SRSF3 通过调节 SP4 的替代剪接抑制 RCC 的肿瘤发生和进展。

IF 4.6 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Biochimica et biophysica acta. Molecular cell research Pub Date : 2024-08-31 DOI:10.1016/j.bbamcr.2024.119841
Liuxu Zhang , Hongning Zhang , Yuangui Tang , Chenyun Dai , Junfang Zheng
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引用次数: 0

摘要

剪接因子表达失调导致的异常替代剪接(AS)在肿瘤发生和发展中起着至关重要的作用。丝氨酸/富精氨酸(SR)RNA结合蛋白家族是调节AS的主要剪接因子。然而,它们在肾细胞癌(RCC)发生和发展中的作用和机制尚未完全清楚。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组织中下调,其低水平与RCC患者总生存时间的缩短有关。SRSF3的过表达抑制了RCC细胞的恶性程度。从机理上讲,SRSF3与SP4第3外显子结合导致SP4第3外显子的包含和RCC细胞中长SP4异构体(L-SP4)水平的增加。L-SP4 而非 S-SP4 的过表达抑制了 RCC 细胞的恶性程度。同时,L-SP4通过转录促进SMAD4的表达,参与SRSF3介导的抗细胞增殖。综上所述,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。
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SRSF3 suppresses RCC tumorigenesis and progression via regulating SP4 alternative splicing

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.

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来源期刊
CiteScore
10.00
自引率
2.00%
发文量
151
审稿时长
44 days
期刊介绍: BBA Molecular Cell Research focuses on understanding the mechanisms of cellular processes at the molecular level. These include aspects of cellular signaling, signal transduction, cell cycle, apoptosis, intracellular trafficking, secretory and endocytic pathways, biogenesis of cell organelles, cytoskeletal structures, cellular interactions, cell/tissue differentiation and cellular enzymology. Also included are studies at the interface between Cell Biology and Biophysics which apply for example novel imaging methods for characterizing cellular processes.
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