Endoplasmic reticulum stress promotes autophagy and apoptosis and reverses chemoresistance in human ovarian cancer cells.

Ovarian cancer presents the highest mortality rate among gynecological tumors. Here, we measured cell viability, proliferation, apoptosis, autophagy, and expression of endoplasmic reticulum stress (ERS)-related proteins, PI3K/AKT/mTOR pathway-related proteins, and apoptosis- and autophagy-related proteins in SKOV3 and SKOV3/CDDP cells treated with combinations of CDDP, tunicamycin, and BEZ235 (blank control, CDDP, CDDP + tunicamycin, CDDP + BEZ235, and CDDP + tunicamycin + BEZ235). Increasing concentrations of tunicamycin and CDDP activated ERS in SKOV3 cells, reduced cell viability and proliferation, increased apoptosis and autophagy, enhanced expression of ERS-related proteins, and inhibited expression of PI3K/AKT/mTOR pathway-related proteins. CDDP, tunicamycin, and BEZ235 acted synergistically to enhance these effects. We also detected lower expression of the ERS-related proteins caspase-3, LC3 II and Beclin 1 in ovarian cancer tissues than adjacent normal tissues. By contrast, expression of Bcl-2 and PI3K/AKT/mTOR pathway-related proteins was higher in ovarian cancer tissues than adjacent normal tissues. Lastly, expression of the ERS-related proteins Beclin 1, caspase-3 and LC3 II was higher in the sensitive group than the resistant group, while expression of Bcl-2, LC3 I, P62 and PI3K/AKT/mTOR pathway-related proteins was decreased. These results show that ERS promotes cell autophagy and apoptosis while reversing chemoresistance in ovarian cancer cells by inhibiting activation of the PI3K/AKT/mTOR signaling pathway.

Identification of a Low-Frequency Missense Variant in E2F Transcription Factor 7 Associated with Colorectal Cancer Risk In A Chinese Population

Background: Transcription factors regulate gene expression and play important role in tumor genesis. Especially, the E2F transcription factor family controls the cell cycle and regulate many tumor suppressors. Missense variants in E2F family genes, which change the amino acid sequence, may alter the capacity for DNA binding or the protein structure, leading to a functional alteration. Material and Methods: We here searched for missense variants in E2F transcription family genes (E2F1~E2F8) and identified two (rs2075995 for E2F2 and rs3829295 for E2F7) with minor allele frequencies >0.01 in Chinese Han Beijing population from the 1000 genome project. We genotyped these two variants in 1,055 colorectal cancer (CRC) patients and 1,936 healthy controls using Taqman genotyping assays and assessed associations between SNPs and risk of CRC using logistic regression adjusted for gender and age. Results: We found rs3829295 at E2F7 to be significantly associated with risk of CRC. Compared with TT genotype carriers, CT and CT+CC genotype carriers had lower risks of CRC with ORs of 0.61 (95% CI: 0.44-0.85, P=0.003) and 0.61 (95% CI: 0.44-0.84, P=0.003), respectively. When stratified by gender and age, significant associations were observed in males (OR= 0.56, 95% CI: 0.38-0.83, P=0.004) for rs3829295, but not females (OR= 0.73, 95% CI: 0.43-1.22, P=0.232). Conclusion: Through a systematic assessment of variants in the E2F transcription factor family, we identified a lowfrequent missense variant in E2F7 significantly associated with CRC risk, indicating that E2F7 may play an important role in development of this tumor type.

[The Levels of IL-4, IL-9, and IgE in Patients Infected with Intestinal Helminths and their Clinical Values].

OBJECTIVE: To investigate the serum levels of interleukin-4 (IL-4), interleukin-9 (IL-9), and immunoglobulin E (IgE) in the patients infected with intestinal helminths, and study their relationship to the clinical symptoms or species of the helminths. METHODS: This study was carried out in the Department of Paediatrics, Henan Provincial People's Hospital from January 2010 to July 2014. The blood samples were collected from 55 infected patients. Among the 55 cases, 18 cases (32.7%) were with ascaris infection, 8 cases (14.5%) of hookworm infection, 7 cases (12.7%) of whipworm infection, and 22 cases (40%) of pinworm infection. ELISA were used to measure the levels of IL-4, IL-9, and IgE in peripheral blood samples from the patients and 15 healthy volunteers. The relationship between the concentration of the cytokines and clinical symptoms or species of the parasites was analyzed. RESULTS: The serum levels of IL-4, IL-9, and IgE in infection group were (157.42 ± 41) pg/ml, (59.9 ± 21.7) pg/ml, and (316.6 ± 129) IU/ml, respectively, which were higher than that of the healthy control[ IL-4 (39.01 ± .5) pg/ml, IL-9 (21.3 ± 12.5) pg/m, IgE (127.7 ± 57.6) IU/ml] (P > 0.01). After treatment by albendazole in the infection group, the level of IL-4, IL-9, and IgE decreased to (98.1 ± 41.7) pg/ml, (38.7 ± 14.1) pg/ml, and (253.1 ± 94.0) IU/ml, respectively, but still higher than that of the control (P < 0.05). IL-9 level in patients with upper gastrointestinal hemorrhage was (76.1 ± 23.5) pg/ml, which was higher than that of those with abdominal discomfort or disruption to bowel habits [(54.3 ± 22.1) g/ml] (P < 0.05), but lower than that of those with allergic dermatitis [(108.5 ± 33.4) pg/ml] (P < 0.05). No significant difference was found in the levels of IL-4 and IgE among the above three groups. The level of IL-9 in patients infected with pinworms was (120.3 ± 41.0) pg/ml, which was higher than that of ascaris infection group [(90.1 ± 29.7) pg/ml], hookworm infection group [(77.3 ± 18.3) pg/ml], and whipworm infection group [(62.5 ± 24.3) pg/ml] (P < 0.01). There was no significant difference in the serum level of IL-9 between ascaris infection group and hookworm infection group (P > 0.05), whereas the IL-9 level in ascaris infection group and hookworm infection group was higher than that of whipworm infection group [(62.5 ± 24.3) pg/ ml] (P < 0.01). There were no significant difference in the serum level of IL-4 and IgE among the patients infected with the species of different helminthes (P > 0.05). CONCLUSION: The levels of IL-4, IgE, and IL-9 are considerably related with intestinal helminth infection, while IL-9 level varied with different helminth species and clinical symptoms.