Small Protein Hidden in lncRNA LOC90024 Promotes "Cancerous" RNA Splicing and Tumorigenesis
Small Protein Hidden in lncRNA LOC90024 Promotes "Cancerous" RNA Splicing and Tumorigenesis
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隐藏在lncRNA LOC90024中的小蛋白促进“癌性”RNA剪接和肿瘤发生
DOI：
10.1002/advs.201903233
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发表时间：
2020-05-01
期刊：
影响因子：
15.1
通讯作者：
Yan, Guang-Rong
中科院分区：
文献类型：
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作者：
Meng, Nan;Chen, Min;Yan, Guang-Rong
晚期结直肠癌（CRC）的常规治疗由于化疗耐药性、复发和转移而效果有限。由长链非编码RNA（lncRNA）编码的“隐藏”蛋白质/肽可能是癌症患者治疗选择的新型资源库。在此，发现lncRNA LOC 90024编码一个小的130个氨基酸的蛋白质，该蛋白质与几种剪接调节因子相互作用，如富含丝氨酸和丝氨酸的剪接因子3（SRSF 3），以调节mRNA剪接，因此该蛋白质被命名为“剪接调节小蛋白”（SRSP）。SRSP而不是L0 C90024 lncRNA本身促进CRC肿瘤发生和进展，而SRSP的沉默抑制CRC肿瘤发生。从机制上讲，SRSP增加了SRSF 3与转录因子Sp 4外显子3的结合，导致包含Sp 4外显子3以诱导“癌性”长Sp 4同种型（L-Sp 4蛋白）的形成并抑制“非癌性”短Sp 4同种型（S-Sp 4肽）的形成，其缺乏反式激活结构域。SRSP水平的上调与结直肠癌患者的恶性表型和不良预后呈正相关。总的来说，这些发现揭示了lncRNA编码的小蛋白SRSP诱导“癌性”Sp 4剪接变体形成，可能是CRC患者的潜在预后生物标志物和治疗靶点。
Conventional therapies for late-stage colorectal cancer (CRC) have limited effects because of chemoresistance, recurrence, and metastasis. The "hidden" proteins/peptides encoded by long noncoding RNAs (lncRNAs) may be a novel resource bank for therapeutic options for patients with cancer. Here, lncRNA LOC90024 is discovered to encode a small 130-amino acid protein that interacts with several splicing regulators, such as serine- and arginine-rich splicing factor 3 (SRSF3), to regulate mRNA splicing, and the protein thus is named "Splicing Regulatory Small Protein" (SRSP). SRSP, but not LOC90024 lncRNA itself, promotes CRC tumorigenesis and progression, while silencing of SRSP suppresses CRC tumorigenesis. Mechanistically, SRSP increases the binding of SRSF3 to exon 3 of transcription factor Sp4, resulting in the inclusion of Sp4 exon 3 to induce the formation of the "cancerous" long Sp4 isoform (L-Sp4 protein) and inhibit the formation of the "noncancerous" short Sp4 isoform (S-Sp4 peptide), which lacks the transactivation domain. The upregulated SRSP level is positively associated with malignant phenotypes and poor prognosis in patients with CRC. Collectively, the findings uncover that a lncRNA-encoded small protein SRSP induces "cancerous" Sp4 splicing variant formation and may be a potential prognostic biomarker and therapeutic target for patients with CRC.