State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430072, China.
Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wuhan University, Wuhan 430072, China.
Biomolecules. 2023 Aug 30;13(9):1331. doi: 10.3390/biom13091331.
FOXM1 is an oncogenic transcriptional factor and includes several isoforms generated by alternative splicing. Inclusion of alternative exon 9 produces FOXM1a, a transcriptionally inactive isoform. However, the role of FOXM1a in tumorigenesis remains unknown. In addition, the regulatory mechanisms of exon 9 splicing are also unclear. In the present study, we found that overexpression of FOXM1a significantly reduced cell proliferation and colony formation of oral squamous cell carcinoma (OSCC) cell proliferation in vitro. Importantly, OSCC cells with FOXM1a overexpression showed significantly slower tumor formation in nude mice. Moreover, we identified a U-rich exonic splicing suppressor (ESS) which is responsible for exon 9 skipping. Splicing factor heterogeneous nuclear ribonucleoprotein C (hnRNP C) can bind to the ESS and suppress exon 9 inclusion and FOXM1a expression. Silence of hnRNP C also significantly suppresses OSCC cell proliferation. HnRNP C is significantly co-expressed with FOXM1 in cancers. Our study uncovered a novel regulatory mechanism of oncogene FOXM1 expression in OSCC.
FOXM1 是一种致癌转录因子，包括几个通过选择性剪接产生的异构体。内含子 9 的选择性剪接产生 FOXM1a，这是一种转录失活的异构体。然而，FOXM1a 在肿瘤发生中的作用尚不清楚。此外，exon 9 剪接的调节机制也不清楚。在本研究中，我们发现 FOXM1a 的过表达显著降低了口腔鳞状细胞癌（OSCC）细胞系体外的增殖和集落形成能力。重要的是，FOXM1a 过表达的 OSCC 细胞在裸鼠中形成肿瘤的速度明显较慢。此外，我们鉴定了一个富含 U 的外显子剪接抑制物（ESS），它负责 exon 9 的跳跃。异质核核糖核蛋白 C（hnRNP C）可以与 ESS 结合，抑制 exon 9 的内含和 FOXM1a 的表达。hnRNP C 的沉默也显著抑制了 OSCC 细胞的增殖。hnRNP C 在癌症中与 FOXM1 显著共表达。我们的研究揭示了 OSCC 中致癌基因 FOXM1 表达的一种新的调节机制。
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