沉默复合物中。免疫染色法检测CRC临床标本中角蛋白80 （Keratin 80, KRT80）的异常表达。利用靶向KRT80的小干扰RNA （siRNA）敲低实验表明，降低KRT80的表达可抑制CRC细胞的恶性转化（癌细胞迁移和侵袭）。重要的是，抑制KRT80的表达减少了CRC细胞中AKT的磷酸化。此外，在转染KRT80 sirna或miR-139-3p的细胞中，己糖激酶-2 （HK2）的表达降低。miRNA乘客链（如miR-139-3p）参与CRC细胞是miRNA研究中的一个新概念。我们基于肿瘤抑制mirna的方法有助于阐明结直肠癌的分子发病机制。
We recently determined the RNA sequencing-based microRNA (miRNA) expression signature of colorectal cancer (CRC). Analysis of the signature showed that the expression of both strands of pre-miR-139 (miR-139-5p, the guide strand, and miR-139-3p, the passenger strand) was significantly reduced in CRC tissues. Transient transfection assays revealed that expression of miR-139-3p blocked cancer cell malignant transformation (e.g., cell proliferation, migration, and invasion). Notably, expression of miR-139-3p markedly blocked RAC-alpha serine/threonine-protein kinase (AKT) phosphorylation in CRC cells. A combination of in silico database and gene expression analyses of miR-139-3p-transfected cells revealed 29 putative targets regulated by miR-139-3p in CRC cells. RNA immunoprecipitation analysis using an Argonaute2 (AGO2) antibody revealed that KRT80 was efficiently incorporated into the RNA-induced silencing complex. Aberrant expression of Keratin 80 (KRT80) was detected in CRC clinical specimens by immunostaining. A knockdown assay using small interfering RNA (siRNA) targeting KRT80 showed that reducing KRT80 expression suppressed the malignant transformation (cancer cell migration and invasion) of CRC cells. Importantly, inhibiting KRT80 expression reduced AKT phosphorylation in CRC cells. Moreover, hexokinase-2 (HK2) expression was reduced in cells transfected with the KRT80 siRNAs or miR-139-3p. The involvement of miRNA passenger strands (e.g., miR-139-3p) in CRC cells is a new concept in miRNA studies. Our tumor-suppressive miRNA-based approach helps elucidate the molecular pathogenesis of CRC.
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DOI：
10.1038/nrc.2017.99
发表时间：
2018-01
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Anastasiadou E;Jacob LS;Slack FJ
通讯作者：
Slack FJ
影响因子：
5.3
作者：
Bhaskar, Prashanth T.;Nogueira, Veronique;Hay, Nissim
通讯作者：
Hay, Nissim
从原发肿瘤的表达变化中识别结直肠癌转移启动 miRNA 靶标调控
影响因子：
4.6
作者：
Lee, Jongmin;Hong, Hye Kyung;Cho, Yong Beom
通讯作者：
Cho, Yong Beom
己二酶I和II的亚细胞定位指导葡萄糖的代谢命运。
影响因子：
3.7
作者：
John S;Weiss JN;Ribalet B
通讯作者：
Ribalet B
影响因子：
5.7
作者：
Desjobert, Cecile;Carrier, Arnaud;Arimondo, Paola B.
通讯作者：
Arimondo, Paola B.