Positive Feedback Loop of OCT4 and c-JUN Expedites Cancer Stemness in Liver Cancer.

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.

Continuous intra-arterial chemotherapy for downstaging locally advanced oral commissure carcinoma.

BACKGROUND: The purpose of this study was to assess the usefulness, safety, and efficacy of intra-arterial (IA) infusion chemotherapy for patients with locally advanced oral commissure cancer. METHODS: Twenty-one patients with stages III and IV squamous cell carcinoma involving the mouth angle were recruited. Methotrexate (MTX; 50 mg/day) was continuously infused into the external carotid artery for a mean period of 8 days, followed by weekly IA bolus of 25 mg MTX for a mean period of 10 weeks. RESULTS: Thirteen patients (62%) achieved a complete response (CR) and 7 patients (33%) had a partial response (PR). At a median follow-up of 69 months, the estimated 1-year, 3-year, and 5-year survival rates of the patients with CR versus PR were 100% versus 57%, 92% versus 43%, and 80% versus 43%, respectively. CONCLUSION: Our data demonstrate that continuous IA chemotherapy could achieve a competitive acceptable survival rate and improved locoregional control of advanced oral commissure cancer.

Jun dimerization protein 2 in oxygen restriction; control of senescence.

Senescent cells show a series of alterations, including a flat and enlarged morphology, increase in nonspecific acidic ß- galactosidase activity, chromatin condensation, and changes in gene expression patterns. The onset and maintenance of senescence are regulated by two tumor suppressor proteins, p53 and Rb, whose expression is controlled by two distinct proteins, p19(Arf) and p16(Ink4a), respectively, which are encoded by the cdkn2a locus. Transcription factor Jun dimerization protein 2 (JDP2) which binds directly to histones and DNA, inhibits the acetylation and methylation of core histones and of reconstituted nucleosomes that contain JDP2-recognition DNA sequences. JDP2-deficient mouse embryonic fibroblasts are known to be resistant to replicative senescence. Oxygen induces the expression of the JDP2 gene and JDP2 then inhibits the recruitment of polycomb repressive complexes (PRCs1 and 2) to the promoter of the gene encoding p16(Ink4a), resulting in the inhibition of methylation of lysine 27 of histone H3. These findings suggest that chromatin-remodeling factors, including the PRC complex controlled by JDP2, are important players in the senescence. The newly defined mechanisms that underlie the action of oxygen in the induction of JDP2 and cellular senescence are reviewed.