LAMA4-Regulating miR-4274 and Its Host Gene SORCS2 Play a Role in IGFBP6-Dependent Effects on Phenotype of Basal-Like Breast Cancer
LAMA4-Regulating miR-4274 and Its Host Gene SORCS2 Play a Role in IGFBP6-Dependent Effects on Phenotype of Basal-Like Breast Cancer
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DOI：
10.3389/fmolb.2019.00122
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发表时间：
2019-11-08
影响因子：
5
通讯作者：
Tonevitsky, Alexander
中科院分区：
文献类型：
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作者：
Shkurnikov, Maxim;Nikulin, Sergey;Tonevitsky, Alexander
RNAi对所选靶标的特异性受到脱靶效应（典型和非典型）的挑战。值得注意的是，超过一半的人类microRNA与宿主蛋白质编码基因共表达。在这里，我们剖析了以IGFBP 6基因为中心的调控子网络，该基因与基底细胞样乳腺癌的低增殖状态和高迁移活性相关。我们在基底样乳腺癌MDA-MB-231的模型细胞系中抑制IGFBP 6基因的表达，然后追踪这种敲除对LAMA 4的二级和三级效应，LAMA 4是一种层粘连蛋白编码基因，有助于三阴性乳腺癌的表型。LAMA 4调节miRNA miR-4274及其宿主基因SORCS 2被强调为LAMA 4表达水平的中间调节因子，其在TCGA的基底样乳腺癌样本子集中与SORCS 2水平负相关。总的来说，我们的研究指出，第二层和第三层的监管互动肯定是低估。由于这些类型的分子事件可能显著有助于基于RNA干扰的敲低后细胞表型的形成，因此有必要进一步研究受RNAi影响的多层分子网络。
Specificity of RNAi to selected target is challenged by off-target effects, both canonical and non-canonical. Notably, more than half of all human microRNAs are co-expressed with hosting them proteincoding genes. Here we dissect regulatory subnetwork centered on IGFBP6 gene, which is associated with low proliferative state and high migratory activity of basal-like breast cancer. We inhibited expression of IGFBP6 gene in a model cell line for basal-like breast carcinoma MDA-MB-231, then traced secondary and tertiary effects of this knockdown to LAMA4, a laminin encoding gene that contributes to the phenotype of triple-negative breast cancer. LAMA4-regulating miRNA miR-4274 and its host gene SORCS2 were highlighted as intermediate regulators of the expression levels of LAMA4, which correlated in a basal-like breast carcinoma sample subset of TCGA to the levels of SORCS2 negatively. Overall, our study points that the secondary and tertiary layers of regulatory interactions are certainly underappreciated. As these types of molecular event may significantly contribute to the formation of the cell phenotypes after RNA interference based knockdowns, further studies of multilayered molecular networks affected by RNAi are warranted.