SNRPA promotes hepatocellular carcinoma proliferation and lenvatinib resistance via B7-H6-STAT3/AKT axis by facilitating B7-H6 pre-mRNA maturation.

IF 5.7 4区 生物学 Q1 BIOLOGY
Jiejun Hu, Junhua Gong, Xia Shu, Xin Dai, Dong Cai, Zhibo Zhao, Jinhao Li, Guochao Zhong, Jianping Gong
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引用次数: 0

Abstract

The pre-mRNAs splicing is important mechanisms of hepatocellular carcinoma (HCC) progression. Hence, this study aimed to explore the function and corresponding mechanisms of small nuclear ribonucleoprotein polypeptide A (SNRPA), a vital RNAs splicing molecule, in HCC. Here, the University of Alabama at Birmingham CANcer data analysis portal (UALCAN), western blotting, and immunohistochemistry indicated that SNRPA levels were elevated in HCC tissues. Moreover, high expression of SNRPA was correlated with unfavorable clinicopathologic features and poor survival in HCC patients. A series of in vitro and in vivo gain/loss-of-function experiments reported that SNRPA promoted the proliferation of HCC cells. Integrated nanopore full-length cDNA sequencing and RNA-binding protein immunoprecipitation sequencing revealed that B7 homologue 6 (B7-H6) was a potential target of SNRPA. Subsequently, western blotting and flow cytometry showed that SNRPA activated B7-H6-STAT3/AKT signaling axis in HCC cells with promotion of G1-S transition in the cell cycle and inhibition of cell apoptosis. Mechanistically, RNA-binding protein immunoprecipitation and polymerase chain reaction with using exon-exon and exon-intron junction primers revealed that SNRPA facilitated B7-H6 pre-mRNA maturation by binding to it directly and contributing to its intron 2 splicing. Moreover, drug sensitivity test found that SNRPA induced HCC cell resistance to lenvatinib. Finally, restoration experiments demonstrated that the effects of SNRPA on HCC cells relied on B7- H6 expression. Taken together, SNRPA promotes HCC growth and lenvatinib resistance via B7-H6-STAT3/AKT axis through facilitating B7-H6 pre-mRNA maturation by maintaining its intron 2 splicing. Thus, SNRPA may be a promising target for HCC therapy and lenvatinib resistance reversion.

SNRPA通过B7-H6- stat3 /AKT轴促进B7-H6前mrna成熟,促进肝癌增殖和lenvatinib耐药。
前mrna剪接是肝细胞癌(HCC)进展的重要机制。因此,本研究旨在探讨小核糖核蛋白多肽A (SNRPA)在HCC中的作用及其机制,SNRPA是一种重要的rna剪接分子。本研究中,阿拉巴马大学伯明翰分校癌症数据分析门户网站(UALCAN)、western blotting和免疫组织化学表明,SNRPA水平在HCC组织中升高。此外,SNRPA的高表达与HCC患者不利的临床病理特征和较差的生存率相关。一系列体外和体内的功能增益/丧失实验报道SNRPA促进了HCC细胞的增殖。整合纳米孔全长cDNA测序和rna结合蛋白免疫沉淀测序结果显示,B7同源物6 (B7- h6)是SNRPA的潜在靶点。随后,western blotting和流式细胞术显示,SNRPA激活HCC细胞B7-H6-STAT3/AKT信号轴,促进细胞周期G1-S转变,抑制细胞凋亡。机制上,rna结合蛋白免疫沉淀和使用外显子-外显子和外显子-内含子连接引物的聚合酶链反应表明,SNRPA通过直接结合B7-H6并参与其内含子2剪接,促进了B7-H6 pre-mRNA的成熟。此外,药敏试验发现SNRPA诱导HCC细胞对lenvatinib产生耐药。最后,修复实验证明SNRPA对HCC细胞的作用依赖于B7- H6的表达。综上所述,SNRPA通过维持其intron 2剪接促进B7-H6 pre-mRNA成熟,通过B7-H6- stat3 /AKT轴促进HCC生长和lenvatinib耐药。因此,SNRPA可能是HCC治疗和lenvatinib耐药逆转的一个有希望的靶点。
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来源期刊
CiteScore
13.60
自引率
1.80%
发文量
47
审稿时长
>12 weeks
期刊介绍: BioScience Trends (Print ISSN 1881-7815, Online ISSN 1881-7823) is an international peer-reviewed journal. BioScience Trends devotes to publishing the latest and most exciting advances in scientific research. Articles cover fields of life science such as biochemistry, molecular biology, clinical research, public health, medical care system, and social science in order to encourage cooperation and exchange among scientists and clinical researchers.
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