Table_1_Oncogenic Role of miR-217 During Clear Cell Renal Carcinoma Progression.xlsx

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 vice versa) 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（Clear cell renal carcinoma, ccRC）是一类异质性显著、进展迅猛且预后不良的疾病。从分子层面的修饰改变角度分析ccRC的进展过程，有助于深化对该疾病的认知，为优化诊断与治疗策略奠定基础。微小RNA（micro-RNAs, miRs）可通过靶向癌基因与抑癌基因参与癌症进程，这一作用已得到广泛认可。尽管已有此类认知，但特定miRs及其靶基因在ccRC进展中的具体作用仍未明确。为探究miRs及其靶基因在ccRC进展过程中的作用，本研究构建了适用于ccRC各进展阶段及癌旁正常肾组织（adjacent-normal renal tissue, NT）的miR-基因共表达网络，具体分为三步：第一步，我们分别推导了ccRC各进展阶段及癌旁正常肾组织中的全部miR-基因共表达互作关系；随后，基于相邻进展阶段（如Ⅰ期与非肿瘤组织、Ⅱ期与Ⅰ期等）间的差异基因与miR表达谱，对全基因组miR-基因共表达网络进行筛选；最终，保留表达呈负相关的miR-基因互作对（即miR高表达对应靶基因低表达，反之亦然），剔除不符合该条件的互作对。研究发现，miR-217在所有对比组中均存在差异表达，但其靶基因随ccRC进展阶段的不同而存在差异。此外，miR-217的靶基因已被证实与癌症进展相关：在Ⅱ期共表达网络中，GALNTL6呈高表达，其功能涉及细胞信号转导、细胞存活与增殖；在Ⅲ期网络中，经广泛研究证实的抑癌基因WNK2呈低表达；在Ⅳ期网络中，作为MYC与PTEN转录后调控因子的IGF2BP2呈高表达。本研究采用的数据驱动型网络分析方法，揭示了在ccRC进展过程中靶基因存在差异的miRs，为该疾病及其他癌症的阶段特异性治疗靶点筛选提供了可行策略。