African Journal of
Biotechnology

  • Abbreviation: Afr. J. Biotechnol.
  • Language: English
  • ISSN: 1684-5315
  • DOI: 10.5897/AJB
  • Start Year: 2002
  • Published Articles: 12218

Full Length Research Paper

Multidrug-resistant hepatocellular carcinoma cells are enriched for CD133+ subpopulation through activation of TGF-β1/Smad3 pathway

Wei Yan
  • Wei Yan
  • Department of General Surgery, Zhongshan Hospital, Xiamen University,Xiamen 361004, People’s Republic of China; Department of Surgery, College of Medicine, Xiamen University, Xiamen 361005, People’s Republic of China.
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Fen Lin
  • Fen Lin
  • Department of General Surgery, Zhongshan Hospital, Xiamen University,Xiamen 361004, People’s Republic of China; Department of Surgery, College of Medicine, Xiamen University, Xiamen 361005, People’s Republic of China.
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Ting Wen
  • Ting Wen
  • Department of General Surgery, Zhongshan Hospital, Xiamen University,Xiamen 361004, People’s Republic of China; Department of Surgery, College of Medicine, Xiamen University, Xiamen 361005, People’s Republic of China.
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Zhongcai Liu
  • Zhongcai Liu
  • Department of General Surgery, Zhongshan Hospital, Xiamen University,Xiamen 361004, People’s Republic of China; Department of Surgery, College of Medicine, Xiamen University, Xiamen 361005, People’s Republic of China.
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Suqiong Lin
  • Suqiong Lin
  • Department of General Surgery, Zhongshan Hospital, Xiamen University,Xiamen 361004, People’s Republic of China; Department of Surgery, College of Medicine, Xiamen University, Xiamen 361005, People’s Republic of China.
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Guoyang Wu*
  • Guoyang Wu*
  • Department of General Surgery, Zhongshan Hospital, Xiamen University,Xiamen 361004, People’s Republic of China.
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  •  Received: 23 October 2011
  •  Accepted: 28 July 2014
  •  Published: 20 August 2014

Abstract

Chemotherapy is a main treatment for cancer, while multidrug-resistance is the main reason for chemotherapy failure, and tumor relapse and metastasis. Cancer stem cells or cancer stem-like cells (CSCs) are a small subset of cancer cells, which may be inherently resistant to the cytotoxic effect of chemotherapy. Some studies suggest that CSCs could be enriched by chemotherapy. However, the mechanism of chemotherapy regulating CSCs remains unknown. Therefore, we investigated whether drug treatment could enrich CSCs in hepatocellular carcinoma (HCC) cells and the molecular mechanism of chemotherapy regulating the expression of CSCs markers. In the present study, a multidrug-resistant (MDR) human HCC subline, Huh7.5.1/PTX, was developed by exposing parental cells to paclitaxel (PTX) repeatedly at a single high concentration. The cell counting kit-8 (CCK-8) assay was used to determine cellular sensitivity of various anticancer drugs. Flow cytometry (FCM) was used to analyze the CSCs markers expression level. Western blotting (WB) was used to analyze the changes of TGF-β1/Smads signaling. Our results show that PTX treatment of HCC cells in vitro resulted in a development of subline six months later, and Huh7.5.1/PTX, with stable MDR phenotype. Huh7.5.1/PTX cells enriched CSCs fraction and strongly activated the TGF-β1/Smad3 signaling. Activation of TGF-β1/Smad3 signaling resulted in enrichment of the CSCs population (CD133+ cells), while inhibition of this pathway activity attenuated the percentage of these cells. Taken together, our results suggest that MDR HCC cells are enriched with CSCs, which is partially dependent on TGF-β1/Smad3 pathway. Inhibition of TGF-β1/Smad3 pathway may be useful for targeting CSCs to develop more effective treatments for HCC.

 

Key words: Hepatocellular carcinoma (HCC) CD133, chemotherapy, cancer stem cells, TGF-β1, Smad3.

Abbreviation

Abbreviations: CSCs, Cancer stem cells or cancer stem-like cells; HCC, hepatocellular carcinoma; MDR, multidrug-resistant or multidrug-resistance; PTX, paclitaxel.