MicroRNAs Induce Epigenetic Reprogramming and Suppress Malignant Phenotypes of Human Colon Cancer Cells.

Although cancer is a genetic disease, epigenetic alterations are involved in its initiation and progression. Previous studies have shown that reprogramming of colon cancer cells using Oct3/4, Sox2, Klf4, and cMyc reduces cancer malignancy. Therefore, cancer reprogramming may be a useful treatment for chemo- or radiotherapy-resistant cancer cells. It was also reported that the introduction of endogenous small-sized, non-coding ribonucleotides such as microRNA (miR) 302s and miR-369-3p or -5p resulted in the induction of cellular reprogramming. miRs are smaller than the genes of transcription factors, making them possibly suitable for use in clinical strategies. Therefore, we reprogrammed colon cancer cells using miR-302s and miR-369-3p or -5p. This resulted in inhibition of cell proliferation and invasion and the stimulation of the mesenchymal-to-epithelial transition phenotype in colon cancer cells. Importantly, the introduction of the ribonucleotides resulted in epigenetic reprogramming of DNA demethylation and histone modification events. Furthermore, in vivo administration of the ribonucleotides in mice elicited the induction of cancer cell apoptosis, which involves the mitochondrial Bcl2 protein family. The present study shows that the introduction of miR-302s and miR-369s could induce cellular reprogramming and modulate malignant phenotypes of human colorectal cancer, suggesting that the appropriate delivery of functional small-sized ribonucleotides may open a new avenue for therapy against human malignant tumors.

Pyruvate kinase M2, but not M1, allele maintains immature metabolic states of murine embryonic stem cells.

The M2 isoform of pyruvate kinase, the final rate-limiting enzyme of aerobic glycolysis, is expressed during embryonic development. In contrast, the M1 isoform is expressed in differentiated cells due to alternative splicing. Here we investigated murine embryonic stem cells (ESCs) with Pkm1 or Pkm2 knock-in alleles. Pkm1 allele knock-in resulted in excessive oxidative phosphorylation and induced the formation of cysteine-thiol disulfide-dependent complexes of forkhead box class-O (FOXO) transcription factors, which resulted in altered endoderm differentiation. In contrast, Pkm2 knock-in induced synthesis of a methylation-donor, S-adenosylmethionine, and increased unsaturated eicosanoid groups, which contributed to the redox control and maintenance of ESC undifferentiated status. Because PKM2 is also a critical enzyme for the cancer-specific Warburg effect, our results demonstrate an important role for the Pkm2 allele in establishing intracellular redox conditions and modulating PKM1-dependent oxidative phosphorylation events to achieve an appropriate ESC differentiation program.

Meta-analysis of laparoscopy-assisted and open distal gastrectomy for gastric cancer.

BACKGROUND: Laparoscopy-assisted distal gastrectomy (LADG) for gastric cancer is a minimally invasive technique. We performed a meta-analysis of five randomized clinical trials (RCTs) to evaluate and compare the benefits of LADG with those of open distal gastrectomy (ODG). METHODS: The present meta-analysis was based on the comparison of LADG with ODG for gastric cancer. The following factors were examined: operative time, estimated blood loss, number of harvested lymph nodes, time to resumption of oral intake, duration of hospital stay, frequency of analgesic administration, complications, tumor recurrence, and mortality. RESULTS: We selected five RCTs to compare LADG with ODG for gastric cancer. A total of 326 patients with gastric cancer were included in this meta-analysis of whom 164 underwent LADG and 162 underwent ODG. There was a significant difference in the volume of intraoperative blood loss, period of hospital stay, frequency of analgesic administration, and rate of complications between LADG and ODG. There was no difference in the resumption of oral intake, rate of tumor recurrence, and mortality. The operative time was significantly longer and the number of harvested lymph nodes was significantly smaller in LADG than in ODG. CONCLUSION: LADG is significantly superior to ODG regarding the volume of blood loss, duration of hospital stay, level of pain, and risk of complications. There was no difference in the resumption of oral intake, rate of tumor recurrence, and mortality. However, LADG was significantly inferior to ODG regarding operative time and also had a smaller number of harvested lymph nodes.