Background: Metformin has been reported to inhibit the growth of various types of cancers, including breast cancer. Yet the mechanisms underlying the anticancer effects of metformin are not fully understood. Growing evidence suggests that metformin's anticancer effects are mediated at least in part by modulating microRNAs, including miR-200c, which has a tumor suppressive role in breast cancer. We hypothesized that miR-200c has a role in the antitumorigenic effects of metformin on breast cancer cells.Methods: To delineate the role of miR-200c in the effects of metformin on breast cancer, plasmids containing pre-miR-200c or miR-200c inhibitor were transfected into breast cancer cell lines. The MDA-MB-231, BT549, MCF-7, and T-47-D cells' proliferation, apoptosis, migration, and invasion were assessed. The antitumor role of metformin in vivo was investigated in a MDA-MB-231 xenograft tumor model in SCID mice.Results: Metformin significantly inhibited the growth, migration, and invasion of breast cancer cells, and induced their apoptosis; these effects were dependent on both dose and time. Metformin also suppressed MDA-MB-231 tumor growth in SCID mice in vivo. Metformin treatment was associated with increased miR-200c expression and decreased c-Myc and AKT2 protein expression in both breast cancer cells and tumor tissues. Overexpression of miR-200c exhibited effects on breast cancer cells similar to those of metformin treatment. In contrast, inhibiting the expression of miR-200c increased the growth, migration, and invasion of MCF-7 and MDA-MB-231 cells.Conclusion: Metformin inhibits the growth and invasiveness of breast cancer cells by upregulation of miR-200c expression by targeting AKT2. These findings provide novel insight into the molecular functions of metformin that suggest its potential as an anticancer agent.

Prostate cancer (PCa) is the second frequently newly diagnosed cancer in men. Androgen deprivation therapy has been widely used to inhibit PCa growth but eventually fails in many patients. Androgen receptor and its downstream molecules like microRNAs could be promising therapeutic targets. We aimed to investigate the involvement of miR-21 in PCa tumorigenesis. We found that miR-21 was an unfavorable factor and correlated positively with tumor grade in PCa patients from TCGA database. MiR-21 was more highly expressed in androgen-independent PCa cells than in androgen-dependent PCa cells. Overexpression of miR-21 promoted androgen-dependent and-independent PCa cell proliferation, migration, invasion, and resistance to apoptosis. Furthermore, increased miR-21 expression promoted mouse xenograft growth. We identified nine genes differentially expressed in PCa tumors and normal tissue which could be potential targets of miR-21 by bioinformatic analyses. We demonstrate that miR-21 directly targeted KLF5 and inhibited KLF5 mRNA and protein levels in PCa. STRING and functional enrichment analysis results suggest that GSK3B might be regulated by KLF5. Our findings demonstrate that miR-21 promotes the tumorigenesis of PCa cells by directly targeting KLF5. These biological effects are mediated through upregulation of GSK3B and activation of the AKT signaling pathway.

GlyoxalaseI (GLOI) is an enzyme that catalyzes methylglyoxal metabolism. Overexpression of GLOI has been documented in numerous tumor tissues, including colorectal cancer (CRC). The antitumor effects of GLOI depletion have been demonstrated in some types of cancer, but its role in CRC and the mechanisms underlying this activity remain largely unknown. Our purpose was to investigate the antitumor effects of depleted GLOI on CRC in vitro and in vivo. RNA interference was used to deplete GLOI activity in four CRC cell lines. The cells’ proliferation, apoptosis, migration, and invasion were assessed by using the Cell Counting Kit-8, plate colony formation assay, flow cytometry, and transwell assays. Protein and mRNA levels were analyzed by western blot and quantitative real-time PCR (qRT-PCR), respectively. The antitumor effect of GLOI depletion in vivo was investigated in a SW620 xenograft tumor model in BALB/c nude mice. Our results show that GLOI is over-expressed in the CRC cell lines. GLOI depletion inhibited the proliferation, colony formation, migration, and invasion and induced apoptosis of all CRC cells compared with the controls. The levels of signal transducer and activator of transcription 1 (STAT1), p53, and Bcl-2 assaciated X protein (Bax) were upregulated by GLOI depletion, while cellular homologue of avian myelocytomatosis virus oncogene (c-Myc) and B cell lymphoma/lewkmia-2 (Bcl-2) were downregulated. Moreover, the growth of SW620-induced CRC tumors in BALB/c nude mice was significantly attenuated by GLOI depletion. The expression levels of STAT1, p53, and Bax were increased and those of c-Myc and Bcl-2 were decreased in the GLOI-depleted tumors. Our findings demonstrate that GLOI depletion has an antitumor effect through the STAT1 or p53 signaling pathways in CRC, suggesting that GLOI is a potential therapeutic target.

Hepatocellular carcinoma (HCC) is the fifth most common type of cancer and the second leading cause of cancer‐related deaths worldwide. Given that the rate of HCC recurrence 5 years after liver resection is as high as 70%, patient with HCC typically has a poor outcome. A biomarker or set of biomarkers that could predict disease recurrence would have a substantial clinical impact, allowing earlier detection of recurrence and more effective treatment. With the aim of identifying a new microRNA (miRNA) signature associated with HCC recurrence, we analyzed data on 306 patients with HCC for whom both miRNA expression profiles and complete clinical information were available from The Cancer Genome Atlas database. Through this analysis, we identified a six‐miRNA signature that could effectively predict patients’ recurrence risk; the high‐risk and low‐risk groups had significantly different recurrence‐free survival rates. Time‐dependent receiver operating characteristic analysis indicated that this signature had a good predictive performance. Multivariable Cox regression and stratified analyses demonstrated that the six‐miRNA signature was independent of other clinical features. Functional enrichment analysis of the gene targets of the six prognostic miRNA indicated enrichment mainly in cancer‐related pathways and important cell biological processes. Our results support use of this six‐miRNA signature as an independent factor for predicting recurrence and outcome of patients with HCC.

Methylglyoxal (MG), an extremely reactive glucose metabolite, exhibits antitumor activity. Glyoxalase I (GLOI), which catalyzes MG metabolism, is associated with the progression of human malignancies. While the roles of MG or GLOI have been demonstrated in some types of cancer, their effects in colon cancer and the mechanisms underlying these effects remain largely unknown. For this study, MG and GLOI levels were manipulated in colon cancer cells and the effects on their viability, proliferation, apoptosis, migration, and invasion in vitro were quantified by Cell Counting Kit-8, colony formation assay, flow cytometry, and transwell assays. The expression levels of STAT1 pathway–associated proteins and mRNAs in these cells were quantified by western blot and qRT-PCR, respectively. The antitumor effects of MG and silencing of GLOI were investigated in vivo in a SW620 colon cancer xenograft model in BALB/c nude mice. Our findings demonstrate that MG in combination with silencing of GLOI synergistically inhibited the cancer cells’ proliferation, colony formation, migration, and invasion and induced apoptosis in vitro compared with the controls. Furthermore, these treatments up-regulated STAT1 and Bax while down-regulating Bcl-2 in vitro. MG treatment alone or in combination with silencing of GLOI also reduced the growth of the SW620 tumors in mice by up-regulation of STAT1 and Bax and down-regulation of Bcl-2. Taken together, our findings suggest that MG in combination with silencing of GLOI merits further evaluation as a targeted therapeutic strategy for colon cancer.