Abstract：
As the second most prevalent malignant tumor of head and neck, laryngeal squamous cell carcinoma (LSCC) imposes a substantial health burden on patients worldwide. Within recent years, resistance to oxidative stress and N6-methyladenosine (m6A) of RNA have been proved to be significantly involved in tumorigenesis. In current study, we investigated the oncogenic role of m6A modified long non coding RNAs (lncRNAs), specifically HOXA10-AS, and its downstream signaling pathway in the regulation of oxidative resistance in LSCC. Bioinformatics analysis revealed that heightened expression of HOXA10-AS was associated with the poor prognosis in LSCC patients, and N (6)-Methyladenosine (m6A) methyltransferase-like 3 (METTL3) was identified as a factor in promoting m6A modification of HOXA10-AS and further intensify its RNA stability. Mechanistically, HOXA10-AS was found to play as a competitive endogenous RNA (ceRNA) by sequestering miR-29 b-3p and preventing its downregulation of Integrin subunit alpha 6 (ITGA6), ultimately enhancing the oxidative resistance of tumor cells and promoting the malignant progression of LSCC. Furthermore, our research elucidated the mechanism by which ITGA6 accelerates Keap1 proteasomal degradation via enhancing TRIM25 expression, leading to increased Nrf2 stability and exacerbating its aberrant activation. Additionally, we demonstrated that ITGA6 enhances γ-secretase-mediated Notch signaling activation, ultimately promoting RBPJ-induced TRIM25 transcription. The current study provides the evidence supporting the effect of m6A modified HOXA10-AS and its downstream miR-29 b-3p/ITGA6 axis on regulating oxidative resistance and malignant progression in LSCC through the Notch and Keap1/Nrf2 pathways, and proposed that targeting this axis holds promise as a potential therapeutic approach for treating LSCC.
摘要：
作为头颈部第二大恶性肿瘤,喉鳞状细胞癌（LSCC）给全球患者带来了巨大的健康负担。近年来,已证明RNA对氧化应激和N6-甲基腺苷（m6A）的抗性与肿瘤发生显着相关。在目前的研究中,我们研究了m6A修饰的长链非编码RNA（lncRNAs）的致癌作用，特别是HOXA10-AS，及其下游信号通路在LSCC氧化抵抗调节中的作用。生物信息学分析显示，HOXA10-AS的高表达与LSCC患者的不良预后有关。和N（6）-甲基腺苷（m6A）甲基转移酶样3（METTL3）被鉴定为促进HOXA10-AS的m6A修饰并进一步增强其RNA稳定性的因子。机械上,发现HOXA10-AS通过螯合miR-29b-3p并阻止其下调整合素亚基α6（ITGA6）而发挥竞争性内源性RNA（ceRNA）的作用，最终增强肿瘤细胞的氧化抵抗并促进LSCC的恶性进展。此外，我们的研究阐明了ITGA6通过增强TRIM25表达加速Keap1蛋白酶体降解的机制，导致Nrf2稳定性增加并加剧其异常激活。此外,我们证明ITGA6增强γ-分泌酶介导的Notch信号激活，最终促进RBPJ诱导的TRIM25转录。目前的研究提供了证据支持m6A修饰的HOXA10-AS及其下游miR-29b-3p/ITGA6轴通过Notch和Keap1/Nrf2途径调节LSCC的氧化抵抗和恶性进展的作用。并提出靶向该轴有望成为治疗LSCC的潜在治疗方法。
