Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing 100069, China.
Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
Biochim Biophys Acta Mol Cell Res. 2024 Dec;1871(8):119841. doi: 10.1016/j.bbamcr.2024.119841. Epub 2024 Aug 31.
Abnormal alternative splicing (AS) caused by dysregulated expression of splicing factors plays a crucial role in tumorigenesis and progression. The serine/arginine-rich (SR) RNA-binding protein family is a major class of splicing factors regulating AS. However, their roles and mechanisms in renal cell carcinoma (RCC) development and progression are not fully understood. Here, we found that SR splicing factor 3 (SRSF3) was an important splicing factor affecting RCC progression. SRSF3 was downregulated in RCC tissues and its low level was associated with decreased overall survival time of RCC patients. SRSF3 overexpression suppressed RCC cell malignancy. Mechanistically, the binding of SRSF3 to SP4 exon 3 led to the inclusion of SP4 exon 3 and the increase of long SP4 isoform (L-SP4) level in RCC cells. L-SP4, but not S-SP4 overexpression suppressed RCC cell malignancy. Meanwhile, L-SP4 participated in SRSF3-mediated anti-proliferation by transcriptionally promoting SMAD4 expression. Taken together, our findings provide new insights into the anticancer mechanism of SRSF3, suggesting that SRSF3 may serve as a novel potential therapeutic target for RCC.
异常的选择性剪接（AS）是由剪接因子表达失调引起的，在肿瘤发生和进展中起着关键作用。丝氨酸/精氨酸丰富（SR）RNA 结合蛋白家族是调节 AS 的主要剪接因子类群。然而，它们在肾细胞癌（RCC）发展和进展中的作用和机制尚不完全清楚。在这里，我们发现 SR 剪接因子 3（SRSF3）是一个影响 RCC 进展的重要剪接因子。SRSF3 在 RCC 组织中下调，其低水平与 RCC 患者总生存时间缩短有关。SRSF3 的过表达抑制了 RCC 细胞的恶性表型。在机制上，SRSF3 与 SP4 外显子 3 的结合导致 SP4 外显子 3 的包含和 RCC 细胞中长 SP4 异构体（L-SP4）水平的增加。L-SP4，而不是 S-SP4 的过表达抑制了 RCC 细胞的恶性表型。同时，L-SP4 通过转录促进 SMAD4 表达参与 SRSF3 介导的抗增殖作用。总之，我们的研究结果为 SRSF3 的抗癌机制提供了新的见解，表明 SRSF3 可能成为 RCC 的一个新的潜在治疗靶点。
