Abstract

Hypoxia is a common feature of the tumor microenvironment (TME) of nearly all solid tumors, leading to therapeutic failure. The changes in stiffness of the extracellular matrix (ECM), pH gradients, and chemical balance that contribute to multiple cancer hallmarks are closely regulated by intratumoral oxygen tension via its primary mediators, hypoxia-inducible factors (HIFs). HIFs, especially HIF-1α, influence these changes in the TME by regulating vital cancer-associated signaling pathways and cellular processes including MAPK/ERK, NF-κB, STAT3, PI3K/Akt, Wnt, p53, and glycolysis. Interestingly, research has revealed the involvement of epigenetic regulation by hypoxia-regulated microRNAs (HRMs) of downstream target genes involved in these signaling. Through literature search and analysis, we identified 48 HRMs that have a functional role in the regulation of 5 key cellular processes: proliferation, metabolism, survival, invasion and migration, and immunoregulation in various cancers in hypoxic condition. Among these HRMs, 17 were identified to be directly associated with HIFs which include miR-135b, miR-145, miR-155, miR-181a, miR-182, miR-210, miR-224, miR-301a, and miR-675-5p as oncomiRNAs, and miR-100-5p, miR-138, miR-138-5p, miR-153, miR-22, miR-338-3p, miR-519d-3p, and miR-548an as tumor suppressor miRNAs. These HRMs serve as a potential lead in the development of miRNA-based targeted therapy for advanced solid tumors. Future development of combined HIF-targeted and miRNA-targeted therapy is possible, which requires comprehensive profiling of HIFs-HRMs regulatory network, and improved formula of the delivery vehicles to enhance the therapeutic kinetics of the targeted cancer therapy (TCT) moving forward.

摘要

缺氧是几乎所有实体瘤肿瘤微环境 (TME) 的一个共同特征，会导致治疗失败。导致多种癌症标志的细胞外基质 (ECM) 刚度、pH 梯度和化学平衡的变化受到肿瘤内氧张力的密切调节它的主要介质是缺氧诱导因子 (HIF)。HIF，尤其是 HIF-1α，通过调节重要的癌症相关信号通路和细胞过程（包括 MAPK/ERK、NF-κB、STAT3、PI3K/Akt、Wnt、p53 和糖酵解）影响 TME 的这些变化。有趣的是，研究表明参与这些信号传导的下游靶基因的缺氧调节 microRNA (HRM) 参与了表观遗传调控。通过文献检索和分析，我们确定了 48 种 HRM，它们在 5 个关键细胞过程的调节中具有功能性作用：增殖、代谢、存活、侵袭和迁移，以及缺氧条件下各种癌症的免疫调节。在这些 HRM 中，有 17 个被鉴定为与 HIF 直接相关，包括 miR-135b、miR-145、miR-155、miR-181a、miR-182、miR-210、miR-224、miR-301a 和 miR-675-5p 作为致癌 miRNA，以及 miR-100-5p、miR-138、miR-138-5p、miR-153、miR-22、miR-338-3p、miR-519d-3p、和 miR-548an 作为肿瘤抑制 miRNA。这些 HRM 可作为开发基于 miRNA 的晚期实体瘤靶向治疗的潜在先导。HIF 靶向和 miRNA 靶向联合治疗的未来发展是可能的，这需要对 HIFs-HRMs 调控网络进行全面分析，并改进运载工具的配方，以增强靶向癌症治疗 (TCT) 的治疗动力学。