title: Tg737 inhibition results in malignant transformation in fetal liver stem/progenitor cells by promoting cell-cycle progression and differentiation arrest.
abstract: Cancer stem/progenitor cells (CSPCs) may originate from the malignant transformation of normal stem cells. However, the mechanism by which normal stem cells undergo such transformation is not understood. Our previous studies provided evidence that Tg737 may play an important role in carcinogenesis of liver stem cells. In this study, we investigated the role of Tg737 in the malignant transformation of fetal liver stem/progenitor cells (FLSPCs). We inhibited Tg737 in FLSPCs using short hairpin RNA (shRNA). The microscopic observations of freshly purified Tg737 normal FLSPCs (nFLSPCs) and Tg737-silent FLSPCs (sFLSPCs), which showed high expression levels of stem cell markers, revealed no significant morphological changes in sFLSPCs. Following RNAi of Tg737, the mRNA and protein levels of sFLSPCs decreased by 81.81% and 80.10% as shown by PCR, Western blot and immunocytochemistry analyses. Excluding apoptosis-related effects, we found that silencing of Tg737 resulted in enhanced cell proliferation through promoting cell-cycle progression via upregulation of cyclin D1 and cyclin B expression (P < 0.05). Silencing of Tg737 also resulted in significant arrest of cell differentiation (P < 0.05), stable expression of both albumin (ALB) and alpha fetoprotein (AFP) (P > 0.05) and quiescent ultrastructure. Assessment of cell malignant traits by transwell migration assays and by growth of xenograft tumors in athymic mice showed that reduced expression of Tg737 greatly promoted cell invasion and hepatocarcinogenesis of FLSPCs (P < 0.05). This work shows that inactivation of Tg737 may play an important role in malignant transformation of FLSPCs.
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, P. R. China.
authors.forename: Nan
authors.initials: N
authors.lastname: You
authors.forename: Weihui
authors.initials: W
authors.lastname: Liu
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhong
authors.forename: Ru
authors.initials: R
authors.lastname: Ji
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Houcheng
authors.initials: H
authors.lastname: You
authors.forename: Kefeng
authors.initials: K
authors.lastname: Dou
authors.forename: Kaishan
authors.initials: K
authors.lastname: Tao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D053686:Fetal Stem Cells / Q000378:metabolism* / Q000637:transplantation / Q000648:ultrastructure; D008099:Liver / Q000166:cytology / Q000196:embryology; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D025521:Tumor Suppressor Proteins