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Oviductus ranae protein hydrolysate (ORPH) inhibits the growth, metastasis and glycolysis of HCC by targeting miR-491-5p/PKM2 axis.
Biomed Pharmacother. 2018 Nov; 107:1692-1704.BP

Abstract

BACKGROUND

Oviductus Ranae (OR) is a valuable Chinese crude drug and has been reported to have a range of biological activities. Protein hydrolysate extracted from OR (ORPH) was previously found to have immune regulatory effect and anti-glioma activity. This study was aimed to investigate the effects of ORPH on hepatocellular carcinoma (HCC) progression.

METHODS

MTT, BrdU, colony formation and transwell assays were used to determine proliferation and mobility of HCC cells in vitro. Glucose consumption and lactate production assays were carried out to measure the glycolysis of HCC cells. The subcutaneous tumor model and lung metastasis model in nude mice were established to detect tumor growth and metastasis of HCC in vivo. The direct binding of miR-491-5p to 3'UTR of pyruvate kinase M2 (PKM2) was confirmed by luciferase reporter assay.

RESULTS

In vitro experiments showed that ORPH significantly inhibited proliferation, migration, invasion, epithelial-to-mesenchymal transition (EMT) and glycolysis of HCC cells. Moreover, ORPH treatment prominently suppressed HCC growth and metastasis in mice. We demonstrated that ORPH effectively decreased the expression of PKM2 in HCC cells. Forced expression of PKM2 abrogated the inhibitory effects of ORPH on HCC cells. Mechanically, ORPH reduced PKM2 expression in a post-transcriptional manner by up-regulating miR-491-5p. miR-491-5p exhibited a similar tumor suppressive effects with ORPH in HCC cells. Moreover, ORPH exerted its inhibitory effects on HCC cells through regulating miR-491-5p/PKM2 axis. Lastly, decreased miR-491-5p level and increased PKM2 expression were correlated with unfavorable clinical features and poor prognosis of HCC patients.

CONCLUSIONS

In all, this study reveals that ORPH inhibits the growth, metastasis and glycolysis of HCC cells by targeting miR-491-5p/PKM2 axis. ORPH may be a potential effective anti-tumor agent for HCC.

Authors+Show Affiliations

Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang Province 310014, China. Electronic address: windway626@sina.com.Department of Hepatobiliary Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang Province 310014, China; Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China. Electronic address: douchangwei168@sina.com.Department of Neurosurgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang Province 310014, China. Electronic address: liuxindongdong@sina.com.Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang Province 310014, China. Electronic address: yangliuqq2003@163.com.Department of General Surgery, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang Province 310014, China. Electronic address: davenc@163.com.School of Basic Medical Sciences, Shandong University, Jinan, Shandong Province 250000, China. Electronic address: 947059896@qq.com.BengBu Medical College, Bengbu, Anhui Province 233030, China. Electronic address: 15605605165@163.com.Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province 710061, China. Electronic address: dr_bobyang@163.com.Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang Province 310014, China. Electronic address: tongxiangmin@163.com.Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital (People's Hospital of Hangzhou Medical College), Hangzhou, Zhejiang Province 310014, China. Electronic address: dshuang@zju.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30257387

Citation

Xu, Qiuran, et al. "Oviductus Ranae Protein Hydrolysate (ORPH) Inhibits the Growth, Metastasis and Glycolysis of HCC By Targeting miR-491-5p/PKM2 Axis." Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, vol. 107, 2018, pp. 1692-1704.
Xu Q, Dou C, Liu X, et al. Oviductus ranae protein hydrolysate (ORPH) inhibits the growth, metastasis and glycolysis of HCC by targeting miR-491-5p/PKM2 axis. Biomed Pharmacother. 2018;107:1692-1704.
Xu, Q., Dou, C., Liu, X., Yang, L., Ni, C., Wang, J., Guo, Y., Yang, W., Tong, X., & Huang, D. (2018). Oviductus ranae protein hydrolysate (ORPH) inhibits the growth, metastasis and glycolysis of HCC by targeting miR-491-5p/PKM2 axis. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 107, 1692-1704. https://doi.org/10.1016/j.biopha.2018.07.071
Xu Q, et al. Oviductus Ranae Protein Hydrolysate (ORPH) Inhibits the Growth, Metastasis and Glycolysis of HCC By Targeting miR-491-5p/PKM2 Axis. Biomed Pharmacother. 2018;107:1692-1704. PubMed PMID: 30257387.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Oviductus ranae protein hydrolysate (ORPH) inhibits the growth, metastasis and glycolysis of HCC by targeting miR-491-5p/PKM2 axis. AU - Xu,Qiuran, AU - Dou,Changwei, AU - Liu,Xin, AU - Yang,Liu, AU - Ni,Chao, AU - Wang,Jiahui, AU - Guo,Yang, AU - Yang,Wei, AU - Tong,Xiangmin, AU - Huang,Dongsheng, Y1 - 2018/09/08/ PY - 2018/05/27/received PY - 2018/06/30/revised PY - 2018/07/13/accepted PY - 2018/9/28/entrez PY - 2018/9/28/pubmed PY - 2019/1/4/medline KW - Hepatocellular carcinoma KW - Metastasis KW - ORPH KW - PKM2 KW - Tumor growth KW - miR-491-5p SP - 1692 EP - 1704 JF - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JO - Biomed Pharmacother VL - 107 N2 - BACKGROUND: Oviductus Ranae (OR) is a valuable Chinese crude drug and has been reported to have a range of biological activities. Protein hydrolysate extracted from OR (ORPH) was previously found to have immune regulatory effect and anti-glioma activity. This study was aimed to investigate the effects of ORPH on hepatocellular carcinoma (HCC) progression. METHODS: MTT, BrdU, colony formation and transwell assays were used to determine proliferation and mobility of HCC cells in vitro. Glucose consumption and lactate production assays were carried out to measure the glycolysis of HCC cells. The subcutaneous tumor model and lung metastasis model in nude mice were established to detect tumor growth and metastasis of HCC in vivo. The direct binding of miR-491-5p to 3'UTR of pyruvate kinase M2 (PKM2) was confirmed by luciferase reporter assay. RESULTS: In vitro experiments showed that ORPH significantly inhibited proliferation, migration, invasion, epithelial-to-mesenchymal transition (EMT) and glycolysis of HCC cells. Moreover, ORPH treatment prominently suppressed HCC growth and metastasis in mice. We demonstrated that ORPH effectively decreased the expression of PKM2 in HCC cells. Forced expression of PKM2 abrogated the inhibitory effects of ORPH on HCC cells. Mechanically, ORPH reduced PKM2 expression in a post-transcriptional manner by up-regulating miR-491-5p. miR-491-5p exhibited a similar tumor suppressive effects with ORPH in HCC cells. Moreover, ORPH exerted its inhibitory effects on HCC cells through regulating miR-491-5p/PKM2 axis. Lastly, decreased miR-491-5p level and increased PKM2 expression were correlated with unfavorable clinical features and poor prognosis of HCC patients. CONCLUSIONS: In all, this study reveals that ORPH inhibits the growth, metastasis and glycolysis of HCC cells by targeting miR-491-5p/PKM2 axis. ORPH may be a potential effective anti-tumor agent for HCC. SN - 1950-6007 UR - https://www.unboundmedicine.com/medline/citation/30257387/Oviductus_ranae_protein_hydrolysate__ORPH__inhibits_the_growth_metastasis_and_glycolysis_of_HCC_by_targeting_miR_491_5p/PKM2_axis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0753-3322(18)33607-2 DB - PRIME DP - Unbound Medicine ER -