Dai Mingrui, Shi Yuhua, Zhao Hailin, Hu Yue, Cong Xianling, Yu Bin, Zhang Haihong, Yu Xianghui, Wu Hui
National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, 130012, China.
Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, Jilin, 130012, China.
Cell Commun Signal. 2025 Jul 9;23(1):328. doi: 10.1186/s12964-025-02280-2.
Long non-coding RNAs (lncRNAs) play crucial roles in cancer pathogenesis, including colorectal cancer (CRC). Distinct lncRNA transcripts from the same gene show diverse regulatory roles in cancer. The MIR100HG, a lncRNA gene characterized by multiple transcript variants, has been implicated in promoting CRC oncogenesis. However, the specific functions of individual MIR100HG transcripts in tumorigenesis remain unclear.
We explored the MIR100HG transcripts upregulated by TGFβ1 treated in CRC cells using RNA-Seq and characterized a novel transcript in CRC cells and tumor tissues via qRT-PCR. Chromatin immunoprecipitation and luciferase assays revealed this transcript's upstream regulation. Functional experiments were performed in vitro and in mouse models. The molecular mechanism was elucidated through RNA-seq, RNA pull-down, mass spectrometry, RNA immunoprecipitation and co-immunoprecipitation. Finally, we evaluated the transcript's therapeutic potential by treating mouse model tumors with antisense oligonucleotide.
We identified a novel transcript, MIR100HG-L, which retains more portion of exon 1 compared to the previously reported shorter transcript. MIR100HG-L was transcriptionally upregulated by TGFβ/SMAD signaling and exhibited elevated expression in CRC tissues. Functionally, this transcript was demonstrated to promote CRC cell proliferation, suppress apoptosis and enhance drug resistance. Mechanistically, MIR100HG-L specifically interacted with BCLAF1, serving as a protein scaffold to connect BCLAF1 with splicing factors. This interaction significantly induced BCLAF1-mediated splicing events of oncogenes related to apoptosis and DNA damage response, enhancing their expression and contributing to CRC development. MIR100HG-L-targeted antisense therapy reduced tumor growth and increased cetuximab sensitivity.
Our study reveals a novel MIR100HG transcript induced by TGFβ/SMAD signaling and explores its distinct oncogenic mechanism through a structure-specific interaction with the BCLAF1. These findings suggest distinct MIR100HG transcripts may exert diverse functions and lead to the identification of novel molecular markers and therapeutic targets for CRC.
长链非编码RNA（lncRNA）在包括结直肠癌（CRC）在内的癌症发病机制中发挥着关键作用。同一基因产生的不同lncRNA转录本在癌症中表现出不同的调控作用。MIR100HG是一个以多种转录变体为特征的lncRNA基因，已被证明与促进CRC肿瘤发生有关。然而，单个MIR100HG转录本在肿瘤发生中的具体功能仍不清楚。
我们使用RNA测序探索了CRC细胞中经TGFβ1处理后上调的MIR100HG转录本，并通过qRT-PCR在CRC细胞和肿瘤组织中鉴定了一种新的转录本。染色质免疫沉淀和荧光素酶测定揭示了该转录本的上游调控。在体外和小鼠模型中进行了功能实验。通过RNA测序、RNA下拉、质谱、RNA免疫沉淀和共免疫沉淀阐明了分子机制。最后，我们通过用反义寡核苷酸处理小鼠模型肿瘤来评估该转录本的治疗潜力。
我们鉴定了一种新的转录本MIR100HG-L，与先前报道的较短转录本相比，它保留了更多的外显子1部分。MIR100HG-L在转录水平上受TGFβ/SMAD信号上调，并在CRC组织中表达升高。在功能上，该转录本被证明可促进CRC细胞增殖、抑制细胞凋亡并增强耐药性。机制上，MIR100HG-L与BCLAF1特异性相互作用，作为连接BCLAF1和剪接因子的蛋白质支架。这种相互作用显著诱导了BCLAF1介导的与细胞凋亡和DNA损伤反应相关的癌基因的剪接事件，增强了它们的表达并促进了CRC的发展。针对MIR100HG-L的反义疗法可减少肿瘤生长并增加西妥昔单抗的敏感性。
我们的研究揭示了一种由TGFβ/SMAD信号诱导的新的MIR100HG转录本，并通过与BCLAF1的结构特异性相互作用探索了其独特的致癌机制。这些发现表明，不同的MIR100HG转录本可能发挥不同的功能，并有助于鉴定CRC的新分子标志物和治疗靶点。
