Pien Tze Huang inhibits metastasis of human colorectal carcinoma cells via modulation of TGF-β1/ZEB/miR-200 signaling network

Abstract

Tumor metastasis, a complex process involving the spread of malignant tumor cells from a primary tumor site to a distant organ, is a major cause of failure of cancer chemotherapy. Epithelial-mesenchymal transition (EMT) is a critical step for the initiation of cancer metastasis. The processes of EMT and metastasis are highly regulated by a double-negative feedback loop consisting of TGF-β1/ZEB pathway and miR-200 family, which therefore has become a promising target for cancer chemotherapy. Pien Tze Huang (PZH), a well-known traditional Chinese formula first prescribed in the Ming Dynasty, has been demonstrated to be clinically effective in the treatment of various types of human malignancy including colorectal cancer (CRC). Our published data proposed that PZH was able to induce apoptosis, inhibit cell proliferation and tumor angiogenesis, leading to the suppression of CRC growth in vitro and in vivo. To further elucidate the mode of action of PZH, in the present study we evaluated its effects on the metastatic capacities of human colorectal carcinoma HCT-8 cells and investigated the underlying molecular mechanisms. We found that PZH significantly inhibited the migration and invasion of HCT-8 cells in a dose-dependent manner. In addition, PZH treatment inhibited the expression of key mediators of TGF-β1 signaling, such as TGF-β1, Smad2/3 and Smad4. Moreover, PZH treatment suppressed the expression of ZEB1 and ZEB2, two critical target genes of TGF-β1 pathway, leading to a decrease in the expression of mesenchymal marker N-cadherin and an increased expression of epithelial marker E-cadherin. Furthermore, PZH treatment upregulated the expression of miR-200a, miR-200b and miR-200c. Collectively, our findings in this study suggest that PZH can inhibit metastasis of colorectal cancer cells via modulating TGF-β1/ZEB/miR-200 signaling network, which might be one of the mechanisms whereby PZH exerts its anticancer function.