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Revealing New Therapeutic Targets in Induced Liver CSCs

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Review of “Positive Feedback Loop of OCT4 and c-JUN Expedites Cancer Stemness in Liver Cancer” from Stem Cells by Stuart P. Atkinson

The presence of cancer stem cells (CSCs) is thought to drive early metastasis and postoperative recurrence in liver cancers [1]. Therefore, targeting and destroying CSCs may be an effective therapy for CSC-associated tumors. 

To study liver CSCs in detail, researchers from the groups of Chang-Shen Lin and Kazunari K. Yokoyama (Kaohsiung Medical University, Taiwan) have reprogramed liver cancer cells into induced liver CSCs using the same strategy used to generate induced pluripotent stem cells (iPSCs) from normal human somatic cells. In their new Stem Cells study, the authors fully describe their strategy and go on to highlight OCT4 and c-JUN as two new therapeutic CSC targets for liver cancer treatment [2].

To first generate liver CSCs, Kuo et al reprogrammed human hepatoblastoma cells with lentiviruses encoding the Yamanaka (OSKM) reprogramming factors and a short hairpin RNA (shRNA) to knockdown TP53 (p53). This strategy permitted the derivation of a CSC-like cell line (rG2-DC-1C) which displayed potent tumorigenic in vivo characteristics and a CSC-like character (high proliferation, self-renewal, potent invasion capacity, and resistance to chemotherapy) in comparison to the parental cancer cell line.

Further analysis of induced liver CSCs highlighted an intricate interplay between the expression of OCT4, a pluripotency-associated transcription factor used in the generation of iPSCs, and c-JUN, an oncogenic transcription factor involved in glioma stem-like cell maintenance [3]. Each transcription factor transactivated the others promoter regions, so generating a positive feedback circuit, and the forced expression of OCT4 and c-JUN in mouse primary hepatocytes led to the acquisition of highly tumorigenic characteristics. Furthermore, the assessment of the OCT4 and c-JUN expression in matched hepatocellular carcinoma (HCC)/normal human tissues demonstrated a significant correlation between OCT4 expression and tumor size, tumor number, and the expression of c-JUN.

This excellent study has identified the relative importance of the OCT4/c-JUN transcriptional circuit to the tumorigenic nature of liver CSCs (See Figure) and, in doing so, may have provided new therapeutic targets and a model system in which to assess responses as well as an excellent biomarker/diagnostic tool.

Stay tuned to the Stem Cells Portal to keep up to date with how this promising research evolves.

References

  1. Bruix J, Boix L, Sala M, et al. Focus on hepatocellular carcinoma. Cancer Cell 2004;5:215-219.
  2. Kuo K-K, Lee K-T, Chen K-K, et al. Positive Feedback Loop of OCT4 and c-JUN Expedites Cancer Stemness in Liver Cancer. STEM CELLS 2016;34:2613-2624.
  3. Yoon CH, Kim MJ, Kim RK, et al. c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells. Oncogene 2012;31:4655-4666.