Long noncoding RNA DGCR5 involves in tumorigenesis of esophageal squamous cell carcinoma via SRSF1-mediated alternative splicing of Mcl-1.
Long noncoding RNA DGCR5 involves in tumorigenesis of esophageal squamous cell carcinoma via SRSF1-mediated alternative splicing of Mcl-1.
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长链非编码RNA DGCR5通过SRSF1介导的Mcl-1选择性剪接参与食管鳞状细胞癌的肿瘤发生
DOI：
10.1038/s41419-021-03858-7
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发表时间：
2021-06-07
影响因子：
9
通讯作者：
Liu L
中科院分区：
文献类型：
--
作者：
Duan Y;Jia Y;Wang J;Liu T;Cheng Z;Sang M;Lv W;Qin J;Liu L
长非编码RNA(LncRNAs)在多种恶性肿瘤的选择性剪接(AS)调控中发挥重要作用。富含丝氨酸和精氨酸的剪接因子1(SRSF1)介导的AS事件是癌症中最重要的分子标志。然而，与SRSF1相关的lncRNAs在食管鳞癌(ESCC)中发生的生物学机制仍不清楚。在本研究中，我们发现LncRNA DiGeorge综合征临界区基因5(DGCR5)在ESCC临床标本中表达上调，这与预后不良有关。通过RNA干扰和过表达的方法，我们证实了DGCR5在体外有助于促进ESCC细胞的增殖、迁移和侵袭，而抑制细胞凋亡。在机制上，DGCR5可以直接与SRSF1结合，增加其稳定性，从而刺激选择性剪接事件。此外，我们阐明了SRSF1调控髓系细胞白血病-1(Mcl-1)的异常剪接，并启动了显著的Mcl-1L(抗凋亡)异构体开关，这有助于Mcl-1全长的表达。此外，细胞衍生异种移植(CDX)模型验证了DGCR5可促进ESCC的体内成瘤。总之，我们的发现确认了lncRNA DGCR5在选择性剪接调控中的关键生物学作用，并强调DGCR5是ESCC潜在的生物标记物和治疗靶点。
Long noncoding RNAs (lncRNAs) emerge as essential roles in the regulation of alternative splicing (AS) in various malignancies. Serine- and arginine-rich splicing factor 1 (SRSF1)-mediated AS events are the most important molecular hallmarks in cancer. Nevertheless, the biological mechanism underlying tumorigenesis of lncRNAs correlated with SRSF1 in esophageal squamous cell carcinoma (ESCC) remains elusive. In this study, we found that lncRNA DiGeorge syndrome critical region gene 5 (DGCR5) was upregulated in ESCC clinical samples, which associated with poor prognosis. Through RNA interference and overexpression approaches, we confirmed that DGCR5 contributed to promote ESCC cell proliferation, migration, and invasion while inhibited apoptosis in vitro. Mechanistically, DGCR5 could directly bind with SRSF1 to increase its stability and thus stimulate alternative splicing events. Furthermore, we clarified that SRSF1 regulated the aberrant splicing of myeloid cell leukemia-1 (Mcl-1) and initiated a significant Mcl-1L (antiapoptotic) isoform switch, which contributed to the expression of the full length of Mcl-1. Moreover, the cell-derived xenograft (CDX) model was validated that DGCR5 could facilitate the tumorigenesis of ESCC in vivo. Collectively, our findings identified that the key biological role of lncRNA DGCR5 in alternative splicing regulation and emphasized DGCR5 as a potential biomarker and therapeutic target for ESCC.
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DOI：
10.1016/j.bpg.2015.09.010
发表时间：
2015-12-01
影响因子：
3.2
作者：
Chung, Chen-Shuan;Lee, Yi-Chia;Wu, Ming-Shiang
通讯作者：
Wu, Ming-Shiang
影响因子：
9.7
作者：
Liu, Jia;Mayekar, Manasi K.;Cao, Wei
通讯作者：
Cao, Wei
影响因子：
3.8
作者：
Liu H;Yang J;Yuan Y;Xia Z;Chen M;Xie L;Ma X;Wang J;Ouyang S;Wu Q;Yu F;Zhou X;Yang Y;Cao Y;Hu J;Yin B
通讯作者：
Yin B
影响因子：
3.7
作者：
Gautrey HL;Tyson-Capper AJ
通讯作者：
Tyson-Capper AJ
影响因子：
7.2
作者：
McIlwain, David R.;Berger, Thorsten;Mak, Tak W.
通讯作者：
Mak, Tak W.