Research Papers:

Increased expression of stemness markers and altered tumor stroma in hepatocellular carcinoma under TACE-induced hypoxia: A biopsy and resection matched study

Ji Hae Nahm, Hyungjin Rhee, Haeryoung Kim, Jeong Eun Yoo, Jee San Lee, Youngsic Jeon, Gi Hong Choi and Young Nyun Park _

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Oncotarget. 2017; 8:99359-99371. https://doi.org/10.18632/oncotarget.22078

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Ji Hae Nahm1,*, Hyungjin Rhee2,3,4,*, Haeryoung Kim5, Jeong Eun Yoo1,4,7, Jee San Lee1,3,4, Youngsic Jeon1,3,4, Gi Hong Choi6 and Young Nyun Park1,3,4,7

1Department of Pathology, Yonsei University College of Medicine, Seoul, Korea

2Department of Radiology, Yonsei University College of Medicine, Seoul, Korea

3Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea

4Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea

5Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

6Departments of General Surgery, Yonsei University College of Medicine, Seoul, Korea

7Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea

*These are contributed equally to this work

Correspondence to:

Young Nyun Park, email: [email protected]

Keywords: hepatocellular carcinoma; stemness; tumor stroma; transarterial chemoembolization; biopsy

Received: November 30, 2016     Accepted: October 11, 2017     Published: October 26, 2017


Background: Hepatocellular carcinomas (HCCs) expressing stemness markers are characterized by an aggressive behavior, which might be promoted by an altered tumor stroma. Transarterial chemoembolization (TACE) induces severe hypoxia, and its effect on stemness and tumor stroma of HCCs remains unclear. The purpose of this study was to evaluate the sequential changes of stemness and tumor stroma under TACE-induced hypoxia using biopsy and resection-matched HCCs.

Methods: Forty-six biopsy and resection matched HCCs including 10 cases with and 36 cases without preoperative TACE were selected. Immunohistochemistry for stemness (keratin 19 [K19], epithelial cell adhesion molecule [EpCAM], and CD133), hypoxia (carbonic anhydrase IX [CAIX] and vascular endothelial growth factor [VEGF]), and tumor stromal (α-smooth muscle actin [α-SMA] and fibroblast activation protein [FAP]) markers were performed and compared in matched biopsied and resected HCCs with and without TACE.

Results: The accuracy of K19, EpCAM, CD133, CAIX, VEGF, α-SMA and FAP detected on biopsied HCCs was 64% ~ 86%, using the expression status in resected HCCs as a reference standard in non-TACE group. The sequential change of hypoxia, stemness and stromal marker expression in matched biopsied and resected HCC was greater in TACE group than in non-TACE group (P < 0.05 for all). The degree of stemness marker expression was well correlated with those of tumor stromal markers, and the degree of CAIX expression was well correlated with that of K19 (P < 0.05).

Conclusions: Stemness marker expression is considered to be increased along with tumor stromal alteration under TACE-induced hypoxia, which might promote the aggressive biology of HCC.

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