CircUCK2(2,3) promotes cancer progression and enhances synergistic cytotoxicity of lenvatinib with EGFR inhibitors via activating CNIH4–TGFα–EGFR signaling
Abstract Background Circular (circ)RNAs have emerged as crucial contributors to cancer progression. Nonetheless, the expression regulation, biological functions, and underlying mechanisms of circRNAs in mediating hepatocellular carcinoma (HCC) progression remain insufficiently elucidated. Methods We...
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2025-01-01
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| Series: | Cellular & Molecular Biology Letters |
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| Online Access: | https://doi.org/10.1186/s11658-025-00690-1 |
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| author | Xindong Wei Anfeng Si Shuai Zhao Yi Fu Jilei Li Kedeerya Aishanjiang Yujie Ma Chang Yu Bo Yu Chunhong Cui Hui Wang Xianming Kong Shibo Li Xiaoni Kong Ying Tong Hailong Wu |
| author_facet | Xindong Wei Anfeng Si Shuai Zhao Yi Fu Jilei Li Kedeerya Aishanjiang Yujie Ma Chang Yu Bo Yu Chunhong Cui Hui Wang Xianming Kong Shibo Li Xiaoni Kong Ying Tong Hailong Wu |
| author_sort | Xindong Wei |
| collection | DOAJ |
| description | Abstract Background Circular (circ)RNAs have emerged as crucial contributors to cancer progression. Nonetheless, the expression regulation, biological functions, and underlying mechanisms of circRNAs in mediating hepatocellular carcinoma (HCC) progression remain insufficiently elucidated. Methods We identified circUCK2(2,3) through circRNA sequencing, RT–PCR, and Sanger sequencing. CircUCK2(2,3) levels were measured in two independent HCC cohorts using quantitative real-time PCR (qRT–PCR). We explored the functions of circUCK2(2,3) using gain- and loss-of-function assays. Techniques such as RNA-sequencing, RNA immunoprecipitation (RIP), polysome fractionation, RNA pulldown, dual luciferase reporter assay, inhibitors of EGFR downstream signaling, CRISPR–Cas9, and medium transfer assays were employed to investigate the regulatory mechanisms and the protumoral activities of circUCK2(2,3). Additionally, in vitro cytotoxic assays and patient-derived xenograft (PDX) models assessed the effects of circUCK2(2,3) on the cytotoxic synergy of lenvatinib and EGFR inhibitors. Results CircUCK2(2,3) is upregulated in HCC tissues and serves as an independent risk factor for poor recurrence-free survival. The expression of circUCK2(2,3) is independent on its host gene, UCK2, but is regulated by its upstream promoter and flanking inverted complementary sequences. Functionally, circUCK2(2,3) enhances HCC proliferation, migration, and invasion, both in vitro and in vivo. Mechanistically, by sponging miR-149-5p, circUCK2(2,3) increases CNIH4 levels, which in turn amplifies TGFα secretion, resulting in the activation of EGFR and downstream pAKT and pERK signaling pathways. Moreover, circUCK2(2,3) overexpression sensitizes HCC cells to EGFR inhibitors, and increases the synergistic cytotoxicity of combined lenvatinib and EGFR inhibitor treatment. Conclusions CircUCK2(2,3) regulates a novel oncogenic pathway, miR-149-5p–CNIH4–TGFα–EGFR, in HCC, presenting a viable therapeutic target and biomarker for the precision treatment of HCC. Graphical Abstract |
| format | Article |
| id | doaj-art-00176a2080aa434c866462a3b9644d07 |
| institution | Kabale University |
| issn | 1689-1392 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Cellular & Molecular Biology Letters |
| spelling | doaj-art-00176a2080aa434c866462a3b9644d072025-02-02T12:33:42ZengBMCCellular & Molecular Biology Letters1689-13922025-01-0130112610.1186/s11658-025-00690-1CircUCK2(2,3) promotes cancer progression and enhances synergistic cytotoxicity of lenvatinib with EGFR inhibitors via activating CNIH4–TGFα–EGFR signalingXindong Wei0Anfeng Si1Shuai Zhao2Yi Fu3Jilei Li4Kedeerya Aishanjiang5Yujie Ma6Chang Yu7Bo Yu8Chunhong Cui9Hui Wang10Xianming Kong11Shibo Li12Xiaoni Kong13Ying Tong14Hailong Wu15Clinical Research Center, Jiading District Central Hospital Affiliated to Shanghai University of Medicine and Health SciencesDepartment of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Transplantation, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of MedicineClinical Research Center, Jiading District Central Hospital Affiliated to Shanghai University of Medicine and Health SciencesClinical Research Center, Jiading District Central Hospital Affiliated to Shanghai University of Medicine and Health SciencesClinical Research Center, Jiading District Central Hospital Affiliated to Shanghai University of Medicine and Health SciencesClinical Research Center, Jiading District Central Hospital Affiliated to Shanghai University of Medicine and Health SciencesCentral Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional MedicineSchool of Clinical Medicine, Shanghai University of Medicine and Health SciencesBasic Medical College, Shanghai University of Medicine and Health SciencesBasic Medical College, Shanghai University of Medicine and Health SciencesCollaborative Research Center for Biomedicines, Shanghai University of Medicine and Health SciencesDepartment of Infectious Disease, Zhoushan Hospital, Wenzhou Medical UniversityCentral Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional MedicineDepartment of Liver Surgery, School of Medicine, Renji Hospital, Shanghai JiaoTong UniversityClinical Research Center, Jiading District Central Hospital Affiliated to Shanghai University of Medicine and Health SciencesAbstract Background Circular (circ)RNAs have emerged as crucial contributors to cancer progression. Nonetheless, the expression regulation, biological functions, and underlying mechanisms of circRNAs in mediating hepatocellular carcinoma (HCC) progression remain insufficiently elucidated. Methods We identified circUCK2(2,3) through circRNA sequencing, RT–PCR, and Sanger sequencing. CircUCK2(2,3) levels were measured in two independent HCC cohorts using quantitative real-time PCR (qRT–PCR). We explored the functions of circUCK2(2,3) using gain- and loss-of-function assays. Techniques such as RNA-sequencing, RNA immunoprecipitation (RIP), polysome fractionation, RNA pulldown, dual luciferase reporter assay, inhibitors of EGFR downstream signaling, CRISPR–Cas9, and medium transfer assays were employed to investigate the regulatory mechanisms and the protumoral activities of circUCK2(2,3). Additionally, in vitro cytotoxic assays and patient-derived xenograft (PDX) models assessed the effects of circUCK2(2,3) on the cytotoxic synergy of lenvatinib and EGFR inhibitors. Results CircUCK2(2,3) is upregulated in HCC tissues and serves as an independent risk factor for poor recurrence-free survival. The expression of circUCK2(2,3) is independent on its host gene, UCK2, but is regulated by its upstream promoter and flanking inverted complementary sequences. Functionally, circUCK2(2,3) enhances HCC proliferation, migration, and invasion, both in vitro and in vivo. Mechanistically, by sponging miR-149-5p, circUCK2(2,3) increases CNIH4 levels, which in turn amplifies TGFα secretion, resulting in the activation of EGFR and downstream pAKT and pERK signaling pathways. Moreover, circUCK2(2,3) overexpression sensitizes HCC cells to EGFR inhibitors, and increases the synergistic cytotoxicity of combined lenvatinib and EGFR inhibitor treatment. Conclusions CircUCK2(2,3) regulates a novel oncogenic pathway, miR-149-5p–CNIH4–TGFα–EGFR, in HCC, presenting a viable therapeutic target and biomarker for the precision treatment of HCC. Graphical Abstracthttps://doi.org/10.1186/s11658-025-00690-1Hepatocellular carcinomacircRNACNIH4TGFα–EGFR signalingLenvatinibEGFR inhibitors |
| spellingShingle | Xindong Wei Anfeng Si Shuai Zhao Yi Fu Jilei Li Kedeerya Aishanjiang Yujie Ma Chang Yu Bo Yu Chunhong Cui Hui Wang Xianming Kong Shibo Li Xiaoni Kong Ying Tong Hailong Wu CircUCK2(2,3) promotes cancer progression and enhances synergistic cytotoxicity of lenvatinib with EGFR inhibitors via activating CNIH4–TGFα–EGFR signaling Cellular & Molecular Biology Letters Hepatocellular carcinoma circRNA CNIH4 TGFα–EGFR signaling Lenvatinib EGFR inhibitors |
| title | CircUCK2(2,3) promotes cancer progression and enhances synergistic cytotoxicity of lenvatinib with EGFR inhibitors via activating CNIH4–TGFα–EGFR signaling |
| title_full | CircUCK2(2,3) promotes cancer progression and enhances synergistic cytotoxicity of lenvatinib with EGFR inhibitors via activating CNIH4–TGFα–EGFR signaling |
| title_fullStr | CircUCK2(2,3) promotes cancer progression and enhances synergistic cytotoxicity of lenvatinib with EGFR inhibitors via activating CNIH4–TGFα–EGFR signaling |
| title_full_unstemmed | CircUCK2(2,3) promotes cancer progression and enhances synergistic cytotoxicity of lenvatinib with EGFR inhibitors via activating CNIH4–TGFα–EGFR signaling |
| title_short | CircUCK2(2,3) promotes cancer progression and enhances synergistic cytotoxicity of lenvatinib with EGFR inhibitors via activating CNIH4–TGFα–EGFR signaling |
| title_sort | circuck2 2 3 promotes cancer progression and enhances synergistic cytotoxicity of lenvatinib with egfr inhibitors via activating cnih4 tgfα egfr signaling |
| topic | Hepatocellular carcinoma circRNA CNIH4 TGFα–EGFR signaling Lenvatinib EGFR inhibitors |
| url | https://doi.org/10.1186/s11658-025-00690-1 |
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