环状 RNA MAPK9 通过沉默 miR-642b-3p 促进 STAT3 和 LDHA 的表达，影响肝癌的进展。
Circ_MAPK9 promotes STAT3 and LDHA expression by silencing miR-642b-3p and affects the progression of hepatocellular carcinoma.
机构信息
Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Road, Guangzhou, Guangdong, China.
Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
出版信息
Biol Direct. 2024 Jan 2;19(1):4. doi: 10.1186/s13062-023-00442-1.
BACKGROUND
Aberrant expression and activation of circular RNAs (circRNAs) are closely associated with various cancers. The role of circ_MAPK9 (hsa_circ_0001566) in cancer progression remains unknown. This study aims to investigate the function, mechanism and clinical significance of circ_MAPK9 in hepatocellular carcinoma (HCC).
METHODS
Circ_MAPK9 expression on the microarray of tumor from clinical HCC patients was detected by in situ hybridization (ISH). Circ_MAPK9 knockdown was achieved with siRNAs in SMMC-7721 and SK-Hep1 HCC cell lines. The biological function of circ_MAPK9 was verified in vitro by CCK8 test, colony formation assay, transwell assay, PI-Annexin V staining, and in vivo by xenograft tumor in nude mice. Fluorescent in situ hybridization (FISH), subcellular fractionation assay, a dual-luciferase reporter assay and rescue experiments were employed for further mechanistic investigation.
RESULTS
The expression of circ_MAPK9 was significantly up-regulated in HCC tissues and cells, which was found to be associated with poor prognosis. Patients with high expression of circ_MAPK9 had a shorter overall survival and disease-free survival in comparison to those with low circ_MAPK9 expression. Functional assays showed that circ_MAPK9 knockdown suppressed cellular proliferation, migration, invasion and tumor growth in vivo, and promoted apoptosis in HCC cells. Moreover, we found that circ_MAPK9 knockdown could inhibit aerobic glycolysis by decreasing the production of adenosine triphosphate (ATP) and lactic acid, which was mediated by lactate dehydrogenase (LDHA). Mechanistically, circ_MAPK9 functioned as ceRNA via sponging miR-642b-3p and alleviated the inhibitory effect of miR-642b-3p on its target signal transducer and activator of transcription 3 (STAT3) and LDHA, thereby leading to STAT3 activation and LDHA expression.
CONCLUSIONS
Circ_MAPK9, as an oncogene, promotes HCC growth and metastasis through miR-642b-3p/STAT3-LDHA axis. Circ_MAPK9 could serve as a potential biomarker for HCC poor prognosis and diagnosis.
背景
环状 RNA（circRNAs）的异常表达和激活与多种癌症密切相关。circMAPK9（hsa_circ_0001566）在癌症进展中的作用尚不清楚。本研究旨在探讨 circMAPK9 在肝细胞癌（HCC）中的功能、机制和临床意义。
方法
通过原位杂交（ISH）检测来自临床 HCC 患者肿瘤微阵列上的 circMAPK9 表达。在 SMMC-7721 和 SK-Hep1 HCC 细胞系中用 siRNA 敲低 circMAPK9。通过 CCK8 试验、集落形成试验、transwell 试验、PI-Annexin V 染色在体外验证 circMAPK9 的生物学功能，并通过裸鼠异种移植肿瘤在体内验证。采用荧光原位杂交（FISH）、亚细胞分离测定、双荧光素酶报告基因测定和挽救实验进行进一步的机制研究。
结果
circMAPK9 在 HCC 组织和细胞中的表达明显上调，与不良预后相关。与低 circMAPK9 表达的患者相比，circMAPK9 高表达的患者总生存期和无病生存期更短。功能测定表明，circMAPK9 敲低抑制 HCC 细胞的增殖、迁移、侵袭和体内肿瘤生长，并促进细胞凋亡。此外，我们发现 circMAPK9 敲低可通过减少三磷酸腺苷（ATP）和乳酸的产生来抑制有氧糖酵解，这是由乳酸脱氢酶（LDHA）介导的。机制上，circMAPK9 通过海绵 miR-642b-3p 发挥 ceRNA 作用，并减轻 miR-642b-3p 对其靶信号转导和转录激活因子 3（STAT3）和 LDHA 的抑制作用，从而导致 STAT3 激活和 LDHA 表达。
结论
circMAPK9 作为一种癌基因，通过 miR-642b-3p/STAT3-LDHA 轴促进 HCC 的生长和转移。circMAPK9 可作为 HCC 预后不良和诊断的潜在生物标志物。
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