Research Papers:

Hepatic cancer stem cell marker granulin-epithelin precursor and β-catenin expression associate with recurrence in hepatocellular carcinoma

Phyllis F.Y. Cheung _, Tan To Cheung, Chi Wai Yip, Linda W.C. Ng, Sze Wai Fung, Chung Mau Lo, Sheung Tat Fan and Siu Tim Cheung

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Oncotarget. 2016; 7:21644-21657. https://doi.org/10.18632/oncotarget.7803

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Phyllis F.Y. Cheung1,2,3, Tan To Cheung3,4, Chi Wai Yip1,3, Linda W.C. Ng1, Sze Wai Fung1,3,5, Chung Mau Lo3,4, Sheung Tat Fan3, Siu Tim Cheung1,3,6

1Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China

2Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China

3Department of Surgery, The University of Hong Kong, Hong Kong, China

4Department of Surgery, Queen Mary Hospital, Hong Kong, China

5School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China

6Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China

Correspondence to:

Siu Tim Cheung, e-mail: [email protected]

Keywords: β-catenin, cancer stem cells, granulin-epithelin precursor, hepatocellular carcinoma

Received: July 17, 2015    Accepted: February 20, 2016    Published: March 01, 2016


Granulin-epithelin precursor (GEP) has been demonstrated to confer enhanced cancer stem-like cell properties in hepatocellular carcinoma (HCC) cell line models in our previous studies. Here, we aimed to examine the GEP-expressing cells in relation to the stem cell related molecules and stem-like cell properties in the prospective HCC clinical cohort. GEP protein levels were significantly higher in HCCs than the paralleled non-tumor liver tissues, and associated with venous infiltration. GEPhigh cells isolated from clinical HCC samples exhibited higher levels of stem cell marker CD133, pluripotency-associated signaling molecules β-catenin, Oct4, SOX2, Nanog, and chemodrug transporter ABCB5. In addition, GEPhigh cells possessed preferential ability to form colonies and spheroids, and enhanced in vivo tumor-initiating ability while their xenografts were able to be serially subpassaged into secondary mouse recipients. Expression levels of GEP and pluripotency-associated genes were further examined in the retrospective HCC cohort and demonstrated significant correlation of GEP with β-catenin. Notably, HCC patients with high GEP and β-catenin levels demonstrated poor recurrence-free survival. In summary, GEP-positive HCC cells directly isolated from clinical specimens showed β-catenin elevation and cancer stem-like cell properties.

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