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Reprogramming of cancer cells into induced pluripotent stem cells (iPSCs) is a compelling idea for inhibiting oncogenesis, especially through modulation of homeobox proteins in this reprogramming process. We examined the role of various long noncoding RNAs (lncRNAs)‐homeobox protein HOXA13 axis on the switching of the oncogenic function of bone morphogenetic protein 7 (BMP7), which is significantly lost in the gastric cancer cell derived iPS‐like cells (iPSLCs). BMP7promoter activation occurred through the corecruitment of HOXA13, mixed‐lineage leukemia 1 lysine N‐methyltransferase, WD repeat‐containing protein 5, and lncRNA HoxA transcript at the distal tip (HOTTIP) to commit the epigenetic changes to the trimethylation of lysine 4 on histone H3 in cancer cells. By contrast, HOXA13 inhibited BMP7 expression in iPSLCs via the corecruitment of HOXA13, enhancer of zeste homolog 2, Jumonji and AT rich interactive domain 2, and lncRNA HoxA transcript antisense RNA (HOTAIR) to various cis‐element of the BMP7promoter. Knockdown experiments demonstrated that HOTTIP contributed positively, but HOTAIR regulated negatively to HOXA13‐mediated BMP7 expression in cancer cells and iPSLCs, respectively. These findings indicate that the recruitment of HOXA13–HOTTIP and HOXA13–HOTAIR to different sites in the BMP7promoter is crucial for the oncogenic fate of human gastric cells. Reprogramming with octamer‐binding protein 4 and Jun dimerization protein 2 can inhibit tumorigenesis by switching off BMP7. StemCells2017;35:2115–2128 Regulation of BMP7 promoter on gastric cancer by LncRNA‐HOXA13. In CS12 cancer cells, HOXA13‐HOTTIP‐WDR5/MLL/TrG complexes are recruited to the S1 site to induce H3K4me3 on BMP7promoter to enhance the BMP7 transcription to develop the tumorigenesis; by contrast, in JDP2/OCT4 reprogrammed CS12iPSLCs, HOXA13‐HOTAIR‐EZH2/SUZ12/PRC2‐JARID2 complexes are recruited to the S2 site to induce H3K27me3 on BMP7promoter to repress and inhibit the tumorigenesis.

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 OCT4stemness 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 OCT4gene and the c‐JUNoncogene, but not of c‐MYC, was significantly elevated in rG2‐DC‐1C, whereas no c‐JUNexpression was observed in HepG2 cells. The positive‐feedback regulation via OCT4‐mediated transactivation of the c‐JUNpromoter and the c‐JUN‐mediated transactivation of the OCT4promoter 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. StemCells2016;34:2613–2624 The OCT4/c‐JUN positive feedback loop found in reprogrammed HepG2‐derived cancer stem cell‐like cells (rG2‐DC‐1C) sheds light on the tumorigenesis of liver cancer. 4F, Yamanaka 4 factors; iPS‐like cells, induced pluripotent stem‐like cells.