Associations between abnormal vitamin D metabolism pathway function and non-small cell lung cancer.

Lung cancer is a type of malignant tumor derived from the respiratory system, which is the leading cause of cancer-associated mortality worldwide, of which ~80% of cases are attributable to non-small cell lung cancer (NSCLC). A previous study demonstrated that 1α,25-Dihydroxyvitamin D3 (1α,25(OH)2D3), derived from the vitamin D metabolic pathway contributes an antitumor effect. Aberrant expression of the essential enzyme encoding genes, Cytochrome P450 Family 27 Subfamily A Member 1 (CYP27A1), Cytochrome P450 Family 27 Subfamily B Member 1 (CYP27B1), and Cytochrome P450 Family 24 Subfamily A Member 1 (CYP24A1) may be associated with lung cancer. However, a lack of evidence exists concerning the association between CYP27A1, CYP27B1, CYP24A1 expression and NSCLC. The aim of the present study was to investigate the functions of CYP27A1, CYP27B1 and CYP24A1 expression in NSCLC. Lung cancer tissue and para-carcinoma control tissue were collected from patients with NSCLC. Reverse transcription-quantitative polymerase chain reaction was applied to analyze CYP27A1, CYP27B1 and CYP24A1 mRNA expression in lung cancer tissues. An association analysis was performed between the aforementioned metabolic enzymes and patients with NSCLC age, gender, tumor node metastasis (TNM) stage, pathological type, differentiation and prognosis. CYP27B1 and CYP24A1 mRNA were upregulated in NSCLC compared with controls (P<0.05). However, no significant differences in CYP27A1 expression were observed between NSCLC and control. In addition, CYP24A1 expression was not associated with age, sex, smoking or TNM stage, but was associated with pathological type, differentiation and prognosis (P<0.05). CYP27B1 expression was significantly associated with TNM stage, differentiation, and prognosis, but not age, sex, smoking or pathological type. In conclusion, CYP27B1 and CYP24A1 may be considered as independent prognostic factors of NSCLC and may be novel therapeutic targets to assist clinical diagnosis, treatment and prognosis of the disease.

Association between C-reactive protein and risk of cancer: a meta-analysis of prospective cohort studies.

BACKGROUND: Associations between elevated C-reactive protein (CRP) and cancer risk have been reported for many years, but the results from prospective cohort studies remains controversial. A meta-analysis of prospective cohort studies was therefore conducted to address this issue. METHODS: Eligible studies were identified by searching the PubMed and EMBASE up to October 2012. Pooled hazard ratios (HR) was calculated by using random effects model. RESULTS: Eleven prospective cohort studies involving a total of 194,796 participants and 11,459 cancer cases were included in this meta-analysis. The pooled HR per natural log unit change in CRP was 1.105 (95% confidence interval (CI): 1.033-1.178) for all-cancer, 1.308 (95% CI: 1.097-1.519) for lung cancer, 1.040 (95% CI: 0.910-1.170) for breast cancer, 1.063 (95% CI: 0.965-1.161) for prostate cancer, and 1.055 (95% CI: 0.925-1.184) for colorectal cancer. Dose-response analysis showed that the exponentiated linear trend for a change of one natural log unit in CRP was 1.012 (95% CI: 1.006-1.018) for all-cancer. No evidence of publication bias was observed. CONCLUSIONS: The results of this meta-analysis showed that the elevated levels of CRP are associated with an increased risk of all-cancer, lung cancer, and possibly breast, prostate and colorectal cancer. The result supports a role of chronic inflammation in carcinogenesis. Further research effort should be performed to identify whether CRP, as a marker of inflammation, has a direct role in carcinogenesis.

[Change of IL-22R1 expression in human airway smooth muscle cells in response to different stimulating agents].

OBJECTIVE: To explore the effects of serum of asthmatic patients, dexamethasone, interleukin-4 (IL-4), interferon-gamma (IFN-γ) and transforming growth factor-ß (TGF-ß) on the expression of interleukin-22 receptor 1 (IL-22R1) mRNA and protein in HASMCs in vitro. METHODS: IL-22R1 mRNA and protein expressions in HASMCs treated with different stimulating agents were measured by real-time PCR and Western blotting, respectively. RESULTS: IL-22R1 mRNA and protein expressions in HASMCs were significantly increased after stimulation by serum from asthmatic patients, but decreased after co-stimulation with dexamethasone. IL-22R1 mRNA and protein expressions in the cells both increased after stimulation by IL-4, IFN-γ and TGF-ß. CONCLUSION: IL-22R1 in HASMCs might be involved in the pathogenesis of asthma, and the therapeutic effect of dexamethasone on asthma is mediated, at least partially, by IL-22R1. The effects of IFN-γ, IL-4, and TGF-ß on asthma may also be attributed to their actions on HASMCs.

[Liver X receptor agonist T0901317 inhibits TGF-ß1-induced α-SMA expression in normal human lung fibroblasts].

OBJECTIVE: To investigate the effect of liver X receptor agonist T0901317 on transforming growth factor-ß1 (TGF-ß1)-induced expression of α-smooth muscle actin (α-SMA) in normal human lung fibroblasts. METHODS: Primary normal human lung fibroblast isolated from the lung specimens of lung cancer patients by explant culture technique were identified with immunostaining for vimentin and keratin. The cells in passages 4 to 10 were treated with T0901317 and/or TGF-ß1, and RT-PCR, Western blotting and immunofluorescence assay were used to detect α-SMA expression in the fibroblasts. RESULTS: Lung fibroblast expressed vimentin but not keratin. The results of RT-PCR, Western blotting and immunofluorescence assay all showed that normal human lung fibroblasts constitutively expressed α-SMA under baseline condition, and TGF-ß1 at 5 ng/ml induced a significant upregulation of α-SMA both at the mRNA and protein levels. Liver X receptor agonist T0901317 (5 µg/ml) significantly inhibited TGF-ß1-induced upregulation of α-SMA expression. CONCLUSION: Liver X receptor agonist T0901317 can inhibit the upregulation of α-SMA in normal human lung fibroblasts induced by TGF-ß1, suggesting the potential value of liver X receptor agonist in the treatment of lung fibrosis.

[Rho-kinase signaling pathway participates in endothelin-1-induced human airway smooth muscle cell migration and cytoskeletal reorganization].

OBJECTIVE: To investigate the role of Rho-kinase signaling pathway in human airway smooth muscle cell (ASMCs) migration and cytoskeletal reorganization induced by endothelin-1 (ET-1). METHODS: Primary cultured human ASMCs obtained by tracheal explant culture method were examined for cell migration in response to ET-1 treatment using modified Boyden chambers. The changes in actin cytoskeletal reorganization were observed under confocal laser scanning microscope, and the phosphorylation of myosin-phosphatase target 1 (p-MYPT1) was examined using Western blot analysis. RESULTS: At the concentration of 0.1, 1, 10, and 100 nmol/L, ET-1 induced migration of the ASMCs, and 10 nmol/L ET-1 produced the most obvious effect (P<0.01). Rho-kinase inhibitor Y-27632 showed a dose-dependent inhibitory effect on ET-1-induced ASMC migration, and in cells exposed to 10 nmol/L ET-1, Y-27632 at 10 micromol/L significantly blocked ASMC migration (P<0.01). ET-1 (10 nmol/L) exposure resulted in reorganization of actin cytoskeleton and formation of stress fibers in the ASMCs, which were obviously inhibited by Y-27632. Compared with the control group, the AMSCs showed significant enhancement of p-MYPT1 protein expression after ET-1 exposure for 15 and 30 min (P<0.01), but prolonged exposure failed to result in the expression enhancement (P>0.05). CONCLUSION: Rho-kinase signaling pathway may play an important role in ET-1-induced ASMC migration and reorganization of actin cytoskeleton.

[Shikonin inhibits the proliferation of human airway smooth muscle cells].

OBJECTIVE: To study the inhibitory effect of shikonin on the proliferation of human airway smooth muscle cells (HASMCs) in vitro. METHODS: HASMCs from the trachea were obtained by primary culture of the tissue explants and adherent culture. The HASMCs were exposed to shikonin at 0 (control group), 0.5, 1, 2, 5, 10, 20, and 40 micromol/L for 12, 24, and 48 h, after which the cell proliferation was assessed by 3-(4,5-carboxymethoxypheny1)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) colorimetric assay. Flow cytometry was used for cell cycle analysis of the HASMCs exposed to shikonin at 40, 20, 10, 5 micromol/L and 0 micromol/L (control group) for 24 h. Immunocytochemistry with SP method was performed to detect the expression of proliferating cell nuclear antigen (PCNA) in the HASMCs treated with shikonin at 20 micromol/L and 0 micromol/L (control group) for 24 h. RESULTS: Shikonin at the concentrations of 20 and 40 micromol/L significantly inhibited the proliferation of the cells (P<0.05), and the effect was especially obvious after 48 h of cell exposure, with inhibition rates of 30.1% and 42.9%, respectively. No significant difference was found between the two concentrations for their cell growth inhibition effects (P>0.05). Shikonin at the concentrations of 20 and 40 micromol/L caused significant cell cycle arrest in G(0)/G(1) phase (P<0.05), the effect of which, however, was not concentration-dependent (P>0.05). Shikohin at 20 micromol/L significantly down-regulated the expression of PCNA in the cells (P<0.05). CONCLUSION: Shikonin can inhibit the proliferation of HASMCs in vitro.