Zamora-Fuentes Jose María, Hernández-Lemus Enrique, Espinal-Enríquez Jesús
Computational Genomics Division, National Institute of Genomic Medicine, Mexico City, Mexico.
Centro de Ciencias de la Complejidad, Universidad Nacional Autόnoma de México, Mexico City, Mexico.
Front Oncol. 2022 Jul 22;12:934711. doi: 10.3389/fonc.2022.934711. eCollection 2022.
Clear cell renal carcinoma (ccRC) comprises a set of heterogeneous, fast-progressing pathologies with poor prognosis. Analyzing ccRC progression in terms of modifications at the molecular level may provide us with a broader understanding of the disease, paving the way for improved diagnostics and therapeutics. The role of micro-RNAs (miRs) in cancer by targeting both oncogenes and tumor suppressor genes is widely known. Despite this knowledge, the role of specific miRs and their targets in the progression of ccRC is still unknown. To evaluate the action of miRs and their target genes during ccRC progression, here we implemented a three-step method for constructing miR-gene co-expression networks for each progression stage of ccRC as well as for adjacent-normal renal tissue (NT). In the first step, we inferred all miR-gene co-expression interactions for each progression stage of ccRC and for NT. Afterwards, we filtered the whole miR-gene networks by differential gene and miR expression between successive stages: stage I with non-tumor, stage II with stage I, and so on. Finally, all miR-gene interactions whose relationships were inversely proportional (overexpressed miR and underexpressed genes and ) were kept and removed otherwise. We found that miR-217 is differentially expressed in all contrasts; however, its targets were different depending on the ccRC stage. Furthermore, the target genes of miR-217 have a known role in cancer progression-for instance, in stage II network, GALNTL6 is overexpressed, and it is related to cell signaling, survival, and proliferation. In the stage III network, WNK2, a widely known tumor suppressor, is underexpressed. For the stage IV network, IGF2BP2, a post-transcriptional regulator of MYC and PTEN, is overexpressed. This data-driven network approach has allowed us to discover miRs that have different targets through ccRC progression, thus providing a method for searching possible stage-dependent therapeutic targets in this and other types of cancer.
透明细胞肾细胞癌（ccRC）由一组异质性、进展迅速且预后不良的病理类型组成。从分子水平的修饰角度分析ccRC的进展，可能会让我们对该疾病有更广泛的了解，为改进诊断和治疗方法铺平道路。微小RNA（miR）通过靶向癌基因和肿瘤抑制基因在癌症中发挥的作用已广为人知。尽管如此，特定miR及其靶标在ccRC进展中的作用仍不清楚。为了评估miR及其靶基因在ccRC进展过程中的作用，我们在此实施了一种三步法，为ccRC的每个进展阶段以及相邻正常肾组织（NT）构建miR-基因共表达网络。第一步，我们推断出ccRC每个进展阶段以及NT的所有miR-基因共表达相互作用。之后，我们通过连续阶段之间的差异基因和miR表达对整个miR-基因网络进行筛选：I期与非肿瘤组织、II期与I期等等。最后，保留所有关系呈反比的miR-基因相互作用（miR过表达而基因低表达以及反之亦然），否则予以去除。我们发现miR-217在所有对比中均有差异表达；然而，其靶标因ccRC阶段而异。此外，miR-217的靶基因在癌症进展中具有已知作用——例如，在II期网络中，GALNTL6过表达，它与细胞信号传导、存活和增殖有关。在III期网络中，广为人知的肿瘤抑制基因WNK2低表达。在IV期网络中，IGF2BP2（MYC和PTEN的转录后调节因子）过表达。这种数据驱动的网络方法使我们能够发现随着ccRC进展具有不同靶标的miR，从而为在这种及其他类型癌症中寻找可能的阶段依赖性治疗靶标提供了一种方法。
