LARP4,即La相关的蛋白4,是一种RNA结合蛋白,参与调节mRNA的翻译和稳定性。LARP4与poly(A)-结合蛋白(PABP)相互作用,进而影响mRNA的命运和功能。LARP4在多种生物学过程中发挥作用,包括细胞迁移、侵袭、增殖和凋亡。
研究表明,LARP4的表达受到肿瘤坏死因子α(TNF-α)的调控。TNF-α能够迅速诱导LARP4的表达,而LARP4的表达又能够被TNF-α诱导的TTP(Tristetraprolin)所下调。TTP是一种RNA结合蛋白,能够与LARP4 mRNA结合,从而影响LARP4的表达水平[1]。此外,LARP4的表达还与多种肿瘤的发生和发展相关。研究发现,在非小细胞肺癌(NSCLC)中,circ LARP4的表达水平下调,而circ LARP4的表达水平与NSCLC患者的预后相关。circ LARP4能够抑制NSCLC细胞的迁移和侵袭,其机制可能与circ LARP4上调SMAD7的表达有关[2]。在卵巢癌中,circ LARP4的表达水平也下调,而circ LARP4的表达水平与卵巢癌患者的预后相关。circ LARP4能够抑制卵巢癌细胞的增殖和迁移,其机制可能与circ LARP4作为miR-513b-5p的竞争性内源RNA(ceRNA)海绵体,从而上调LARP4的表达有关[3]。此外,circ LARP4还能够抑制卵巢癌细胞的增殖、迁移和侵袭,其机制可能与circ LARP4作为miR-223-3p的竞争性内源RNA海绵体,从而上调LARP4的表达有关[4]。LARP4的表达还能够抑制卵巢癌细胞的迁移和侵袭,其机制可能与LARP4下调RhoA的表达有关[5]。此外,LARP4的表达还与唾液腺透明细胞癌的进展相关。研究发现,在唾液腺透明细胞癌中,LARP4与EWSR1基因融合形成EWSR1::LARP4融合基因,而EWSR1::LARP4融合基因的表达与唾液腺透明细胞癌的“高级别转化”和不良预后相关[6]。LARP4的表达还与糖尿病肾病(DN)的进展相关。研究发现,在DN细胞模型中,circ LARP4的表达水平下调,而circ LARP4的表达水平下调与细胞增殖和纤维化相关。circ LARP4的表达能够抑制DN细胞模型的细胞增殖和纤维化,其机制可能与circ LARP4作为miR-424的竞争性内源RNA海绵体,从而上调LARP4的表达有关[7]。LARP4的表达还与病毒复制相关。研究发现,LARP4在病毒工厂中富集,而LARP4的表达能够促进病毒复制[8]。
综上所述,LARP4是一种重要的RNA结合蛋白,参与调节mRNA的翻译和稳定性。LARP4在多种生物学过程中发挥作用,包括细胞迁移、侵袭、增殖、凋亡和病毒复制。LARP4的表达受到多种因素的调控,包括TNF-α、TTP、circ LARP4和miRNA。LARP4的表达还与多种肿瘤的发生和发展相关,包括NSCLC、卵巢癌和唾液腺透明细胞癌。LARP4的研究有助于深入理解RNA结合蛋白的生物学功能和疾病发生机制,为疾病的治疗和预防提供新的思路和策略。
参考文献:
1. Mattijssen, Sandy, Maraia, Richard J. 2015. LARP4 Is Regulated by Tumor Necrosis Factor Alpha in a Tristetraprolin-Dependent Manner. In Molecular and cellular biology, 36, 574-84. doi:10.1128/MCB.00804-15. https://pubmed.ncbi.nlm.nih.gov/26644407/
2. Shi, J-Q, Wang, B, Cao, X-Q, Luo, B-J, Liu, Z-D. . Circular RNA_LARP4 inhibits the progression of non-small-cell lung cancer by regulating the expression of SMAD7. In European review for medical and pharmacological sciences, 24, 1863-1869. doi:10.26355/eurrev_202002_20364. https://pubmed.ncbi.nlm.nih.gov/32141555/
3. Wang, Yakun, Qi, Yinghui, Ji, Tingting, Zheng, Pengxi, Bai, Shoujun. 2020. Circ_LARP4 regulates high glucose-induced cell proliferation, apoptosis, and fibrosis in mouse mesangial cells. In Gene, 765, 145114. doi:10.1016/j.gene.2020.145114. https://pubmed.ncbi.nlm.nih.gov/32891769/
4. Seetharaman, Shailaja, Flemyng, Ella, Shen, Jiazhen, Conte, Maria R, Ridley, Anne J. 2016. The RNA-binding protein LARP4 regulates cancer cell migration and invasion. In Cytoskeleton (Hoboken, N.J.), 73, 680-690. doi:10.1002/cm.21336. https://pubmed.ncbi.nlm.nih.gov/27615744/
5. Kobayashi, Kenya, Kawazu, Masahito, Yoshimoto, Seiichi, Mano, Hiroyuki, Mori, Taisuke. 2023. Genome Doubling Shapes High-Grade Transformation and Novel EWSR1::LARP4 Fusion Shows SOX10 Immunostaining in Hyalinizing Clear Cell Carcinoma of Salivary Gland. In Laboratory investigation; a journal of technical methods and pathology, 103, 100213. doi:10.1016/j.labinv.2023.100213. https://pubmed.ncbi.nlm.nih.gov/37479138/
6. Lin, Wumei, Ye, Haiyan, You, Keli, Chen, Le. 2020. Up-regulation of circ_LARP4 suppresses cell proliferation and migration in ovarian cancer by regulating miR-513b-5p/LARP4 axis. In Cancer cell international, 20, 5. doi:10.1186/s12935-019-1071-z. https://pubmed.ncbi.nlm.nih.gov/31911757/
7. Lu, Meirong, Gong, Bianrong, Wang, Yi, Li, Jingyan. 2022. CircBNC2 affects epithelial ovarian cancer progression through the miR-223-3p/ LARP4 axis. In Anti-cancer drugs, 34, 384-394. doi:10.1097/CAD.0000000000001423. https://pubmed.ncbi.nlm.nih.gov/36730544/
8. Egiz, Mahy, Usui, Toshinori, Ishibashi, Masumi, Kitatani, Kazuyuki, Yaegashi, Nobuo. . La-Related Protein 4 as a Suppressor for Motility of Ovarian Cancer Cells. In The Tohoku journal of experimental medicine, 247, 59-67. doi:10.1620/tjem.247.59. https://pubmed.ncbi.nlm.nih.gov/30686809/