The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
Curr Gene Ther. 2022;22(5):397-405. doi: 10.2174/1566523222666220511162934.
Signal transducer and activator of transcription 3 (STAT3) is an oncogene and frequently overexpressed in cancers. However, the regulatory mechanisms of STAT3 expression are not fully understood. Poly(rC)-binding protein1 (PCBP1) is an RNA-binding protein that regulates mRNA stability, splicing, and translation. PCBP1 is a tumor suppressor and can inhibit the translation of several oncogenic genes.
We aimed to understand the regulatory mechanisms of STAT3 expression.
The 5' UTR or 3' UTR regions of the human STAT3 gene were inserted upstream or downstream of the green fluorescent gene (GFP), respectively, which were used as reporter systems to analyze the inhibitory effects of PCBP1 on the STAT3 gene expression. The deletion and point mutation in 5' UTR were used to search the essential regulatory sequences of the translation inhibition. The mutations of PCBP1 protein were analyzed in the cBioPortal online service. The effects of mutated PCBP1 proteins on STAT3 expression, cancer cell proliferation, and colony formation were analyzed in oral squamous cell carcinoma (OSCC) cell lines.
PCBP1 inhibits mRNA translation through a motif in the 5' UTR of STAT3. Moreover, we found two leucine residues (Leu100 and Leu102) of PCBP1 protein frequently mutated in cancers. These mutations abolished the inhibition function of PCBP1 on STAT3 translation. Surprisingly, in contrast to wild-type PCBP1 protein, these mutations can promote the growth and colony formation of cancer cells.
Overall, we demonstrate that PCBP1 can inhibit the expression of STAT3 through its 5' UTR, and two leucine residues of PCBP1 protein are essential for its functions.
信号转导子和转录激活子 3（STAT3）是一种癌基因，在癌症中经常过表达。然而，STAT3 表达的调控机制尚不完全清楚。聚（C）结合蛋白 1（PCBP1）是一种 RNA 结合蛋白，可调节 mRNA 的稳定性、剪接和翻译。PCBP1 是一种肿瘤抑制因子，可以抑制几个致癌基因的翻译。
我们旨在了解 STAT3 表达的调控机制。
将人 STAT3 基因的 5'UTR 或 3'UTR 区域分别插入绿色荧光基因（GFP）的上游或下游，分别作为报告系统，分析 PCBP1 对 STAT3 基因表达的抑制作用。对 5'UTR 进行缺失和点突变，以搜索翻译抑制的必需调节序列。在 cBioPortal 在线服务中分析 PCBP1 蛋白的突变。在口腔鳞状细胞癌（OSCC）细胞系中分析突变的 PCBP1 蛋白对 STAT3 表达、癌细胞增殖和集落形成的影响。
PCBP1 通过 STAT3 的 5'UTR 抑制 mRNA 翻译。此外，我们发现 PCBP1 蛋白中的两个亮氨酸残基（Leu100 和 Leu102）在癌症中经常发生突变。这些突变消除了 PCBP1 对 STAT3 翻译的抑制功能。令人惊讶的是，与野生型 PCBP1 蛋白相比，这些突变可以促进癌细胞的生长和集落形成。
总的来说，我们证明了 PCBP1 可以通过其 5'UTR 抑制 STAT3 的表达，PCBP1 蛋白的两个亮氨酸残基对于其功能是必需的。
