Hedyotis diffusa Willd-Scutellaria barbata D.Don Suppresses Colorectal Cancer Liver Metastasis by Targeting hsa_circ_0039933-Mediated Epithelial-Mesenchymal Transition.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Hedyotis diffusa Willd-Scutellaria barbata D.Don Suppresses Colorectal Cancer Liver Metastasis by Targeting hsa_circ_0039933-Mediated Epithelial-Mesenchymal Transition.
Συγγραφείς: Yuan S; Department of Traditional Chinese Medicine, Ganzhou People's Hospital, No.16, Meiguan Avenue, Zhanggong District, Ganzhou City, 341000, Jiangxi Province, China., Li S; Department of Traditional Chinese Medicine, Ganzhou People's Hospital, No.16, Meiguan Avenue, Zhanggong District, Ganzhou City, 341000, Jiangxi Province, China., Chen C; Department of Traditional Chinese Medicine, Ganzhou People's Hospital, No.16, Meiguan Avenue, Zhanggong District, Ganzhou City, 341000, Jiangxi Province, China. c15793478243@126.com.
Πηγή: Biochemical genetics [Biochem Genet] 2026 Oct; Vol. 64 (5), pp. 7608-7627. Date of Electronic Publication: 2026 Jun 08.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Kluwer Academic/Plenum Publishers Country of Publication: United States NLM ID: 0126611 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-4927 (Electronic) Linking ISSN: 00062928 NLM ISO Abbreviation: Biochem Genet Subsets: MEDLINE
Imprint Name(s): Publication: 1999- : New York : Kluwer Academic/Plenum Publishers
Original Publication: New York, Plenum Press.
Ιατρικοί όροι (MeSH): Colorectal Neoplasms*/pathology , Colorectal Neoplasms*/drug therapy , Colorectal Neoplasms*/genetics , Colorectal Neoplasms*/metabolism , Epithelial-Mesenchymal Transition*/drug effects , Liver Neoplasms*/secondary , Liver Neoplasms*/drug therapy , Liver Neoplasms*/genetics , Liver Neoplasms*/metabolism , Hedyotis*/chemistry , RNA, Circular*/genetics , RNA, Circular*/metabolism , Drugs, Chinese Herbal*/pharmacology, Cell Proliferation/drug effects ; Cell Movement/drug effects ; Animals ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Cell Line, Tumor ; Male
Περίληψη: Colorectal cancer (CRC) liver metastasis remains a major cause of mortality, necessitating novel therapeutic strategies. Hedyotis diffusa Willd -Scutellaria barbata D.Don (HD-SB), a traditional Chinese herbal formulation, has demonstrated anti-tumor potential. However, its mechanism in CRC metastasis, particularly through the regulation of circular RNAs, remains unexplored. A CRC liver metastasis model was established in Balb/c nude mice via intrasplenic injection of HCT-15 cells. Mice received HD-SB treatment. Hematoxylin-eosin staining, Masson staining, and immunohistochemistry (Ki67 and Cytokeratin 19 [CK19]) were carried out to observe pathologic changes in CRC liver metastases. In vitro, HCT-15 cells were treated with tumor necrosis factor-α (TNF-α) to induce metastasis. hsa_circ_0039933 was knocked down and overexpressed in vitro. Transwell, wound healing, EdU, and cell counting kit-8 assays were employed to assess cell invasion, migration and proliferation, respectively. The levels of epithelial-mesenchymal transition (EMT) markers were evaluated by quantitative real-time polymerase chain reaction and western blot. HD-SB treatment dose-dependently reduced hepatic tumor nodules, fibrosis, Ki67 and CK19 expression in vivo, with high-dose HD-SB showing superior efficacy. EMT reverse (upregulated E-cadherin, downregulated N-cadherin/Vimentin) and hsa_circ_0039933 suppression were observed in HD-SB treated CRC mouse. In vitro, HD-SB attenuated TNF-α-induced proliferation, migration, and invasion, synergizing with hsa_circ_0039933 knockdown to suppress EMT and metastatic phenotypes. Conversely, hsa_circ_0039933 overexpression exacerbated TNF-α-driven aggressiveness, which was effectively counteracted by HD-SB. Collectively, HD-SB inhibits CRC liver metastasis by targeting hsa_circ_0039933 and modulating EMT. These findings highlight HD-SB as a promising circRNA-directed therapeutic agent for metastatic CRC.
(© 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Competing Interests: Declarations. Competing Interests: The authors declare no competing interests. Ethical Approval and Consent to Participate: The experiments conformed to the Guide for the Care and Use of Laboratory Animals. Animal study has been approved by the Animal Ethics Committee of Nanchang University (SYXK (Ganzhou) 2021-0004). All methods are reported in accordance with ARRIVE guidelines.
References: Al Zein M, Boukhdoud M, Shammaa H, Mouslem H, El Ayoubi LM, Iratni R, Issa K, Khachab M, Assi HI, Sahebkar A et al (2023) Immunotherapy and immunoevasion of colorectal cancer. Drug Discov Today 28(9):103669. (PMID: 10.1016/j.drudis.2023.10366937328052)
Alotaibi AG, Li JV, Gooderham NJ (2023) Tumour Necrosis Factor-Alpha (TNF-α)-induced metastatic phenotype in colorectal cancer epithelial cells: mechanistic support for the role of MicroRNA-21. Cancers (Basel). https://doi.org/10.3390/cancers15030627. (PMID: 10.3390/cancers150306273820156010777962)
Baidoun F, Elshiwy K, Elkeraie Y, Merjaneh Z, Khoudari G, Sarmini MT, Gad M, Al-Husseini M, Saad A (2021) Colorectal cancer epidemiology: recent trends and impact on outcomes. Curr Drug Targets 22(9):998–1009. (PMID: 10.2174/18735592MTEx9NTk2y33208072)
Cai K, Cao XY, Chen F, Zhu Y, Sun DD, Cheng HB, Duan JA, Su SL (2024) Xianlian Jiedu Decoction alleviates colorectal cancer by regulating metabolic profiles, intestinal microbiota and metabolites. Phytomedicine 128:155385. (PMID: 10.1016/j.phymed.2024.15538538569292)
Cañellas-Socias A, Sancho E, Batlle E (2024) Mechanisms of metastatic colorectal cancer. Nat Rev Gastroenterol Hepatol 21(9):609–625. (PMID: 10.1038/s41575-024-00934-z38806657)
Chen R, He J, Tong X, Tang L, Liu M (2016) The Hedyotis diffusa Willd. (Rubiaceae): a review on phytochemistry, pharmacology, quality control and pharmacokinetics. Molecules. https://doi.org/10.3390/molecules21060710. (PMID: 10.3390/molecules21060710280428586273873)
Chen L, Shan G (2021) CircRNA in cancer: fundamental mechanism and clinical potential. Cancer Lett 505:49–57. (PMID: 10.1016/j.canlet.2021.02.00433609610)
Conn VM, Chinnaiyan AM, Conn SJ (2024) Circular RNA in cancer. Nat Rev Cancer 24(9):597–613. (PMID: 10.1038/s41568-024-00721-739075222)
Feng J, Jin Y, Peng J, Wei L, Cai Q, Yan Z, Lai Z, Lin J (2017) Hedyotis diffusa willd extract suppresses colorectal cancer growth through multiple cellular pathways. Oncol Lett 14(6):8197–8205. (PMID: 293442625755052)
Gonzalez-Gutierrez L, Motiño O, Barriuso D, de la Puente-Aldea J, Alvarez-Frutos L, Kroemer G, Palacios-Ramirez R, Senovilla L (2024) Obesity-associated colorectal cancer. Int J Mol Sci. https://doi.org/10.3390/ijms25168836. (PMID: 10.3390/ijms251688363920152211354800)
Horn SR, Stoltzfus KC, Lehrer EJ, Dawson LA, Tchelebi L, Gusani NJ, Sharma NK, Chen H, Trifiletti DM, Zaorsky NG (2020) Epidemiology of liver metastases. Cancer Epidemiol 67:101760. (PMID: 10.1016/j.canep.2020.10176032562887)
Hsu CY, Faisal A, Jumaa SS, Gilmanova NS, Ubaid M, Athab AH, Mirzaei R, Karampoor S (2024) Exploring the impact of circRNAs on cancer glycolysis: insights into tumor progression and therapeutic strategies. Non-coding RNA Res 9(3):970–994. (PMID: 10.1016/j.ncrna.2024.05.001)
Li Q, Geng S, Luo H, Wang W, Mo YQ, Luo Q, Wang L, Song GB, Sheng JP, Xu B (2024) Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy. Signal Transduct Target Ther 9(1):266. (PMID: 10.1038/s41392-024-01953-73937045511456611)
Li H, Lai Z, Yang H, Peng J, Chen Y, Lin J (2019) Hedyotis diffusa Willd. inhibits VEGF–C–mediated lymphangiogenesis in colorectal cancer via multiple signaling pathways. Oncol Rep 42(3):1225–1236. (PMID: 10.3892/or.2014.332731322263)
Liu L, Liu T, Tao W, Liao N, Yan Q, Li L, Tan J, Shen W, Cheng H, Sun D (2022) Flavonoids from Scutellaria barbata D. Don exert antitumor activity in colorectal cancer through inhibited autophagy and promoted apoptosis via ATF4/sestrin2 pathway. Phytomedicine 99:154007. (PMID: 10.1016/j.phymed.2022.15400735259610)
Long F, Li L, Xie C, Ma M, Wu Z, Lu Z, Liu B, Yang M, Zhang F, Ning Z et al (2023) Intergenic CircRNA Circ_0007379 inhibits colorectal cancer progression by modulating miR-320a biogenesis in a KSRP-dependent manner. Int J Biol Sci 19(12):3781–3803. (PMID: 10.7150/ijbs.850633756419810411474)
Lu L, Liu Y, Zhang G, Xu Y, Hu D, Ji G, Xu H (2022) The circRNA expression profile of colorectal inflammatory cancer transformation revealed potential predictive biomarkers. Aging 14(22):9280–9299. (PMID: 10.18632/aging.204406364463519740358)
Lv J, Jia Y, Li J, Kuai W, Li Y, Guo F, Xu X, Zhao Z, Lv J, Li Z (2019) Gegen Qinlian decoction enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by remodelling the gut microbiota and the tumour microenvironment. Cell Death Dis 10(6):415. (PMID: 10.1038/s41419-019-1638-6311387796538740)
Lv Q, Xia Q, Li A, Wang Z (2022) circRNA_101277 influences cisplatin resistance of colorectal cancer cells by modulating the miR-370/IL-6 axis. Genet Res 2022:4237327. (PMID: 10.1155/2022/4237327)
Ma TT, Zhang GL, Dai CF, Zhang BR, Cao KX, Wang CG, Yang GW, Wang XM (2020) Scutellaria barbata and Hedyotis diffusa herb pair for breast cancer treatment: Potential mechanism based on network pharmacology. J Ethnopharmacol 259:112929. (PMID: 10.1016/j.jep.2020.11292932416245)
Ning Q, Jin Q, Zhao L, Wang Y, Wang J, Yang L, Han Y, Zhi Q, Zheng J, Chen F et al (2025) Transcriptome-scale analysis of functional alternative back-splicing events in colorectal cancer. J translational Med 23(1):468. (PMID: 10.1186/s12967-025-06479-2)
Ou L, Li M, Hou Y (2024) Network pharmacology, bioinformatics, and experimental validation to identify the role of Hedyotis diffusa willd against gastric cancer through the activation of the endoplasmic reticulum stress. Heliyon 10(7):e28833. (PMID: 10.1016/j.heliyon.2024.e288333857656810990957)
Pan LT, Sheung Y, Guo WP, Rong ZB, Cai ZM (2016) Hedyotis diffusa plus Scutellaria barbata induce bladder cancer cell apoptosis by inhibiting Akt signaling pathway through downregulating miR-155 expression. Evid Based Complement Alternat Med 2016:9174903. (PMID: 10.1155/2016/9174903269894274773537)
Sendi H, Yazdimamaghani M, Hu M, Sultanpuram N, Wang J, Moody AS, McCabe E, Zhang J, Graboski A, Li L et al (2022) Nanoparticle delivery of miR-122 inhibits colorectal cancer liver metastasis. Cancer Res 82(1):105–113. (PMID: 10.1158/0008-5472.CAN-21-226934753773)
Shang A, Gu C, Wang W, Wang X, Sun J, Zeng B, Chen C, Chang W, Ping Y, Ji P et al (2020) Exosomal circPACRGL promotes progression of colorectal cancer via the miR-142-3p/miR-506-3p- TGF-β1 axis. Mol Cancer 19(1):117. (PMID: 10.1186/s12943-020-01235-0327133457384220)
Shin AE, Giancotti FG, Rustgi AK (2023) Metastatic colorectal cancer: mechanisms and emerging therapeutics. Trends Pharmacol Sci 44(4):222–236. (PMID: 10.1016/j.tips.2023.01.0033682875910365888)
Sui X, Gao B, Zhang L, Wang Y, Ma J, Wu X, Zhou C, Liu M, Zhang L (2024) Scutellaria barbata D.Don and Hedyotis diffusa Willd herb pair combined with cisplatin synergistically inhibits ovarian cancer progression through modulating oxidative stress via NRF2-FTH1 autophagic degradation pathway. J Ovarian Res 17(1):246. (PMID: 10.1186/s13048-024-01570-63970230211658162)
Underwood PW, Ruff SM, Pawlik TM (2024) Update on targeted therapy and immunotherapy for metastatic colorectal cancer. Cells. https://doi.org/10.3390/cells13030245. (PMID: 10.3390/cells130302453833463710854977)
Wang Z, Dan W, Zhang N, Fang J, Yang Y (2023) Colorectal cancer and gut microbiota studies in China. Gut Microbes 15(1):2236364. (PMID: 10.1080/19490976.2023.22363643748265710364665)
Wang Y, Zhao T, Huang C, Liu F, Zhang Y, Kong D, Fan Z (2024) Effect and mechanism of Banxia Xiexin decoction in colorectal cancer: a network pharmacology approach. Phytomedicine 123:155174. (PMID: 10.1016/j.phymed.2023.15517438039904)
Wei J, Liu Z, He J, Liu Q, Lu Y, He S, Yuan B, Zhang J, Ding Y (2022) Traditional Chinese medicine reverses cancer multidrug resistance and its mechanism. Clin Transl Oncol 24(3):471–482. (PMID: 10.1007/s12094-021-02716-434643878)
Xie Q, Liu X, Liu R, Pan J, Liang J (2024) Cellular mechanisms of combining innate immunity activation with PD-1/PD-L1 blockade in treatment of colorectal cancer. Mol Cancer 23(1):252. (PMID: 10.1186/s12943-024-02166-w3952905811555832)
Xu H, Liu Y, Cheng P, Wang C, Liu Y, Zhou W, Xu Y, Ji G (2020) CircRNA_0000392 promotes colorectal cancer progression through the miR-193a-5p/PIK3R3/AKT axis. J Exp Clin Cancer Res CR 39(1):283. (PMID: 333175967735421)
Xu X, Chen F, Zhang L, Liu L, Zhang C, Zhang Z, Li W (2021) Exploring the mechanisms of anti-ovarian cancer of Hedyotis diffusa Willd and Scutellaria barbata D. Don through focal adhesion pathway. J Ethnopharmacol 279:114343. (PMID: 10.1016/j.jep.2021.11434334147618)
Yang M, Sun M, Zhang H (2022) The Interaction Between Epigenetic Changes, EMT, and Exosomes in Predicting Metastasis of Colorectal Cancers (CRC). Front Oncol 12:879848. (PMID: 10.3389/fonc.2022.879848357125129197117)
Yang Y, Luo D, Shao Y, Shan Z, Liu Q, Weng J, He W, Zhang R, Li Q, Wang Z et al (2023) circCAPRIN1 interacts with STAT2 to promote tumor progression and lipid synthesis via upregulating ACC1 expression in colorectal cancer. Cancer Commun (London England) 43(1):100–122. (PMID: 10.1002/cac2.12380)
Zeng K, Peng J, Xing Y, Zhang L, Zeng P, Li W, Zhang W, Pan Z, Zhou C, Lin J (2023) A positive feedback circuit driven by m(6)A-modified circular RNA facilitates colorectal cancer liver metastasis. Mol Cancer 22(1):202. (PMID: 10.1186/s12943-023-01848-13808732210717141)
Zhang Y, Luo J, Yang W, Ye WC (2023) CircRNAs in colorectal cancer: potential biomarkers and therapeutic targets. Cell Death Dis 14(6):353. (PMID: 10.1038/s41419-023-05881-23729610710250185)
Zhao W, Jin L, Chen P, Li D, Gao W, Dong G (2022) Colorectal cancer immunotherapy-Recent progress and future directions. Cancer Lett 545:215816. (PMID: 10.1016/j.canlet.2022.21581635810989)
Zhou J, Song Q, Li H, Han Y, Pu Y, Li L, Rong W, Liu X, Wang Z, Sun J et al (2024) Targeting circ-0034880-enriched tumor extracellular vesicles to impede SPP1(high)CD206(+) pro-tumor macrophages mediated pre-metastatic niche formation in colorectal cancer liver metastasis. Mol Cancer 23(1):168. (PMID: 10.1186/s12943-024-02086-93916475811334400)
Zhu D, Yuan S, Chen C (2023) Hedyotis diffusa-Sculellaria barbata (HD-SB) suppresses the progression of colorectal cancer cells via the hsa_circ_0039933/hsa-miR-204-5p/wnt11 axis. Sci Rep 13(1):13331. (PMID: 10.1038/s41598-023-40393-13758720710432535)
Zou Y, Wang S, Zhang H, Gu Y, Chen H, Huang Z, Yang F, Li W, Chen C, Men L et al (2024) The triangular relationship between traditional Chinese medicines, intestinal flora, and colorectal cancer. Med Res Rev 44(2):539–567. (PMID: 10.1002/med.2198937661373)
Grant Information: 202510095 Jiangxi Provincial Health Technology Project; 2023LNS17457 Ganzhou Municipal Science and Technology Project; BSQD2020011 Doctoral research start-up fund project of Ganzhou People's Hospital
Contributed Indexing: Keywords: Hedyotis diffusa Willd-Scutellaria barbata D.Don; Colorectal cancer; Epithelial-mesenchymal transition; Hsa_circ_0039933; Liver metastasis
Substance Nomenclature: 0 (RNA, Circular)
0 (Drugs, Chinese Herbal)
Entry Date(s): Date Created: 20260608 Date Completed: 20260906 Latest Revision: 20260906
Update Code: 20260907
DOI: 10.1007/s10528-026-11392-4
PMID: 42258086
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1573-4927
DOI:10.1007/s10528-026-11392-4