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In vitro and in vivo anti-metastatic effect of the alkaliod matrine from Sophora flavecens on hepatocellular carcinoma and its mechanisms.
Phytomedicine. 2021 Jul; 87:153580.P

Abstract

BACKGROUNDS

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancer with high metastasis and recurrence rates. Hypoxia-induced miRNAs and HIF-1α are demonstrated to play essential roles in tumor metastasis. Matrine (C15H24N2O), an alkaloid extracted from Sophora flavescens Aiton, has been used as adjuvant therapy for liver cancer in China. The anti-metastasis effects of matrine on HCC and the underlying mechanisms remain poorly understood.

PURPOSE

We aimed to investigate the effects of matrine on metastasis of HCC both in vitro and in vivo, and explored whether miR-199a-5p and HIF-1α are involved in the action of matrine.

METHODS

MTT method, colony formation, wound healing and matrigel transwell assays were performed to evaluate the effects of matrine on cell proliferation, migration and invasion. Nude mice xenograft model and immunohistochemistry (IHC) assay were employed to investigate the anti-metastatic action of matrine in vivo. Quantitative real-time PCR, western blot and dual luciferase reporter assay were conducted to determine the underlying mechanisms of matrine.

RESULTS

Matrine exerted stronger anti-proliferative action on Bel7402 and SMMC-7721 cells under hypoxia than that in normoxia. Both matrine and miR-199a-5p exhibited significant inhibitory effects on migration, invasion and EMT in Bel7402 and SMMC-7721 cells under hypoxia. Further study showed that miR-199a-5p was downregulated in HCC cell lines, and this microRNA was identified to directly target HIF-1α, resulting in decreased HIF-1α expression. Matrine induced miR-199a-5p expression, decreased HIF-1α expression and inhibited metastasis of Bel7402 and SMMC-7721 cells, while miR-199a-5p knockdown reversed the inhibitory effects of matrine on cell migration, invasion, EMT and HIF-1α expression. In vivo, matrine showed significant anti-metastatic activity in the nude mouse xenograft model. H&E and IHC analysis indicated that lung and liver metastasis nodules were reduced, and the protein expression of HIF-1α and Vimentin were significantly decreased by i.p injection of matrine.

CONCLUSIONS

Matrine exhibits significant anti-metastatic effect on HCC, which is attributed to enhanced miR-199a-5p expression and subsequently impaired HIF-1α signaling and EMT. These findings suggest that miR-199a-5p is a potential therapeutic target of HCC, and matrine may represent a promising anti-metastatic medication for HCC therapy.

Authors+Show Affiliations

Department of Pharmacy, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Boulevard (North), Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.Department of Pharmacy, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Boulevard (North), Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.Department of Pharmacy, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Boulevard (North), Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.Department of Pharmacy, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Boulevard (North), Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.Department of Pharmacy, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou Boulevard (North), Guangzhou 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: nfyyyxb@smu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34029939

Citation

Dai, Meiqin, et al. "In Vitro and in Vivo Anti-metastatic Effect of the Alkaliod Matrine From Sophora Flavecens On Hepatocellular Carcinoma and Its Mechanisms." Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, vol. 87, 2021, p. 153580.
Dai M, Chen N, Li J, et al. In vitro and in vivo anti-metastatic effect of the alkaliod matrine from Sophora flavecens on hepatocellular carcinoma and its mechanisms. Phytomedicine. 2021;87:153580.
Dai, M., Chen, N., Li, J., Tan, L., Li, X., Wen, J., Lei, L., & Guo, D. (2021). In vitro and in vivo anti-metastatic effect of the alkaliod matrine from Sophora flavecens on hepatocellular carcinoma and its mechanisms. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, 87, 153580. https://doi.org/10.1016/j.phymed.2021.153580
Dai M, et al. In Vitro and in Vivo Anti-metastatic Effect of the Alkaliod Matrine From Sophora Flavecens On Hepatocellular Carcinoma and Its Mechanisms. Phytomedicine. 2021;87:153580. PubMed PMID: 34029939.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro and in vivo anti-metastatic effect of the alkaliod matrine from Sophora flavecens on hepatocellular carcinoma and its mechanisms. AU - Dai,Meiqin, AU - Chen,Nana, AU - Li,Jinzhou, AU - Tan,Lizhuan, AU - Li,Xiaojuan, AU - Wen,Jiayong, AU - Lei,Linsheng, AU - Guo,Dan, Y1 - 2021/04/27/ PY - 2020/02/20/received PY - 2020/09/21/revised PY - 2021/04/18/accepted PY - 2021/5/25/pubmed PY - 2021/7/7/medline PY - 2021/5/24/entrez KW - EMT KW - HIF-1α KW - Hepatocellular carcinoma KW - Matrine KW - Metastasis KW - MiR-199a-5p SP - 153580 EP - 153580 JF - Phytomedicine : international journal of phytotherapy and phytopharmacology JO - Phytomedicine VL - 87 N2 - BACKGROUNDS: Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancer with high metastasis and recurrence rates. Hypoxia-induced miRNAs and HIF-1α are demonstrated to play essential roles in tumor metastasis. Matrine (C15H24N2O), an alkaloid extracted from Sophora flavescens Aiton, has been used as adjuvant therapy for liver cancer in China. The anti-metastasis effects of matrine on HCC and the underlying mechanisms remain poorly understood. PURPOSE: We aimed to investigate the effects of matrine on metastasis of HCC both in vitro and in vivo, and explored whether miR-199a-5p and HIF-1α are involved in the action of matrine. METHODS: MTT method, colony formation, wound healing and matrigel transwell assays were performed to evaluate the effects of matrine on cell proliferation, migration and invasion. Nude mice xenograft model and immunohistochemistry (IHC) assay were employed to investigate the anti-metastatic action of matrine in vivo. Quantitative real-time PCR, western blot and dual luciferase reporter assay were conducted to determine the underlying mechanisms of matrine. RESULTS: Matrine exerted stronger anti-proliferative action on Bel7402 and SMMC-7721 cells under hypoxia than that in normoxia. Both matrine and miR-199a-5p exhibited significant inhibitory effects on migration, invasion and EMT in Bel7402 and SMMC-7721 cells under hypoxia. Further study showed that miR-199a-5p was downregulated in HCC cell lines, and this microRNA was identified to directly target HIF-1α, resulting in decreased HIF-1α expression. Matrine induced miR-199a-5p expression, decreased HIF-1α expression and inhibited metastasis of Bel7402 and SMMC-7721 cells, while miR-199a-5p knockdown reversed the inhibitory effects of matrine on cell migration, invasion, EMT and HIF-1α expression. In vivo, matrine showed significant anti-metastatic activity in the nude mouse xenograft model. H&E and IHC analysis indicated that lung and liver metastasis nodules were reduced, and the protein expression of HIF-1α and Vimentin were significantly decreased by i.p injection of matrine. CONCLUSIONS: Matrine exhibits significant anti-metastatic effect on HCC, which is attributed to enhanced miR-199a-5p expression and subsequently impaired HIF-1α signaling and EMT. These findings suggest that miR-199a-5p is a potential therapeutic target of HCC, and matrine may represent a promising anti-metastatic medication for HCC therapy. SN - 1618-095X UR - https://www.unboundmedicine.com/medline/citation/34029939/In_vitro_and_in_vivo_anti_metastatic_effect_of_the_alkaliod_matrine_from_Sophora_flavecens_on_hepatocellular_carcinoma_and_its_mechanisms_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0944-7113(21)00122-7 DB - PRIME DP - Unbound Medicine ER -