RESUMEN
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). BMP7 promoter 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 BMP7 promoter. 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 BMP7 promoter 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. Stem Cells 2017;35:2115-2128.
Asunto(s)
Técnicas de Reprogramación Celular/métodos , Proteínas de Homeodominio/genética , ARN Largo no Codificante/genética , Neoplasias Gástricas/genética , Proteína Morfogenética Ósea 7/genética , Proteína Morfogenética Ósea 7/metabolismo , Línea Celular Tumoral , Proliferación Celular , Proteínas de Homeodominio/metabolismo , Humanos , Regiones Promotoras Genéticas , ARN Largo no Codificante/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
Lung cancer is one of the leading types of cancer that lead to mortalities in the male and female populations. The existing lung cancer-specific markers are not able to accurately predict the condition of the disease, and the response of these markers can vary under various pathological conditions. The ability for tumors to regenerate following treatment can be more aggressive, and this may be due to the remaining lung cancer-specific stem cells, which are resistant to chemotherapeutic drugs. Evaluating cancer stem cells under various pathological conditions, as well as prior and subsequent to treatment, can help to increase the understanding of the underlying mechanisms. In the present study, a mouse model with initial and advanced forms of lung cancer was developed using tobacco smoke carcinogen. It was observed from tissue sections that there were many actively dividing cells spread throughout the mouse lung tissue with the initial stages of lung cancer, and these cells aggregated in advanced stages of lung cancer. Furthermore, immunohistochemical staining indicated that there was an increased number of octamer-binding protein 4 (Oct-4)-positive cells present in mouse tissues with advanced stages of the disease compared with tissues without lung cancer or at the initial stages of disease. The cancer stem cell population following salirasib treatment was also investigated in two groups. The mice in the early treatment group were administered with salirasib following 1 month of tumor growth, and the delayed treatment group was treated following 2 months of tumor growth. The number of cancer stem cells was markedly reduced in the early treatment group. However, salirasib failed to have any observable effect in the delayed treatment group. Cancer stem cells were analyzed using the marker Oct-4 to improve an understanding of the proliferative ability of cancer stem cells under various pathological conditions, which may lead to the development of novel cancer therapeutics.