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

Chi Man Tsang, Kenneth Chat Pan Cheung, Yuk Chun Cheung, Kwan Man, Vivian Wai Yan Lui, Sai Wah Tsao, Yibin Feng

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

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 (10. mg/kg/2. days) 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.

Original languageEnglish (US)
Pages (from-to)541-551
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1852
Issue number3
DOIs
StatePublished - Mar 1 2015
Externally publishedYes

Keywords

  • Anti-cancer
  • Berberine
  • Hepatocellular carcinoma
  • Id-1
  • Metastasis

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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