Background & Aims Constitutive activation of NF-κB and STAT3 pathways in human colorectal cancers links inflammation to CRC development and progression. However, the underlying mechanisms remain to be elucidated. Here we investigated the roles of miR-221 and miR-222 in regulating both NF-κB and STAT3 activities and colorectal tumorigenesis. Methods miR-221/222 mimics and their inhibitors/sponges were transiently or stably transfected into cells. Dual luciferase reporter assays were utilized to examine the activation of both NF-κB and STAT3 signaling, as well as the regulation of miR-221/222. Quantitative PCR and immunoblot analysis were employed to examine the mRNA and protein expression. MTT assay, flow cytometric analysis and xenotransplant of tumor cells were performed to investigate the CRC cell growth in vitro and in vivo. Results miR-221 and miR-222 positively regulate both NF-κB and STAT3 activities, which in return induce miR-221/222 expression, creating a positive feedback loop in human CRCs. miR-221/222 directly bind to the coding region of RelA, leading to increased RelA mRNA stability. In addition, miR-221/222 reduce ubiquitination of RelA and STAT3 proteins by directly targeting the 3′ UTR of PDLIM2, an E3 ligase for both RelA and STAT3. We demonstrate that disruption of the positive feedback loop suppresses human CRC cell growth in vitro and in vivo. The expression of miR-221/222 correlates with the expression of RelA, STAT3 and PDLIM2 in human CRC clinical samples. Conclusions Our findings define a novel miR-221/222 mediated mechanism underlying constitutive activation of NF-κB and STAT3 pathways in human CRCs and provide a promising therapeutic target for human CRCs.

BackgroundThe increasing prevalence of colorectal cancer (CRC) in China and the paucity of information about relevant expenditure highlight the necessity of better understanding the financial burden and effect of CRC diagnosis and treatment. We performed a survey to quantify the direct medical and non-medical expenditure as well as the resulting financial burden of CRC patients in China.MethodsWe conducted a multicenter, cross-sectional survey in 37 tertiary hospitals in 13 provinces across China between 2012 and 2014. Each enrolled patient was interviewed using a structured questionnaire. All expenditure data were inflated to the 2014 Chinese Yuan (CNY; 1 CNY = 0.163 USD). We quantified the overall expenditure and financial burden and by subgroup (hospital type, age at diagnosis, sex, education, occupation, insurance type, household income, clinical stage, pathologic type, and therapeutic regimen). We then performed generalized linear modeling to determine the factors associated with overall expenditure.ResultsA total of 2356 patients with a mean age of 57.4 years were included, 57.1% of whom were men; 13.9% of patients had stage I cancer; and the average previous-year household income was 54,525 CNY. The overall average direct expenditure per patient was estimated to be 67,408 CNY, and the expenditures for stage I, II, III, and IV disease were 56,099 CNY, 59,952 CNY, 67,292 CNY, and 82,729 CNY, respectively. Non-medical expenditure accounted for 8.3% of the overall expenditure. The 1-year out-of-pocket expenditure of a newly diagnosed patient was 32,649 CNY, which accounted for 59.9% of their previous-year household income and caused 75.0% of families to suffer an unmanageable financial burden. Univariate analysis showed that financial burden and overall expenditure differed in almost all subgroups (P < 0.05), except for sex. Multivariate analysis showed that patients who were treated in specialized hospitals and those who were diagnosed with adenocarcinoma or diagnosed at a later stage were likely to spend more, whereas those with a lower household income and those who underwent surgery spent less (all P < 0.05).ConclusionsFor patients in China, direct expenditure for the diagnosis and treatment of CRC seemed catastrophic, and non-medical expenditure was non-ignorable. The financial burden varied among subgroups, especially among patients with different clinical stages of disease, which suggests that, in China, CRC screening might be cost-effective.

Lung cancer remains the leading cause of cancer-associated death worldwide. MiR-21 and miR-155 are the most amplified miRNAs in non-small cell lung carcinoma (NSCLC), and are critical promoters of NSCLC progression. However, it remains unclear how miR-21 and miR-155 induce cancer progression, and whether these miRNAs share common targets, such as tumor suppressor genes required to prevent NSCLC. Here we report that miR-21 and miR-155 levels are elevated in NSCLC and are proportional to the progression of the disease. In addition, miR-21 and miR-155 share nearly 30% of their predicted target genes, including SOCS1, SOCS6, and PTEN, three tumor suppressor genes often silenced in NSCLC. Consequently, antagonizing miR-21, miR-155 or both potently inhibited tumor progression in xenografted animal models of NSCLC. Treatment with miR-21 and miR-155 inhibitors in combination was always more effective against NSCLC than treatment with a single inhibitor. Furthermore, levels of miR-21 and miR-155 expression correlated inversely with overall and disease-free survival of NSCLC patients. Our findings reveal that miR-21 and miR-155 promote the development of NSCLC, in part by downregulating SOCS1, SOCS6, and PTEN. Combined inhibition of miR-21 and miR-155 could improve the treatment of NSCLC.

Trace elements play important roles in human health, but little is known about their functions in humoral immunity. Here, we show an important role for iron in inducing cyclin E and B cell proliferation. We find that iron-deficient individuals exhibit a significantly reduced antibody response to the measles vaccine when compared to iron-normal controls. Mice with iron deficiency also exhibit attenuated T-dependent or T-independent antigen-specific antibody responses. We show that iron is essential for B cell proliferation; both iron deficiency and α-ketoglutarate inhibition could suppress cyclin E1 induction and S phase entry of B cells upon activation. Finally, we demonstrate that three demethylases, KDM2B, KDM3B and KDM4C, are responsible for histone 3 lysine 9 (H3K9) demethylation at the cyclin E1 promoter, cyclin E1 induction and B cell proliferation. Thus, our data reveal a crucial role of H3K9 demethylation in B cell proliferation, and the importance of iron in humoral immunity.

Early detection and treatment of breast cancer might be effective for decreasing the economic burden, because costs escalate as the degree of malignancy increases.

Interleukin (IL) 17-producing T helper (Th17) cells play critical roles in the clearance of extracellular bacteria and fungi as well as the pathogenesis of various autoimmune diseases, such as multiple sclerosis, psoriasis, and ulcerative colitis. Although a global transcriptional regulatory network of Th17 cell differentiation has been mapped recently, the participation of epigenetic modifications in the differentiation process has yet to be elucidated. We demonstrated here that histone H3 lysine-27 (H3K27) demethylation, predominantly mediated by the H3K27 demethylase Jmjd3, crucially regulated Th17 cell differentiation. Activation of naïve CD4(+) T cells immediately induced high expression of Jmjd3. Genetic depletion of Jmjd3 in CD4(+) T cells specifically impaired Th17 cell differentiation both in vitro and in vivo. Ectopic expression of Jmjd3 largely rescued the impaired differentiation of Th17 cells in vitro in Jmjd3-deficient CD4(+) T cells. Importantly, Jmjd3-deficient mice were resistant to the induction of experimental autoimmune encephalomyelitis (EAE). Furthermore, inhibition of the H3K27 demethylase activity with the specific inhibitor GSK-J4 dramatically suppressed Th17 cell differentiation in vitro. At the molecular level, Jmjd3 directly bound to and reduced the level of H3K27 trimethylation (me3) at the genomic sites of Rorc, which encodes the master Th17 transcription factor Rorγt, and Th17 cytokine genes such as Il17, Il17f, and Il22. Therefore, our studies established a critical role of Jmjd3-mediated H3K27 demethylation in Th17 cell differentiation and suggest that Jmjd3 can be a novel therapeutic target for suppressing autoimmune responses.

The detection of cancer at an early stage is often significant in the successful treatment of the disease. Tumor cells have been reported to generate unique cancer volatile organic compound (VOC) profiles which can reflect the disease conditions. The detection and analysis of VOC biomarkers from exhaled breath has been recognized as a new frontier in cancer diagnostics and health inspections owing to its potential in developing rapid, noninvasive, and inexpensive cancer screening tools. To detect specific VOCs of low concentrations from exhaled breath, and to enhance the accuracy of early diagnosis, many breath collection and analysis approaches have been developed. This paper will summarize and critically review the exhaled-breath VOC-related sampling, collection, detection, and analytical methods, especially the recent development in VOC sensors. VOC sensors are commonly inexpensive, portable, programmable, easy to use, and can obtain data in real time with high sensitivities. Therefore, many sensor-based VOC detection techniques have huge potential in clinical point-of-care use.

Total synthesis and photophysical properties of PENB-DDAO, a photoactivatable 1,3-dichloro-9,9-dimethyl-9H-acridin-2(7)-one (DDAO) derivative of a far-red emitting fluorophore, are described. The photoremovable group of the DDAO phenolic function comprises a donor/acceptor biphenyl platform which allows an efficient (> or = 95%) and rapid (< 15 micros time-range) release of the fluorescent signal and displays remarkable two-photon uncaging cross sections (delta(a) x Phi(u) = 3.7 GM at 740 nm). PENB-DDAO is cell permeable as demonstrated by the triggering of cytoplasmic red fluorescent signal in HeLa cells after one-photon irradiation (lambda(exc) around 360 nm) or by the generation of a red fluorescent signal in a delineated area of a single cell after two-photon photoactivation (lambda(exc) = 770 nm).