PMID- 36348379 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20221116 IS - 2162-3619 (Print) IS - 2162-3619 (Electronic) IS - 2162-3619 (Linking) VI - 11 IP - 1 DP - 2022 Nov 8 TI - circRanGAP1/miR-27b-3p/NRAS Axis may promote the progression of hepatocellular Carcinoma. PG - 92 LID - 10.1186/s40164-022-00342-6 [doi] LID - 92 AB - BACKGROUND: Though circular RNAs (circRNAs) are the key regulators in tumor carcinogenesis, they remain largely unexplored in hepatocellular carcinoma (HCC). METHODS: The expression of RanGAP1-derived circRNAs (circ_0063531, circ_0063534, circ_0063513, circ_0063518, circ_0063507, circ_0063723) were evaluated in eight paired HCC and normal tissues, and the correlation between circRanGAP1 (circ_0063531) expression and clinicopathological characteristics in 40 HCC patients was determined. The association between miR-27b-3p and circRanGAP1 or NRAS was predicted using bioinformatics analysis. The expression of circRanGAP1, miR-27b-3p, and NRAS were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The potential oncogenic role of circ-RanGAP1 was assessed using CCK-8, colony formation, transwell assays in vitro, subcutaneous tumor mouse model, vein tail metastatic model, and orthotopically implanted intrahepatic HCC model in vivo. Luciferase reporter and RNA immunoprecipitation (RIP) assays were used to explore the binding site between miR-27b-3p and circ-RanGAP1 or NRAS. Protein expression was detected using western blotting. The localization of miR-27b-3p and circ-RanGAP1 was investigated using fluorescence in situ hybridization (FISH). The level of immune infiltration was assessed by bioinformatics analysis, flow cytometry, and orthotopically implanted intrahepatic HCC models. RESULTS: Here, we found elevated circRanGAP1 in the cells and clinical tissues of patients with HCC. Increased circRanGAP1 levels are associated with enlarged tumors and the advanced stage of TNM. CircRanGAP1 promotes the growth, migration, and HCC cell invasion, concurrently with the growth and metastasis of tumors in-vivo. Moreover, circRanGAP1 is mainly located inside the cytoplasm. Mechanistically, circRanGAP1 as an oncogene promotes HCC progression by miR-27b-3p/NRAS/ERK axis, furthermore, affects the infiltration level of tumor-associated macrophages probably by sponging miR-27b-3p. Immune infiltration analysis shows that NRAS is positively correlated with the levels of CD68+ tumor-associated macrophages in HCC samples and that NRAS and CD68 are related to the poor outcome of HCC. CONCLUSION: These results reveal that circRanGAP1 is a HCC oncogene that function by the miR-27b-3p/NRAS/ERK axis and regulates the infiltration levels of tumor-associated macrophages by sponging miR-27b-3p. Therefore, circRANGAP1/ NRAS axis may be an important potential treatment target against HCC. CI - (c) 2022. The Author(s). FAU - Lin, Xia-Hui AU - Lin XH AD - Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. AD - Shanghai Institute of Liver Disease, Shanghai, 200032, China. FAU - Liu, Zhi-Yong AU - Liu ZY AD - Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. AD - Shanghai Institute of Liver Disease, Shanghai, 200032, China. FAU - Zhang, Dan-Ying AU - Zhang DY AD - Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. AD - Shanghai Institute of Liver Disease, Shanghai, 200032, China. FAU - Zhang, Si AU - Zhang S AD - Key Laboratory of Glycoconjugate Research Ministry of Public Health, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. FAU - Tang, Wen-Qing AU - Tang WQ AD - Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. AD - Shanghai Institute of Liver Disease, Shanghai, 200032, China. FAU - Li, Dong-Ping AU - Li DP AD - Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. AD - Shanghai Institute of Liver Disease, Shanghai, 200032, China. FAU - Zhang, Feng AU - Zhang F AD - Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. AD - Shanghai Institute of Liver Disease, Shanghai, 200032, China. FAU - Chen, Rong-Xin AU - Chen RX AD - Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, China. FAU - Weng, Shu-Qiang AU - Weng SQ AD - Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. weng.shuqiang@zs-hospital.sh.cn. AD - Shanghai Institute of Liver Disease, Shanghai, 200032, China. weng.shuqiang@zs-hospital.sh.cn. FAU - Xue, Ru-Yi AU - Xue RY AD - Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. xue.ruyi@zs-hospital.sh.cn. AD - Shanghai Institute of Liver Disease, Shanghai, 200032, China. xue.ruyi@zs-hospital.sh.cn. FAU - Dong, Ling AU - Dong L AD - Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. dong.ling@zs-hospital.sh.cn. AD - Shanghai Institute of Liver Disease, Shanghai, 200032, China. dong.ling@zs-hospital.sh.cn. LA - eng PT - Journal Article DEP - 20221108 PL - England TA - Exp Hematol Oncol JT - Experimental hematology & oncology JID - 101590676 PMC - PMC9644583 OTO - NOTNLM OT - Circular RNA OT - Hepatocellular carcinoma OT - Immune-related genes OT - Progression OT - Tumor-associated macrophage COIS- The authors declare that they have no competing interests. EDAT- 2022/11/09 06:00 MHDA- 2022/11/09 06:01 PMCR- 2022/11/08 CRDT- 2022/11/08 23:59 PHST- 2022/07/20 00:00 [received] PHST- 2022/10/17 00:00 [accepted] PHST- 2022/11/08 23:59 [entrez] PHST- 2022/11/09 06:00 [pubmed] PHST- 2022/11/09 06:01 [medline] PHST- 2022/11/08 00:00 [pmc-release] AID - 10.1186/s40164-022-00342-6 [pii] AID - 342 [pii] AID - 10.1186/s40164-022-00342-6 [doi] PST - epublish SO - Exp Hematol Oncol. 2022 Nov 8;11(1):92. doi: 10.1186/s40164-022-00342-6.