缺氧微环境代表实体瘤包括结直肠癌(CRC)的标志,并促进血管生成和化疗耐药,导致预后不良。lncRNANORAD充当致癌基因,通过调节细胞增殖和迁移来协调癌症进展。值得注意的是,一项新的研究证实了胰腺癌缺氧期间NORAD的升高.然而,其在缺氧诱发CRC中的生物学作用尚不清楚.在这里,在CRC组织中证实了NORAD和缺氧诱导因子-1α(HIF-1α)的表达增强。此外,在CRC组织中,NORAD与HIF-1α呈正相关。暴露于缺氧的CRC细胞表现出更强的形成血管生成拟态(VM)的能力和对5-氟尿嘧啶(5-FU)的抗性,伴随着NORAD的较高表达。NORAD敲除抑制缺氧诱导的VM形成和VM标记物VE-cadherin的表达。此外,NORAD敲低通过降低细胞活力和增加细胞凋亡来抵消CRC细胞对5-FU的抗性。此外,NORAD损失通过增加E-cadherin和抑制N-cadherin表达来减少缺氧诱导的HIF-1α表达和随后的上皮-间质转化(EMT)。有趣的是,HIF-1α过表达逆转了NORAD下调介导的VM形成抑制和5-FU抗性。miR-495-3p在CRC组织中低表达。此外,NORAD可以作为miR-495-3p的竞争性内源性RNA调节HIF-1α。重要的是,抑制miR-495-3p减弱了NORAD在缺氧诱导的EMT中的功效,VM,和化学抗性。因此,目前的数据表明,NORAD敲低可能通过抑制VM形成和化学抗性来拮抗缺氧触发的CRC恶性肿瘤,通过形成miR-495-3p/HIF-1α来调节EMT,支持CRC难治性缺氧的有希望的治疗目标。
Hypoxic microenvironment represents the hallmark of solid tumors including colorectal cancer (CRC) and facilitates angiogenesis and chemoresistance, leading to poor prognosis. lncRNA NORAD acts as an oncogenic gene to orchestrate cancer progression by regulating cell proliferation and migration. Notably, an emerging study corroborates the elevation of NORAD during hypoxic conditions in pancreatic cancer. Nevertheless, its biological role in hypoxia-evoked CRC remains unclear. Herein, enhanced expression of NORAD and hypoxia-inducible factor-1α (HIF-1α) was validated in CRC tissues. Furthermore, there was a positive association between NORAD and HIF-1α in CRC tissues. CRC cells exposed to hypoxia exhibited a stronger ability to form vasculogenic mimicry (
VM) and resistance to 5-fluorouracil (5-FU), concomitant with higher expression of NORAD. NORAD knockdown restrained hypoxia-induced
VM formation and
VM marker VE-cadherin expression. Moreover, knockdown of NORAD counteracted CRC cell resistance to 5-FU by decreasing cell viability and increasing cell apoptosis. Additionally, NORAD loss reduced hypoxia-induced HIF-1α expression and subsequent epithelial-mesenchymal transition (EMT) by increasing E-cadherin and inhibiting N-cadherin expression. Intriguingly, HIF-1α overexpression reversed NORAD downregulation-mediated inhibition of
VM formation and 5-FU resistance. There was a low expression of miR-495-3p in CRC tissues. Furthermore, NORAD could act as a competitive endogenous RNA of miR-495-3p to regulate HIF-1α. Importantly, inhibition of miR-495-3p muted the efficacy of NORAD loss in hypoxia-induced EMT,
VM, and chemoresistance. Thus, the current data highlight that NORAD knockdown may antagonize hypoxia-triggered CRC malignancy by suppressing
VM formation and chemoresistance by sponging miR-495-3p/HIF-1α to regulate EMT, supporting a promising therapeutic target for refractory hypoxia in CRC.