Berberine suppresses Id-1 expression and inhibits the growth and development of lung metastases in hepatocellular carcinoma

• Published in: Biochimica et biophysica acta 2015-03, Vol.1852 (3), p.541-551
• Main Authors: Tsang, Chi Man, Cheung, Kenneth Chat Pan, Cheung, Yuk Chun, Man, Kwan, Lui, Vivian Wai-Yan, Tsao, Sai Wah, Feng, Yibin
• Format: Article
• Language: English
• Subjects: Animals; Anti-cancer; Berberine; Berberine - pharmacology; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic - drug effects; Hepatocellular carcinoma; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Id-1; Inhibitor of Differentiation Protein 1 - biosynthesis; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - prevention & control; Metastasis; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins - biosynthesis; Signal Transduction - drug effects; Vascular Endothelial Growth Factor A - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2014.12.004

Hepatocellular carcinoma (HCC) is an invasive cancer with a high rate of recurrence and metastasis. Agents with anti-proliferative as well as anti-metastatic activity will be ideal for effective treatment. Here, we demonstrated that berberine, an isoquinoline alkaloid, harbored potent anti-metastatic and anti-proliferative activities in vivo. Using an orthotopic model of HCC (MHCC-97L), which spontaneously develops lung metastases (one of the most common sites of HCC metastasis), we found that berberine treatment (10mg/kg/2days) significantly reduced lung metastasis from the liver tumors by ~85% (quantitated by bioluminescence emitted from lung metastases). Histological examination also confirmed the reduced incidence and number of lung metastases in berberine-treated mice. Furthermore, berberine effectively suppressed extra-tumor invasion of the primary HCC implant into the surrounding normal liver tissue, illustrating its potent anti-metastatic action in vivo. Consistent with previous reports in other cancer, berberine's anti-tumor activity was accompanied by suppression of cellular proliferation, invasiveness and HIF-1α/VEGF signaling. Strikingly, further mechanistic investigation revealed that berberine exerted profound inhibitory effect on the expression of Id-1, which is a key regulator for HCC development and metastasis. Berberine could suppress the transcription level of Id-1 through inhibiting its promotor activity. Specific downregulation of Id-1 by knocking down its RNA transcripts in HCC cells inhibited cellular growth, invasion and VEGF secretion, demonstrating the functional relevance of Id-1 downregulation induced by berberine. Lastly, berberine's anti-proliferative and anti-invasive activities could be partially rescued by Id-1 overexpression in HCC models, revealing a novel anti-cancer/anti-invasive mechanism of berberine via Id-1 suppression. •HCC growth and metastasis are suppressed by berberine in orthotopic mice model.•Berberine reduces local invasion and lung metastasis from the liver tumors.•Berberine downregulates Id-1 expression by inhibiting the Id-1 promoter.•Id-1 knockdown inhibits cellular proliferation and invasion of HCC cells.•The anti-growth and anti-metastatic effects of berberine are mediated by Id-1.