miRNAs (microRNAs) are frequently and aberrantly expressed in many cancers. MiR-873 has been revealed to be downregulated in colorectal cancer and glioblastoma. However, its function remains unclear. Here we report that miR-873 is downregulated in breast tumor compared with normal tissue. Enforced expression of miR-873 decreases the transcriptional activity of ER (estrogen receptor)-α but not ERβ through the modulation of ERα phosphorylation in ER-positive breast cancer cells. We also found that miR-873 inhibits breast cancer cell proliferation and tumor growth in nude mice. Reporter gene assays revealed cyclin-dependent kinase 3 (CDK3) as a direct target of miR-873. CDK3 was shown to be overexpressed in breast cancer and phosphorylate ERα at Ser104/116 and Ser118. Furthermore, we found that Mir-873 inhibits ER activity and cell growth via targeting CDK3. Interestingly, miR-873 was observed to be downregulated in tamoxifen-resistant MCF-7/TamR cells, while CDK3 is overexpressed in these cells. More importantly, re-expression of miR-873 reversed tamoxifen resistance in MCF-7/TamR cells. Our data demonstrate that miR-873 is a novel tumor suppressor in ER-positive breast cancer and a potential therapeutic approach for treatment of tamoxifen-resistant breast cancer.

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Sulfur mustard (SM) is a highly reactive alkylation vesicant and cytotoxic agent that has been recognized as an animal and human carcinogen. Although the exact mechanism of toxicology is vague, DNA alkylation seems to be responsible for the triggering of apoptosis. In this study, after male adult Sprague-Dawley rats were cutaneous exposed to a low concentration of SM at parts-per-million levels, their lungs, livers, pancreases, spleens, marrow, and brains were collected at 11 different time points and analyzed. N7-[2-[(2-hydroxyethyl)thio]-ethyl]guanine (N7-HETEG), N3-[2-[(2-hydroxyethyl)thio]-ethyl]adenine (N3-HETEA), and bis[2-(guanin-7-yl)ethyl]sulfide (Bis-G) as the biomarkers for DNA damage were measured in the vital tissues by isotope dilution ultraperformance liquid chromatography tandem mass spectrometry (ID-UPLC-MS/MS). At the same time, general variations and pathological changes were monitored and detected to evaluate the tissue damage. Time- and dose-dependent data showed that SM had strong permeability and reactivity and that three SM-DNA adducts were detected in all investigated tissues only after 10 min after exposure. Obvious dose-dependency was observed except in the brain and pancreas. Most times to peak (tmax) of all three adducts were less than 3 h, while half-lifetimes (t1/2) were less than 24 h. We also suggested that the lipophilic SM can easily pass through the blood-brain barrier and can be stored in the fatty organs. To the best of our knowledge, the abundant adducts in marrow were found and reported for the first time. The surveillance of N7-HETEG in vivo, which was the most abundant adduct, may be the most efficient indicator to validate SM exposure even without any symptoms. Bis-G can be regarded as a biomarker of effect, which is directly related to the extent of damage. The most abundant Bis-G was found in the most sensitive tissues, marrow, spleen, and lung, which is in good accordance with histopathologic results. General variations and pathological changes were evaluated as well. After cutaneous exposure to SM, the body weights of rats heavily decreased in the first 4 days and were inversely proportional to the applied doses, and then recovered at the last experimental day except for those of the rats at the highest dosing level, in which the relative weights of rat spleens were obviously lost. Moreover, we found remarkable histological changes of the lung and skin, such as encephalemia, at the very beginning of the sampling procedure, and plentiful mononuclear cells in marrow appeared 6 h after exposure. The micronucleus test of marrow cells showed that the micronucleus rate had a positively dose-dependent effect.

Our previous study revealed the potential linkage of PC-1/PrLZ, a novel isolated prostate-specific gene, to the progression of prostate cancer (PCa) in vitro and in vivo. To gain more insight into the mechanism of PC-1-induced promotion of PCa, expression analysis of differential genes induced by PC-1 was scanned by microarray. Among all the differentially expressed genes, EphA3 was altered to the greatest extent. EphA3 has been identified to be associated with multiple tumor progression. However, little is known concerning the function of EphA3 in PCa. In the present study, we aimed to ascertain whether EphA3 is induced by PC-1 and the functional significance of EphA3 expression in PCa. We found that overexpression of PC-1 increased the amount of EphA3 and that knockdown of PC-1 led to a decrease in EphA3 in PCa cells. The functional significance and mechanisms by which EphA3 contributes to PCa was investigated in vitro using cell lines, and in vivo using a mouse model and clinical specimens. The results showed that EphA3 enhanced the proliferation and survival of LNCaP cells and suppression of EphA3 inhibited the survival of C4-2B cells. EphA3 enhanced the tumor development of LNCaP cells in null mice. A positive correlation between the levels of EphA3 and the Gleason grade of PCa was identified in clinical PCa specimens. In addition, cellular localization changed with Gleason grade. We further detected that EphA3 increased phosphorylation of Akt (Ser473 and Thr308), indicating that EphA3 activated the Akt pathway. Taken together, EphA3 was induced by PC-1 and contributed to the malignant progression of prostate cancer. Our results provide the first demonstration that EphA3 is a novel promoter of human prostate cancer development and progression.