Knockdown of CENPF inhibits the progression of lung adenocarcinoma mediated by ERß2/5 pathway.

Many studies have reported that estrogen (E2) promotes lung cancer by binding to nuclear estrogen receptors (ER), and altering ER related nuclear protein expressions. With the GEO database analysis, Human centromere protein F (CENPF) is highly expressed in lung adenocarcinoma (LUAD), and the co-expression of CENPF and ERß was found in the nucleus of LUAD cells through immunofluorescence. We identified the nuclear protein CENPF and explored its relationship with the ER pathway. CENPF and ERß2/5 were related with T stage and poor prognosis (P<0.05). CENPF knockout significantly inhibited LUAD cell growth, the tumor growth of mice and the expression of ERß2/5 (P<0.05). The protein expression of CENPF and ERß2/5 in the CENPF-Knockdown+Fulvestrant group was lower than CENPF- Negative Control +Fulvestrant group (P=0.002, 0.004, 0.001) in A549 cells. The tumor size and weight of the CENPF-Knockdown+Fulvestrant group were significantly lower than CENPF- Negative Control +Fulvestrant group (P=0.001, 0.039) in nude mice. All the results indicated that both CENPF and ERß2/5 play important roles in the progression of LUAD, and knockdown CENPF can inhibit the progression of LUAD by inhibiting the expression of ER2/5. Thus, the development of inhibitors against ERß2/5 and CENPF remained more effective in improving the therapeutic effect of LUAD.

Sex-dependent differences in water homeostasis in wild-type and V-ATPase B1-subunit deficient mice.

Men tend to dehydrate more than women after prolonged exercise, possibly due to lower water intake and higher perspiration rate. Women are prone to exercise-associated hyponatremia, primarily attributed to the higher water consumption causing hypervolemia. Since aquaporin-2 (AQP2) water channels in the kidney collecting duct (CD) principal cells (PCs) are involved in maintaining water balance, we investigated their role in sex-dependent water homeostasis in wild-type (WT) C57BL/6 mice. Because CD intercalated cells (ICs) may also be involved in water balance, we also assessed the urine concentrating ability of V-ATPase B1 subunit-deficient (Atp6v1b1-/-) mice. Upon 12-hour water deprivation, urine osmolality increased by 59% in WT female mice and by only 28% in males. This difference was abolished in Atp6v1b1-/- mice, in which dehydration induced a ~30% increase in urine osmolarity in both sexes. AQP2 levels were highest in WT females; female Atp6v1b1-/- mice had substantially lower AQP2 expression than WT females, comparable to the low AQP2 levels seen in both Atp6v1b1-/- and WT males. After dehydration, AQP2 relocates towards the PC apical pole, especially in the inner stripe and inner medulla, and to a greater extent in WT females than in WT males. This apparent sex-dependent concentrating advantage was absent in Atp6v1b1-/- females, whose reduced AQP2 apical relocation was similar to WT males. Accordingly, female mice concentrate urine better than males upon dehydration due to increased AQP2 expression and mobilization. Moreover, our data support the involvement of ICs in water homeostasis, at least partly mediated by V-ATPase, in a sex-dependent manner.

Interaction between epidermal growth factor receptor and interleukin-6 receptor in NSCLC progression.

Even though the interaction between epithelial growth factor receptor (EGFR) and interleukin-6 receptor (IL-6R) has been found in many tumors, there is a lack of relevant in-depth study of lung cancer. The following study investigates the interaction of EGFR and IL-6R in lung cancer. In the current study, EGFR, IL-6, and glycoprotein 130 (GP130) were highly expressed in non-small cell lung cancer (NSCLC) tissue samples and were associated with clinicopathological features and poor prognosis of patients with NSCLC. Furthermore, the effect of EGF and IL-6 on biological behavior of lung cancer cells (cell proliferation, invasion, cycle, and apoptosis) and the expression of EGFR, GP130, p-protein kinase B (p-AKT), and p-p44/42 mitogen-activated protein kinase (p-p44/42 MAPK) was significantly stronger compared with other treatment groups (all P < 0.05). These results suggest that EGFR and IL-6R have synergistic effects on NSCLC progression. This could help to solve the problem of EGFR inhibitors in the treatment of lung cancer resistance and improve the efficacy of current treatment for lung cancer through a combination of EGFR and IL-6R signaling pathways.

ß-Naphthoflavone treatment attenuates neonatal hyperoxic lung injury in wild type and Cyp1a2-knockout mice.

Exposure to supraphysiological concentrations of oxygen (hyperoxia) leads to bronchopulmonary dysplasia (BPD), one of the most common pulmonary morbidities in preterm neonates, which is more prevalent in males than females. Beta-naphthoflavone (BNF) is protective against hyperoxic lung injury in adult and neonatal wild type (WT) mice and in and mice lacking Cyp1a1gene. In this investigation, we tested the hypothesis that BNF treatment will attenuate neonatal hyperoxic lung injury in WT and Cyp1a2-/- mice, and elucidated the effect of sex-specific differences. Newborn WT or Cyp1a2-/- mice were treated with BNF (10mg/kg) or the vehicle corn oil (CO) i.p., from postnatal day (PND) 2 to 8 once every other day, while being maintained in room air or hyperoxia (85% O2) for 14days. Hyperoxia exposure lead to alveolar simplification and arrest in angiogenesis in WT as well as Cyp1a2-/- mice No significant differences were seen between WT and Cyp1a2-/- mice. Cyp1a2-/- female mice had better preservation of pulmonary angiogenesis at PND15 compared to similarly exposed males. BNF treatment attenuated lung injury and inflammation in both genotypes, and this was accompanied by a significant induction of hepatic and pulmonary CYP1A1 in WT but not in Cyp1a2-/- mice. BNF treatment increased NADPH quinone oxidoreductase (NQO1) mRNA levels in Cyp1a2-/- mouse livers compared to WT mice. These results suggest that BNF is protective in neonatal mice exposed to hyperoxia independent of CYP1A2 and this may entail the protective effect of phase II enzymes like NQO1.

Hyperoxia-mediated transcriptional activation of cytochrome P4501A1 (CYP1A1) and decreased susceptibility to oxygen-mediated lung injury in newborn mice.

Hyperoxia contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. In this study, we tested the hypothesis that newborn transgenic mice carrying the human CYP1A1-Luc promoter will display transcriptional activation of the human CYP1A1 promoter in vivo upon exposure to hyperoxia, and that these mice will be less susceptible to hyperoxic lung injury and alveolar simplification than similarly exposed wild type (WT) mice. Newborn WT (CD-1) or transgenic mice carrying a 13.2 kb human CYP1A1 promoter and the luciferase (Luc) reporter gene (CYP1A1-luc) were maintained in room air or exposed to hyperoxia (85% O2) for 7-14 days. Hyperoxia exposure of CYP1A1-Luc mice for 7 and 14 days resulted in 4- and 30-fold increases, respectively, in hepatic Luc (CYP1A1) expression, compared to room air controls. In lung, hyperoxia caused a 2-fold induction of reporter Luc at 7 days, but the induction declined after 14 days. The newborn CYP1A1-Luc mice were less susceptible to lung injury and alveolar simplification than similarly exposed wild type (WT) CD-1 mice. Also, the CYP1A1-Luc mice showed increased levels of hepatic and pulmonary CYP1A1 expression and hepatic CYP1A2 activity after hyperoxia exposure. Hyperoxia also increased NADP(H) quinone reductase (NQO1) pulmonary gene expression in both CD-1 and CYP1A1-Luc mice at both time points, but this was more pronounced in the latter at 14 days. Our results support the hypothesis that hyperoxia activates the human CYP1A1 promoter in newborn mice, and that increased endogenous expression of CYP1A1 and NADP(H) quinone reductase (NQO1) contributes to the decreased susceptibilities to hyperoxic lung injury in the transgenic animals. This is the first report providing evidence of hyperoxia-mediated transcriptional activation of the human CYP1A1 promoter in newborn mice, and this in conjunction with decreased lung injury, suggests that these phenomena have important implications for BPD.