Shuai You, Ma Zhonghua, Yue Jian, Li Chunxiao, Ju Jie, Wang Xue, Qian Haili, Yuan Peng
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Endoscopy, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
Int J Biol Sci. 2025 May 27;21(8):3689-3704. doi: 10.7150/ijbs.104483. eCollection 2025.
Long noncoding RNAs (lncRNAs) critically regulate tumorigenesis and chemosensitivity. Despite the pivotal role of lncRNAs in breast cancer (BC), their specific functions and underlying mechanism, particularly in the context of drug resistance, remain largely unexplored. We discovered that MNX1-AS1 is significantly elevated in BC and contributes to paclitaxel resistance through the PI3K/AKT pathway. Moreover, elevated MNX1-AS1 expression exhibits close association with unfavourable prognosis in BC. Mechanistically, MNX1-AS1 interacts with YBX1, preventing its SMURF2-mediated ubiquitination and subsequent degradation, thereby increasing YBX1 protein levels. Upregulated YBX1 transcriptionally activates the expression of ITGA6 by binding to its promoter in the nucleus. Furthermore, MNX1-AS1 binds to IGF2BP2, promoting the stability of ITGA6 mRNA in an m6A-dependent manner within the cytoplasm. MNX1-AS1 increases ITGA6 expression at transcriptional and post-transcriptional levels, thereby activating the PI3K/AKT pathway. Notably, lipid nanoparticles were implicated to effectively deliver MNX1-AS1 siRNA to tumor-bearing mice, resulting in significant antitumor effects. These findings underscore the role of MNX1-AS1 in activating the ITGA6/PI3K/AKT pathway, which facilitates tumor progression and induces chemoresistance in BC. Targeting MNX1-AS1 may represent a promosing therapeutic strategy to enhance chemotherapy efficacy in BC patients.
长链非编码RNA（lncRNAs）对肿瘤发生和化疗敏感性起着关键的调控作用。尽管lncRNAs在乳腺癌（BC）中具有关键作用，但其具体功能和潜在机制，尤其是在耐药背景下，仍 largely未被探索。我们发现MNX1-AS1在BC中显著升高，并通过PI3K/AKT途径导致紫杉醇耐药。此外，MNX1-AS1表达升高与BC患者的不良预后密切相关。机制上，MNX1-AS1与YBX1相互作用，阻止其由SMURF2介导的泛素化及随后的降解，从而增加YBX1蛋白水平。上调的YBX1通过在细胞核中结合ITGA6的启动子转录激活其表达。此外，MNX1-AS1与IGF2BP2结合，以m6A依赖的方式在细胞质中促进ITGA6 mRNA的稳定性。MNX1-AS1在转录和转录后水平增加ITGA6表达，从而激活PI3K/AKT途径。值得注意的是，脂质纳米颗粒被证明可有效地将MNX1-AS1 siRNA递送至荷瘤小鼠体内，产生显著的抗肿瘤作用。这些发现强调了MNX1-AS1在激活ITGA6/PI3K/AKT途径中的作用，该途径促进肿瘤进展并诱导BC中的化疗耐药。靶向MNX1-AS1可能是提高BC患者化疗疗效的一种有前景的治疗策略。
