选择性前 mRNA 剪接的失调在癌症的进展中发挥着关键作用，但其潜在的分子机制仍然很大程度上未知。据报道，结肠癌转移相关蛋白 1 (MACC1) 是包括肺腺癌在内的多种癌症的新型预后和预测标记物。在这里，我们揭示了癌基因 MACC1 通过控制癌症相关剪接事件来特异性驱动肺腺癌的进展。 MACC1 耗竭通过触发 IRAK1 从长亚型 IRAK1-L 转变为较短亚型 IRAK1-S 来抑制肺腺癌进展。从机制上讲，MACC1 与剪接因子 HNRNPH1 相互作用，以阻止 IRAK1 mRNA 短亚型的产生。具体来说，MACC1和HNRNPH1之间的相互作用依赖于MACC1的SH3结构域和HNRNPH1的GYR结构域的参与。此外，HNRNPH1可以与IRAK1的前mRNA片段（包括外显子11）相互作用，从而桥接MACC1对IRAK1剪接的调节。我们的研究不仅揭示了癌症中的异常剪接调节，还揭示了 MACC1 在肿瘤进展中迄今为止未知的功能，从而为临床治疗提供了一个新的潜在治疗靶点。© 2024 Wiley periodicals LLC。

Dysregulation of alternative pre-mRNA splicing plays a critical role in the progression of cancers, yet the underlying molecular mechanisms remain largely unknown. It is reported that metastasis-associated in colon cancer 1 (MACC1) is a novel prognostic and predictive marker in many types of cancers, including lung adenocarcinoma. Here, we reveal that the oncogene MACC1 specifically drives the progression of lung adenocarcinoma through its control over cancer-related splicing events. MACC1 depletion inhibits lung adenocarcinoma progression through triggering IRAK1 from its long isoform, IRAK1-L, to the shorter isoform, IRAK1-S. Mechanistically, MACC1 interacts with splicing factor HNRNPH1 to prevent the production of the short isoform of IRAK1 mRNA. Specifically, the interaction between MACC1 and HNRNPH1 relies on the involvement of MACC1's SH3 domain and HNRNPH1's GYR domain. Further, HNRNPH1 can interact with the pre-mRNA segment (comprising exon 11) of IRAK1, thereby bridging MACC1's regulation of IRAK1 splicing. Our research not only sheds light on the abnormal splicing regulation in cancer but also uncovers a hitherto unknown function of MACC1 in tumor progression, thereby presenting a novel potential therapeutic target for clinical treatment.© 2024 Wiley Periodicals LLC.