lncRNA EPS15-AS1 affects the biological behavior of liver cancer stem cells by regulating EPS15 expression.

OBJECTIVE: To investigate whether long non-coding RNA (lncRNA) EPS15-antisense RNA (EPS15-AS1) affects the biological behavior of liver cancer stem cells (LCSCs) by targeting EPS15. METHODS: The expression of EPS15 in liver cancer was analyzed based on TCGA database. The expression of EPS15-AS1 and EPS15 in LCSCs was detected by real-time quantitative PCR (RT-qPCR). MTT method, flow cytometry, and Transwell assay were used to detect the effects of EPS15-AS1 and EPS15 expression on the biological behavior of LCSCs. RESULTS: EPS15 was highly expressed in liver cancer tissues in TCGA, and EPS15 was closely related to the survival and prognosis of liver cancer patients (P<0.05). EPS15 was highly expressed in LCSCs, while lncRNA EPS15-AS1 was lowly expressed in LCSCs (P<0.05). After silencing lncRNA EPS15-AS1, the proliferation, invasion, and EPS15 protein expression of LCSCs were promoted (P<0.05) while apoptosis was suppressed (P<0.05). After overexpression of lncRNA EPS15-AS1, the proliferation, invasion, and EPS15 protein expression of LCSCs were suppressed while the apoptosis ability was promoted. However, simultaneous overexpression of lncRNA EPS15-AS1 and EPS15 attenuated the effect of lncRNA EPS15-AS1 overexpression alone on proliferation and apoptosis of LCSCs. CONCLUSION: lncRNA EPS15-AS1 overexpression can inhibit proliferation and invasion but promote apoptosis of LCSCs by down-regulating the expression of EPS15.

Current progress of immune checkpoint inhibitors in the treatment of advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide. The onset of the disease is occult and develops rapidly. As a result, the disease is often detected when it is already in advanced stages, resulting in patients losing the best opportunity for liver transplantation and surgical treatment. Therefore, effective treatment of HCC is particularly important in clinical practice. During the past decades, there have been considerable advances in the treatment of HCC, and immunotherapy is increasingly recognized as a promising approach in clinical trials. In this review, an overview of immune checkpoint (ICP) inhibitors (ICIs) and their role in the treatment of liver cancers, particularly advanced HCC, is presented and the recent therapeutic progress with treatment with different ICIs alone or in combination with other methods/therapeutic agents is summarized. In addition, the identification of biomarkers to predict treatment response and the limitations of current ICIs are analyzed, and future directions for ICI treatment are discussed.

Association between Mismatch-repair Genetic variation and the Risk of Multiple Primary Cancers: A Meta-Analysis.

Microsatellites instability (MSI) is a risk factor for multiple primary cancers (MPCs). However, a variety of studies focused on the risk in the hereditary non-polyposis colorectal cancer (HNPCC) not the sporadic colorectal cancer (CRC) patients. The aim of this meta-analysis was to comprehensive overview and quantitative summary the association between MSI and risk of MPCs. A comprehensive literature search in MEDLINE, EMBASE, Web of science, ScienceDirect, Weily and OVID was conducted. Up to May 2016, we identified 22 observational studies. We calculated the summary relative risk (RR) for the risk of MPCs in MSI patients compared with microsatellites stability (MSS) patients using fixed- or random-effects models. The RR of the association between mismatch-repair gene (MMR) genotype and MPCs was 2.59 (95% confidence interval [CI], 2.06 to 3.27); the RR was 2.14 (95% CI, 1.78 to 2.57) for sporadic CRC and 5.59 (95% CI, 2.69 to 11.59) for HNPCC for the MSI versus MSS category. The subgroup analyses showed different mutant gene, mutant locus, and mutant level of MMR with different influence on the patients susceptible to MPCs. In addition, MSI genotype increase the risk of MPC was not associated with an apparently specific in regard to site, timing, age and detection method. In conclusion, this meta-analysis indicates that MSI is associated with an increased risk of MPCs both in the HNPCC and sporadic CRC patients. Our findings will form the backbone of the treatment for MSI genotype may be an important valuable strategy for MPCs prevention.

Effect of Polygonatum odoratum extract on human breast cancer MDA-MB-231 cell proliferation and apoptosis.

Traditional Chinese medicine (TCM) is important in the provision of anti-tumor drugs. Recently, studies have shown that certain types of TCM agents are able to control the growth of tumors, enhance the body's immune function and enhance the therapeutic effect of chemotherapeutic drugs. In women, breast carcinoma is the most common tumor type and the second most common cause of death from cancer. Polygonatum odoratum (P. odoratum) is commonly used in TCM. The aim of the present study was to investigate the effects of P. odoratum extract on the proliferation and apoptosis of MDA-MB-231 breast cancer cells. Cell proliferation was assessed using MTT and colony formation assays. In addition, propidium iodide (PI)/Annexin V-FITC staining was used to investigate the apoptosis of MDA-MB-231 cells following treatment with P. odoratum extract. The protein expression levels of B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) were also detected using western blot analysis, while a JC-1 staining assay was used to assess the mitochondrial membrane potential (ΔΨm). The results of the MTT assay showed that the proliferation and colony formation of MDA-MB-231 cells were inhibited following treatment with the extract. Furthermore, the PI/Annexin-V staining showed that the apoptosis of MDA-MB-231 cells was enhanced by the extract, in a concentration-dependent manner. The extract also lowered the ΔΨm of MDA-MB-231 cells, upregulated the expression of Bax and inhibited the expression of Bcl-2. In conclusion, these results showed that the P. odoratum extract inhibited the proliferation and induced apoptosis of breast cancer MDA-MB-231 cells.

Smac mimetic­induced caspase­independent necroptosis requires RIP1 in breast cancer.

There is an urgent requirement for the development of novel targeted therapies to treat breast cancer, which is the most comment type of malignancy among women. The evasion of apoptosis is a hallmark of cancer, and is often due to the upregulation of inhibitor of apoptosis proteins (IAPs) in tumor cells. Second mitochondrial­derived activator of caspase/direct IAP­binding protein with low PI is a natural IAP antagonist, which is found in the mitochondrion; this protein has a motif, which binds to a surface groove on the baculovirus IAP repeat domains of the IAPs. In the present study, the effects of the LCL161 Smac mimetic, a small molecule IAP antagonist, on breast cell lines was examined. The results from MTT and colony formation assays demonstrated that LCL161 markedly inhibited the proliferation and induced the apoptosis of MDA­MB­231 and MCF­7 cell lines. As determined by western blotting, cIAP1 was degraded in the breast cancer cells, which occurred in an LCL161­dependent manner. Upon caspase activation, LCL161 treatment induced necroptosis, another form of programmed cell death. The downregulation of receptor­interacting protein kinase­1 via small interfering RNA protected the cells from LCL161­induced necroptosis. Taken together, the results of the present study showed that LCL161 can induce multiple forms of programmed cell death in breast cancer cells, and may thus offer promise as an anticancer agent in diverse genotypic backgrounds.

Mechanisms underlying 3-bromopyruvate-induced cell death in colon cancer.

3-Bromopyruvate (3BP) is an energy-depleting drug that inhibits Hexokinase II activity by alkylation during glycolysis, thereby suppressing the production of ATP and inducing cell death. As such, 3BP can potentially serve as an anti-tumorigenic agent. Our previous research showed that 3BP can induce apoptosis via AKT /protein Kinase B signaling in breast cancer cells. Here we found that 3BP can also induce colon cancer cell death by necroptosis and apoptosis at the same time and concentration in the SW480 and HT29 cell lines; in the latter, autophagy was also found to be a mechanism of cell death. In HT29 cells, combined treatment with 3BP and the autophagy inhibitor 3-methyladenine (3-MA) exacerbated cell death, while viability in 3BP-treated cells was enhanced by concomitant treatment with the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone (z-VAD-fmk) and the necroptosis inhibitor necrostatin (Nec)-1. Moreover, 3BP inhibited tumor growth in a SW480 xenograft mouse model. These results indicate that 3BP can suppress tumor growth and induce cell death by multiple mechanisms at the same time and concentration in different types of colon cancer cell by depleting cellular energy stores.

Vitamin intake reduce the risk of gastric cancer: meta-analysis and systematic review of randomized and observational studies.

AIM: The association between vitamin intake and gastric cancer (GC) has been widely debated due to the relatively weak evidence. In this study, a meta-analysis of prospective and well designed observational studies were performed to explore this association. METHODS: MEDLINE, Cochrane Library, and Sciencedirect were searched for studies of vitamin consumption and gastric cancer. This produced 47 relevant studies covering 1,221,392 human subjects. Random effects models were used to estimate summary relative risk (RR). Dose-response, subgroup, sensitivity, meta-regression, and publication bias analyses were conducted. RESULTS: The RR of gastric cancer in the group with the highest vitamin intake was compared to that of the lowest intake group. Total vitamin intake was 0.78 (95% CI, 0.71-0.83). In 9 studies that individuals were given doses at least 4 times above the tolerable upper intake (UL) vitamins, the RR was 1.20 (95% CI, 0.99-1.44). However, in 17 studies that individuals received doses below the UL, the RR was 0.76 (95% CI, 0.68-0.86). Dose-response analysis was conducted on different increments in different types of vitamins (vitamin A: 1.5 mg/day, vitamin C: 100 mg/day, vitamin E: 10 mg/day) intake with a significant reduction in the risk of gastric cancer, respectively, 29% in vitamin A, 26% in vitamin C, and 24% in vitamin E. CONCLUSION: This meta-analysis clearly demonstrated that low doses of vitamins can significantly reduce the risk of GC, especially vitamin A, vitamin C, vitamin E.