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World J Gastroenterol. Dec 21, 2013; 19(47): 8850-8860
Published online Dec 21, 2013. doi: 10.3748/wjg.v19.i47.8850
Cellular reprogramming and hepatocellular carcinoma development
Yun-Wen Zheng, Yun-Zhong Nie, Hideki Taniguchi
Yun-Wen Zheng, Yun-Zhong Nie, Hideki Taniguchi, Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan
Yun-Wen Zheng, Jiangsu University Hospital, Zhenjiang, Jiangsu 212001, China
Hideki Taniguchi, Advanced Medical Research Center, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan
Author contributions: Zheng YW and Nie YZ contributed equally to this work; Zheng YW designed, wrote, reviewed and revised the manuscript; Nie YZ wrote the paper; Taniguchi H approved the final version.
Supported by Grants-in-Aid No.18591421, No. 20591531 and No. 23591872 for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, grant from the Research Center Network for Realization of Regenerative Medicine and grants for Strategic Promotion of Innovative Research and Development (S-innovation, 62890004) from the Japan Science and Technology Agency
Correspondence to: Hideki Taniguchi, MD, PhD, Department of Regenerative Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan.
Telephone: +81-45-7878963 Fax: +81-45-7878963
Received: September 28, 2013
Revised: November 13, 2013
Accepted: November 28, 2013
Published online: December 21, 2013

Hepatocellular carcinoma (HCC) is one of the most common cancers, and is also the leading cause of death worldwide. Studies have shown that cellular reprogramming contributes to chemotherapy and/or radiotherapy resistance and the recurrence of cancers. In this article, we summarize and discuss the latest findings in the area of cellular reprogramming in HCC. The aberrant expression of transcription factors OCT4, KLF4, SOX2, c-MYC, NANOG, and LIN28 have been also observed, and the expression of these transcription factors is associated with unfavorable clinical outcomes in HCC. Studies indicate that cellular reprogramming may play a critical role in the occurrence and recurrence of HCC. Recent reports have shown that DNA methylation, miRNAs, tumor microenvironment, and signaling pathways can induce the expression of stemness transcription factors, which leads to cellular reprogramming in HCC. Furthermore, studies indicate that therapies based on cellular reprogramming could revolutionize HCC treatment. Finally, a novel therapeutic concept is discussed: reprogramming control therapy. A potential reprogramming control therapy method could be developed based on the reprogramming demonstrated in HCC studies and applied at two opposing levels: differentiation and reprogramming. Our increasing understanding and control of cellular programming should facilitate the exploitation of this novel therapeutic concept and its application in clinical HCC treatment, which may represent a promising strategy in the future that is not restricted to liver cancer.

Keywords: Reprogramming, Hepatocellular carcinomas, Cancer stem cells, Transcription factor, Therapeutics

Core tip: Cellular reprogramming contributes to chemoresistance and radioresistance and cancer recurrence in hepatocellular carcinoma (HCC). Recent findings on cellular reprogramming in HCC are summarized and discussed, including stemness transcription factors, DNA methylation, miRNAs, tumor microenvironments, and signaling pathways. The novel therapeutic concept of reprogramming control therapy is also described, which may be a promising strategy for HCC therapy in the future.