Dysregulated inclusion of BOLA3 exon 3 promoted by HNRNPC accelerates the progression of esophageal squamous cell carcinoma.

IF 3.9 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL
Bo Tian, Yan Bian, Yanan Pang, Ye Gao, Chuting Yu, Xun Zhang, Siwei Zhou, Zhaoshen Li, Lei Xin, Han Lin, Luowei Wang
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引用次数: 0

Abstract

Dysregulated RNA splicing events produce transcripts that facilitate esophageal squamous cell carcinoma (ESCC) progression, but how this splicing process is abnormally regulated remains elusive. Here, we unveiled a novel alternative splicing axis of BOLA3 transcripts and its regulator HNRNPC in ESCC. The long-form BOLA3 (BOLA3-L) containing exon 3 exhibited high expression levels in ESCC and was associated with poor prognosis. Functional assays demonstrated the protumorigenic function of BOLA3-L in ESCC cells. Additionally, HNRNPC bound to BOLA3 mRNA and promoted BOLA3 exon 3 inclusion forming BOLA3-L. High HNRNPC expression was positively correlated with the presence of BOLA3-L and associated with an unfavorable prognosis. HNRNPC knockdown effectively suppressed the malignant biological behavior of ESCC cells, which were significantly rescued by BOLA3-L overexpression. Moreover, BOLA3-L played a significant role in mitochondrial structural and functional stability. E2F7 acted as a key transcription factor that promoted the upregulation of HNRNPC and inclusion of BOLA3 exon 3. Our findings provided novel insights into how alternative splicing contributes to ESCC progression.

由 HNRNPC 促进的 BOLA3 第 3 外显子的异常包含加速了食管鳞状细胞癌的进展。
失调的 RNA 剪接事件产生的转录本会促进食管鳞状细胞癌(ESCC)的进展,但这种剪接过程是如何被异常调控的仍然令人费解。在这里,我们揭示了 ESCC 中 BOLA3 转录本及其调控因子 HNRNPC 的新型替代剪接轴。含有第 3 号外显子的长形 BOLA3(BOLA3-L)在 ESCC 中表现出较高的表达水平,并与不良预后相关。功能测试证明了 BOLA3-L 在 ESCC 细胞中的致癌功能。此外,HNRNPC 与 BOLA3 mRNA 结合,并促进 BOLA3 第 3 外显子包涵形成 BOLA3-L。HNRNPC的高表达与BOLA3-L的存在呈正相关,并与预后不良有关。敲除 HNRNPC 能有效抑制 ESCC 细胞的恶性生物学行为,而 BOLA3-L 的过表达则能明显缓解这种行为。此外,BOLA3-L在线粒体结构和功能稳定性方面发挥着重要作用。E2F7 是促进 HNRNPC 上调和 BOLA3 第 3 外显子包含的关键转录因子。我们的研究结果为了解替代剪接如何促进 ESCC 的进展提供了新的视角。
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来源期刊
Frontiers of Medicine
Frontiers of Medicine ONCOLOGYMEDICINE, RESEARCH & EXPERIMENTAL&-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
18.30
自引率
0.00%
发文量
800
期刊介绍: Frontiers of Medicine is an international general medical journal sponsored by the Ministry of Education of China. The journal is jointly published by the Higher Education Press and Springer. Since the first issue of 2010, this journal has been indexed in PubMed/MEDLINE. Frontiers of Medicine is dedicated to publishing original research and review articles on the latest advances in clinical and basic medicine with a focus on epidemiology, traditional Chinese medicine, translational research, healthcare, public health and health policies.
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