SRSF3 通过调节 SP4 选择性剪接抑制 RCC 肿瘤发生和进展。
SRSF3 suppresses RCC tumorigenesis and progression via regulating SP4 alternative splicing.
发表日期：2024 Aug 31
作者：
Liuxu Zhang, Hongning Zhang, Yuangui Tang, Chenyun Dai, Junfang Zheng
来源：
CLINICAL PHARMACOLOGY & THERAPEUTICS
摘要：
由剪接因子表达失调引起的异常选择性剪接（AS）在肿瘤的发生和进展中起着至关重要的作用。富含丝氨酸/精氨酸 (SR) RNA 结合蛋白家族是调节 AS 的一类主要剪接因子。然而，它们在肾细胞癌（RCC）发生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）是影响RCC进展的重要剪接因子。 SRSF3 在 RCC 组织中表达下调，其低水平与 RCC 患者总生存时间缩短相关。 SRSF3 过表达可抑制 RCC 细胞恶性肿瘤。从机制上讲，SRSF3 与 SP4 外显子 3 的结合导致了 SP4 外显子 3 的包含以及 RCC 细胞中长 SP4 亚型 (L-SP4) 水平的增加。 L-SP4（而非 S-SP4）过表达可抑制 RCC 细胞恶性肿瘤。同时，L-SP4通过转录促进SMAD4表达参与SRSF3介导的抗增殖。总而言之，我们的研究结果为 SRSF3 的抗癌机制提供了新的见解，表明 SRSF3 可能作为 RCC 的新的潜在治疗靶点。版权所有 © 2024。由 Elsevier B.V 出版。
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.Copyright © 2024. Published by Elsevier B.V.