| Primary liver cancer is the most common malignancy in China. It is also recognized as the third cause of cancer death worldwide, and the second in China. Despite enormous progress made in the research field and surgical resection or orthotopic liver transplantation has been considered as the efficient therapy for patients with HCC, metastasis and recurrence remain the major obstacles for further prolonged survival. Elucidating molecular mechanisms of HCC recurrence/metastasis and searching for effective target therapies are the most important pathway to improve survival.In 2006, Yamanaka et al. first reprogrammed mouse somatic fibroblasts into induced pluripotent stem (iPS) cells by forced expression of four transcription factors:OCT4,SOX2,KLF4 and C-MYC. In 2007, Thomson's group used the lentiviral transduction to reprogram human somatic cells to iPS with defined factors:OCT4,SOX2,NANOG,LIN28. Like ES cells, iPS cells have the potential to generate all the cell types of the body, and have important characteristics including self-renewal, pluripotency. These studies suggested OCT4,SOX2,C-MYC,KLF4,NANOG and LIN28 were the key genes for self-renewal, pluripotency.Based on cancer stem cell theory, cancer stem cells share many common features with embryonic stem cells such as potency of self-renewal, pluripotency. There is growing evidence of cross-talk and correlation between stemness pathways, tumor progression, and metastasis; If cancer stem cells are the origin of tumor recurrence and metastasis, the related signal pathway may play an important role in tumor progression. Cancer cells with high expression of OCT4,SOX2,C-MYC,KIF4,NANOG, LIN28 in HCC may be stem-like cells and probably are the seeds of recurrence and metastasis after radical treatment.To elucidate the role of OCT4,SOX2,C-MYC,KLF4,NANOG,LIN28 in hepatocellular carcinoma recurrence and metastasis, allow a better understanding of HCC initiation and progression, as well as establish precise targets for the development of more effective therapies, expression of transcription factors OCT4,SOX2,C-MYC,KLF4,NANOG,1IN28 were detected in normal hepatic cells,five HCC cell lines with different metastatic potentials and clinical tumor samples by Western blot, Realtime RT-PCR and immunohistochemistry method.Partâ… Expression of iPS transcription factors in hepatocellular carcinoma cell linesObjective:We detected the expression of OCT4,SOX2,C-MYC,KLF4,NANOG,LIN28 in hepatocellular carcinoma cell lines with Western blot and q RT-PCR.Methods:Total protein and RNA were extracted from normal hepatic cell line 7701 and HCC cell lines with different metastatic potentials. Expression of iPS transcription factors were detected by Western blot and Realtime RT-PCR.Results:Results from Western blot and Realtime RT-PCR showed high expression of OCT4, NANOG were leveled with increasing metastatic potential of cell lines. The different expression reached statistic significance (P<0.001, P=0.007). Expression of SOX2 also higher in high metastatic potential cell lines than low metastatic potential cell lines, but did not reach statistic significance (P=0.12).This study identified three potential iPS transcription factors correlated to invasive ability and metastasis in hepatocellular carcioma.Partâ…¡Expression of iPS transcription factors in hepatocellular carcinoma samples and their relationship with postoperative recurrence. Objective:The purpose of this study is to investigate the relationship between iPS transcription factors with postoperative recurrence in patients with hepatocellular carcinoma.Methods:Total RNA were extracted from clinical tumor samples of 57 patients undergoing surgical resection from 2006-2008 in Zhongshan Hospital, Liver Cancer Institute, Fudan University.57 patients were divided into two groups according to postoperative recurrence. mRNA expression of six iPS transcription factors were measured in two groups.Results:mRNA expression of OCT4 and NANOG were higher in recurrent group than non-recurrent group, although the difference did not reach statistic significance. The result suggested high expression of OCT4 and NANOG may be risk factors for postoperative recurrence.Partâ…¢Role of transcription factors OCT4 and NANOG in recurrence,metastasis and prognosis of hepatocellular carcinoma.Objective:To evaluate the expression of OCT4 and NANOG in hepatocellular carcinoma and discuss its clinical implications with recurrence,metastasis and prognosis.Methods:323 cases of HCC patients underwent radical resections from January 2003 to March 2004 in Zhongshan Hospital, Liver Cancer Institute, Fudan University. The corresponding blocks were manufactured into two groups of tissue microarray:group HCC and their corresponding tumor adjacent tissues. The expression of OCT4, NANOG were studied by immunohistochcmistry method. Difference between expression of OCT4, NANOG in HCC and adjacent liver tissues, and the relationship of the two iPS transcription factors with clinical pathological features and prognosis of HCC were analyzed. Results:Expression of OCT4 and NANOG were significantly higher in tumor tissues than that in tumor adjacent tissues.In tumor tissues,78.4% patients were found positively expressed of OCT4 in tumor cell nuclear and 69.4% patients were found positively expressed of NANOG. Expressive rate in nuclear were 0.5%-24.6% (mean:7.6%)for OCT4 and 1%-12.4%(mean:5.4%) for NANOG.There was no relationship between OCT4 or NANOG with clinical pathological features. Double positive expression of OCT4 and NANOG were found correlated with tumor size (P=0.03) and vascular invasion (P=0.006).Survival analysis revealed that co-expression of OCT4 and NANOG correlated to unfavorable overall survival after operation. As for patients with co-expression of OCT4 and NANOG, risk for postoperative death were 1.9 higher than that of negative patients. Although OCT4 and NANOG were identified important prognostic factors for survival in univariate analysis, they were not independent factors for prognosis in multivariate analysis. Co-expression of OCT4 and NANOG was an independent risk factor for unfavorable prognosis (P<0.001).Compared with OCT4 negative group, the 1,3,5 year recurrent rates were significantly higher in OCT4 positive group(P=0.006). The recurrent rates of NANOG positive group was also higher than NANOG negative group, but no difference were found with statistic significance (P=0.09). COX proportional hazard model identified expression of OCT4 (P=0.005) or co-expression of OCT4 and NANOG (P=0.007) were independent risk factor of postoperative recurrence.ConclusionsSelf-renewal and pluripotency are the central features in the definition of embryonic stem cells (ESC), in which OCT4 and NANOG play a key role in the maintenance of these processes. The preset study has demonstrated the expression of OCT4 and NANOG were correlated with recurrence, metastasis and poor prognosis in HCC. We speculate the two transcription factor can induce cancer stem cell-like properties and tumor cells with double positivity of OCT4 and NANOG may be stem-like cells, the seed of the tumorigenesis, recurrence, metastasis in HCC. We propose that OCT4 and NANOG would be potential markers of prognosis and novel targets of therapy for HCC.Novelty1. We first demonstrate iPS transcription factors OCT4 and NANOG, which are the key factors maintaining potency of self-renewal, pluripotency in ESC, attributed to recurrence/metastatic potentials in hepatocellular carcinoma.2.OCT4 and NANOG can be new targets for therapy inhibiting recurrence and metastasis after radical treatment in HCC. |
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