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Delineating Tcf7l1-mediated Liver Cancer Stem Cell Regulation

Review of “Tcf7l1 Acts as a Suppressor for the Self‐Renewal of Liver Cancer Stem Cells and Is Regulated by IGF/MEK/ERK Signaling Independent of β‐Catenin” from STEM CELLS by Stuart P. Atkinson

Multiple reports have linked the elevated expression of Transcription factor 7-like 1 (Tcf7l1), a key effector of the Wnt/β‐catenin signaling pathway, to tumorigenesis [1-4]. Additionally, a previous study from the laboratories of Yuanliang Wang and Cheng Qian (Chongqing University, Chongqing, China) established Tcf7l1 as a microRNA‐449a target and demonstrated its downregulated expression in liver cancer stem cells (CSCs) from hepatocarcinoma patients [5]. Further analyses also determined that Tcf7l1 overexpression reduced sphere and colony formation abilities, thereby implicating Tcf7l1 in the regulation of liver CSC self‐renewal; however, we still lack information regarding the mechanisms and signaling pathways associated with Tcf7l1 in hepatocarcinoma. 

Now, the team returns with a new STEM CELLS study that has investigated the expression patterns and potential roles of Tcf7l1, thereby elucidating the regulatory mechanism of Tcf7l1 in hepatocarcinoma and liver CSCs [6]. These findings provide new insight into the extracellular signals that modulate liver CSC self‐renewal and highlight the inhibitory roles of Tcf7l1 in cancer.

Shan et al. first assessed Tcf7l1 expression in hepatocarcinoma patients, finding aberrantly low Tcf7l1 expression in cancer cells when compared to nearby healthy tissues, a negative correlation between Tcf7l1 expression and pathological grade/tumor stage, and a significantly poorer prognosis for those patients with low expression levels of Tcf7l1 in tumors.

The team also confirmed low levels of expression of Tcf7l1 in liver CSCs when compared to non-CSCs, and subsequently discovered  found that ectopic expression of Tcf7l1 inhibited CSC self‐renewal abilities (reduced colony formation and sphere formation) by the significant transcriptional downregulation of pluripotency-associated genes, including Nanog, Oct4, Klf4, and upregulation of differentiation-associated genes, including G6p and transthyretin. The authors also provided evidence that Tcf7l1 directly repressed the expression of the Nanog gene, which contains three Tcf7l1 recognition sites close to the transcriptional start site. 

Interestingly, Tcf7l1 overexpression also reduced the tumorigenic potential of liver CSCs, as evidenced by an increased sensitivity of liver CSCs to Adriamycin and impaired liver CSC tumor initiation and growth. Furthermore, the authors demonstrated that the overexpression of a β‐catenin binding‐deficient Tcf7l1 prompted similar effects to wild-type Tcf7l1, suggesting that Tcf7l1‐suppressed self‐renewal of liver CSCs is independent of β‐catenin.

Finally, the study sought to understand the potential control of liver CSCs by extrinsic factors and intrinsic responsive signals and they established, for the first time, that insulin‐like growth factor (IGF) signaling (IGF2 specifically) markedly repressed Tcf7l1 protein expression by stimulating the phosphorylation, ubiquitylation, and the subsequent degradation of Tcf7l1 (also independently of β‐catenin) through the mitogen‐activated protein kinase (MEK)/extracellular signal‐regulated kinase (ERK) pathway; a finding that provides new insight into how extracellular signals modulates liver CSC self‐renewal.

For more information on the mechanisms and signaling pathways associated with Tcf7l1 in hepatocarcinoma and liver cancer stem cells, stay tuned to the Stem Cells Portal!

References

  1. Slyper M, Shahar A, Bar-Ziv A, et al., Control of Breast Cancer Growth and Initiation by the Stem Cell–Associated Transcription Factor TCF3. Cancer Research 2012;72:5613.
  2. Murphy M, Chatterjee SS, Jain S, et al., TCF7L1 Modulates Colorectal Cancer Growth by Inhibiting Expression of the Tumor-Suppressor Gene EPHB3. Scientific Reports 2016;6:28299.
  3. Eshelman MA, Shah M, Raup-Konsavage WM, et al., TCF7L1 recruits CtBP and HDAC1 to repress DICKKOPF4 gene expression in human colorectal cancer cells. Biochemical and Biophysical Research Communications 2017;487:716-722.
  4. Ku AT, Shaver TM, Rao AS, et al., TCF7L1 promotes skin tumorigenesis independently of β-catenin through induction of LCN2. eLife 2017;6:e23242.
  5. Zhang Q, Yang Z, Shan J, et al., MicroRNA-449a maintains self-renewal in liver cancer stem-like cells by targeting Tcf3. Oncotarget 2017;8:110187-110200.
  6. Shan J, Shen J, Wu M, et al., Tcf7l1 Acts as a Suppressor for the Self-Renewal of Liver Cancer Stem Cells and Is Regulated by IGF/MEK/ERK Signaling Independent of β-Catenin. STEM CELLS 2019;37:1389-1400.