RRC ID 39657
Author Kuo KK, Lee KT, Chen KK, Yang YH, Lin YC, Tsai MH, Wuputra K, Lee YL, Ku CC, Miyoshi H, Nakamura Y, Saito S, Wu CC, Chai CY, Eckner R, Steve Lin CL, Wang SS, Wu DC, Lin CS, Yokoyama KK.
Title Positive Feedback Loop of OCT4 and c-JUN Expedites Cancer Stemness in Liver Cancer.
Journal Stem Cells
Abstract The network of stemness genes and oncogenes in human patient-specific reprogrammed cancer stem cells (CSCs) remains elusive, especially in liver cancer. HepG2-derived induced pluripotent stem cell-like cells (HepG2-iPS-like cells) were generated by introducing Yamanaka factors and the knockdown vector shTP53. They exhibited features of stemness and a higher tumorigenesis after xenograft transplantation compared with HepG2 cells. The cancerous mass of severe combined immunodeficiency (SCID) mice derived from one colony was dissected and cultured to establish reprogrammed HepG2-derived CSC-like cells (designated rG2-DC-1C). A single colony exhibited 42% occurrence of tumors with higher proliferation capacities. rG2-DC-1C showed continuous expression of the OCT4 stemness gene and of representative tumor markers, potentiated chemoresistance characteristics, and invasion activities. The sphere-colony formation ability and the invasion activity of rG2-DC-1C were also higher than those of HepG2 cells. Moreover, the expression of the OCT4 gene and the c-JUN oncogene, but not of c-MYC, was significantly elevated in rG2-DC-1C, whereas no c-JUN expression was observed in HepG2 cells. The positive-feedback regulation via OCT4-mediated transactivation of the c-JUN promoter and the c-JUN-mediated transactivation of the OCT4 promoter were crucial for promoting cancer development and maintaining cancer stemness in rG2-DC-1C. Increased expression of OCT4 and c-JUN was detected in the early stage of human liver cancer. Therefore, the positive feedback regulation of OCT4 and c-JUN, resulting in the continuous expression of oncogenes such as c-JUN, seems to play a critical role in the determination of the cell fate decision from iPS cells to CSCs in liver cancer. Stem Cells 2016;34:2613-2624.
Volume 34(11)
Pages 2613-2624
Published 2016-11-1
DOI 10.1002/stem.2447
PMID 27341307
MeSH Aged Animals Antineoplastic Agents / pharmacology Cell Differentiation Cellular Reprogramming Cisplatin / pharmacology Doxorubicin / pharmacology Drug Resistance, Neoplasm / genetics Feedback, Physiological* Female Fluorouracil / pharmacology Gene Expression Regulation, Neoplastic* Hep G2 Cells Humans Induced Pluripotent Stem Cells / drug effects Induced Pluripotent Stem Cells / metabolism Induced Pluripotent Stem Cells / pathology JNK Mitogen-Activated Protein Kinases / genetics* JNK Mitogen-Activated Protein Kinases / metabolism Liver Neoplasms / drug therapy Liver Neoplasms / genetics* Liver Neoplasms / metabolism Liver Neoplasms / pathology Male Mice Mice, SCID Middle Aged Neoplastic Stem Cells / drug effects Neoplastic Stem Cells / metabolism* Neoplastic Stem Cells / pathology Octamer Transcription Factor-3 / genetics* Octamer Transcription Factor-3 / metabolism Signal Transduction Spheroids, Cellular / drug effects Spheroids, Cellular / metabolism Spheroids, Cellular / pathology Transcriptional Activation Tumor Burden / drug effects Xenograft Model Antitumor Assays
IF 5.614
Times Cited 16
DNA material AxCAmc-Jun (forward) (RDB02762) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394)
Human and Animal Cells Hep G2(RCB1886) 293T(RCB2202) iPS-Hep-FB/Ng/gfp-103C-1(APS0007)