Citri Reticulatae Pericarpium-Reynoutria japonica Houtt. herb pair suppresses breast cancer liver metastasis by targeting ECM1-mediated cholesterol biosynthesis pathway

Jue Wang; Yueqiang Chen; Zhanyang Luo; Qionglian Huang; Yu Zhang; Hanjuan Ning; Sheng Liu; Jianyi Wang; Xianghui Han

doi:10.1016/j.phymed.2023.154896

Citri Reticulatae Pericarpium-Reynoutria japonica Houtt. herb pair suppresses breast cancer liver metastasis by targeting ECM1-mediated cholesterol biosynthesis pathway

Phytomedicine. 2023 Jul 25:116:154896. doi: 10.1016/j.phymed.2023.154896. Epub 2023 May 22.

Authors

Jue Wang¹, Yueqiang Chen¹, Zhanyang Luo¹, Qionglian Huang¹, Yu Zhang², Hanjuan Ning¹, Sheng Liu³, Jianyi Wang⁴, Xianghui Han⁵

Affiliations

¹ Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
² Department of Liver Disease, Shanghai Yueyang Integrated Traditional Chinese Medicine and Western Medicine Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
³ Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: lshtcm@126.com.
⁴ Department of Liver Disease, Shanghai Yueyang Integrated Traditional Chinese Medicine and Western Medicine Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: wjydyj@163.com.
⁵ Institute of Chinese Traditional Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: hanxianghui1106@163.com.

PMID: 37247588
DOI: 10.1016/j.phymed.2023.154896

Abstract

Background: Liver metastasis is a frequent event in breast cancer that causes low survival rate and poor prognosis. Citri Reticulatae Pericarpium-Reynoutria japonica Houtt. (CR), a traditional Chinese herb pair, is used for the treatment of breast cancer liver metastasis or cholesterol gallstone disease in clinics.

Purpose: This study attempted to investigate the potential therapeutic target and mechanism of CR herb pair on breast cancer liver metastasis.

Methods: The anti-metastatic and cholesterol-lowering activities of CR extract were evaluated in triple-negative breast cancer (TNBC) cell lines and an experimental liver metastasis model. The role of extracellular matrix protein 1 (ECM1) in the cholesterol biosynthesis pathway was determined by the knockdown and overexpression of ECM1 gene of TNBC cells. Changes in the gene and protein expression levels of ECM1 and the cholesterol biosynthesis pathway after CR treatment were detected in vitro and in vivo by real-time PCR and Western blot.

Results: The invasive and metastatic potentials and hypercholesterol levels of TNBC cells were positively associated with ECM1 expression. ECM1 knockdown reduced tumor cholesterol levels via downregulating cholesterol biosynthesis genes, including ACAT2, HMGCS1, HMGCR, MVK, and MVD, whereas ECM1 overexpression elicited the opposite effects. CR herb pair exerts the potential therapeutic effects on TNBC liver metastasis, which is partially mediated by disrupting ECM1-activated cholesterol biosynthesis process in TNBC cells.

Conclusion: This study reveals that ECM1 is a novel target for the activation of cholesterol biosynthesis to promote TNBC liver metastasis occurrence. CR herb pair, an ECM1 inhibitor, maybe be considered to serve as an adjuvant therapeutic drug for liver metastasis in clinical practice.

Keywords: Citri Reticulatae Pericarpium; Reynoutria japonica Houtt.; breast cancer liver metastasis; cholesterol biosynthesis; extracellular matrix protein 1; herb pair.

MeSH terms

Cell Line, Tumor
Extracellular Matrix Proteins
Humans
Liver Neoplasms* / drug therapy
Reynoutria
Triple Negative Breast Neoplasms* / drug therapy

Substances

ECM1 protein, human
Extracellular Matrix Proteins