Identification of microRNAs specific for epithelial cell... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Identification of microRNAs specific for epithelial cell adhesion molecule–positive tumor cells in hepatocellular carcinoma

Ji, Junfang*,1,2,3; Zheng, Xin2; Forgues, Marshonna3; Yamashita, Taro4; Wauthier, Eliane L.5; Reid, Lola M.5; Wen, Xinyu6; Song, Young6; Wei, Jun S.6; Khan, Javed6; Thorgeirsson, Snorri S.7; Wang, Xin Wei*,3

1Life Sciences Institute, Zhejiang UniversityHangzhouChina

2University of Hawaii Cancer Center, Cancer Biology Program (Ji), Epidemiology Program (Zheng)HonoluluHI

3Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer InstituteBethesdaMD

4Department of GastroenterologyKanazawa University HospitalKanazawaJapan

5Department of Cell Biology and Physiology and Program in Molecular Biology and BiotechnologyUNC School of MedicineChapel HillNC

6Genetics BranchCenter for Cancer Research, National Cancer InstituteBethesdaMD

7Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of HealthBethesdaMD

*Address reprint requests to: Xin Wei Wang, Ph.D., National Cancer Institute, 37 Convent Drive, MSC 4258, Bethesda, MD 20892. E‐mail: [email protected]; fax: +1‐301‐496‐0497; or Junfang Ji, Ph.D., University of Hawaii Cancer Center, 701 Ilalo Street, Room 336, Honolulu, HI 96813. E‐mail: [email protected]; fax: +1 808 587 0742; or Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang Province, China 310058. E‐mail: [email protected]; fax: +86‐571‐88981336.

Abstract

Therapies that target cancer stem cells (CSCs) hold promise in eliminating cancer burden. However, normal stem cells are likely to be targeted owing to their similarities to CSCs. It is established that epithelial cell adhesion molecule (EpCAM) is a biomarker for normal hepatic stem cells (HpSCs), and EpCAM+AFP+ hepatocellular carcinoma (HCC) cells have enriched hepatic CSCs. We sought to determine whether specific microRNAs (miRNAs) exist in hepatic CSCs that are not expressed in normal HpSCs. We performed a pair‐wise comparison of the miRNA transcriptome of EpCAM+ and corresponding EpCAM− cells isolated from two primary HCC specimens, as well as from two fetal livers and three healthy adult liver donors by small RNA deep sequencing. We found that miR‐150, miR‐155, and miR‐223 were preferentially highly expressed in EpCAM+ HCC cells, which was further validated. Their gene surrogates, identified using miRNA and messenger RNA profiling in a cohort of 292 HCC patients, were associated with patient prognosis. We further demonstrated that miR‐155 was highly expressed in EpCAM+ HCC cells, compared to corresponding EpCAM− HCC cells, fetal livers with enriched normal hepatic progenitors, and normal adult livers with enriched mature hepatocytes. Suppressing miR‐155 resulted in a decreased EpCAM+ fraction in HCC cells and reduced HCC cell colony formation, migration, and invasion in vitro. The reduced levels of identified miR‐155 targets predicted the shortened overall survival and time to recurrence of HCC patients. Conclusion: miR‐155 is highly elevated in EpCAM+ HCC cells and might serve as a molecular target to eradicate the EpCAM+ CSC population in human HCCs. (Hepatology 2015;62:829–840)