Recent studies have unequivocally identified multipotent stem/progenitor cells in mammary glands, offering a tractable model system to unravel genetic and epigenetic regulation of epithelial stem/progenitor cell development and homeostasis. In this study, we show that Pygo2, a member of an evolutionarily conserved family of plant homeo domain–containing proteins, is expressed in embryonic and postnatal mammary progenitor cells. Pygo2 deficiency, which is achieved by complete or epithelia-specific gene ablation in mice, results in defective mammary morphogenesis and regeneration accompanied by severely compromised expansive self-renewal of epithelial progenitor cells. Pygo2 converges with Wnt/β-catenin signaling on progenitor cell regulation and cell cycle gene expression, and loss of epithelial Pygo2 completely rescues β-catenin–induced mammary outgrowth. We further describe a novel molecular function of Pygo2 that is required for mammary progenitor cell expansion, which is to facilitate K4 trimethylation of histone H3, both globally and at Wnt/β-catenin target loci, via direct binding to K4-methyl histone H3 and recruiting histone H3 K4 methyltransferase complexes.

Autophagy is a process of cell self-renewal that is dependent on the degradation of the cytoplasmic proteins or organelles of lysosomes. Many diseases, such as metabolic diseases, cancer, neurodegenerative diseases, and lung diseases, have been confirmed to be associated with elevated or impaired levels of autophagy. At present, studies have found that autophagy participates in the regulation of chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, pulmonary hypertension, acute lung injury, lung cancer, and other pulmonary diseases. Using recent literature on the signal transduction mechanisms of autophagy and the effects of autophagy signalling on lung diseases, this review intends to clarify the mechanisms of lung disease to guide the treatment of related diseases. The reviews of this paper are available via the supplemental material section.

BackgroundHistones chaperones have been found to play critical roles in tumor development and progression. However, the role of histone chaperone CHAF1A in gastric carcinogenesis and its underlying mechanisms remain elusive.MethodsCHAF1A expression in gastric cancer (GC) was analyzed in GEO datasets and clinical specimens. CHAF1A knockdown and overexpression were used to explore its functions in gastric cancer cells. The regulation and potential molecular mechanism of CHAF1A expression in gastric cancer cells were studied by using cell and molecular biological methods.FindingsCHAF1A was upregulated in GC tissues and its high expression predicted poor prognosis in GC patients. Overexpression of CHAF1A promoted gastric cancer cell proliferation both in vitro and in vivo, whereas CHAF1A suppression exhibited the opposite effects. Mechanistically, CHAF1A acted as a co-activator in the Wnt pathway. CHAF1A directly interacted with TCF4 to enhance the expression of c-MYC and CCND1 through binding to their promoter regions. In addition, the overexpression of CHAF1A was modulated by specificity protein 1 (Sp1) in GC. Sp1 transcriptionally enhanced the expression of CHAF1A in GC. Furthermore, CHAF1A expression induced by Helicobacter pylori was Sp1 dependent.InterpretationCHAF1A is a potential oncogene in GC, and may serve as a novel therapeutic target for GC treatment.

The aim of the present study was to characterize and quantify the numbers and expression levels of cells markers associated with dendritic cell (DC) maturation in small airways in current smokers and non-smokers with or without chronic obstructive pulmonary disease (COPD). Lung tissues from the following 32 patients were obtained during resection for lung cancer: Eight smokers with COPD, eight non-smokers with COPD, eight current smokers without COPD and eight non-smokers without COPD, serving as a control. The tissue sections were immunostained for cluster of differentiation (CD)83+ and CD1a+ to delineate mature and immature DCs, and chemokine receptor type 7 (CCR7+) to detect DC migratory ability. Myeloid DCs were collected from the lung tissues, and subsequently the CD83+ and CCR7+ expression levels in the lung myeloid DCs were detected using flow cytometry. The expression levels of CD83+, CD1a+ and CCR7+ mRNA in total lung RNA were evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Evident chronic bronchitis and emphysema pathological changes were observed in the lung tissues of patients with COPD. The results revealed that the numbers of CD83+ and CCR7+ DCs were reduced but the numbers of CD1a+ DCs were significantly increased in the COPD group as compared with the control group (P<0.05, respectively). Using RT-qPCR, the expression levels of CCR7+ and CD83+ mRNA were found to be reduced in the smokers with COPD as compared with the non-smokers without COPD group (P<0.05, respectively). Excessive local adaptive immune responses are key elements in the pathogenesis of COPD. Cigarette smoke may stimulate immune responses by impairing the homing of airway DCs to the lymph nodes and reduce the migratory potential of DCs. The present study revealed that COPD is associated with reduced numbers of mature CD83+ DCs and lower CCR7+ expression levels in small airways.

Kuding tea (Ilex kudingcha C.J. Tseng) is drunk widely in China. The in vitro anticancer effects of Kuding tea were evaluated in TCA8113 human tongue carcinoma cells using a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay. At a concentration of 200 μg/ml, Kuding tea exhibited an inhibitory effect of 75% in TCA8113 cells, which was higher than that observed at concentrations of 100 and 50 μg/ml (41 and 10% inhibition, respectively). Reverse transcription-polymerase chain reaction (RT-PCR) and western blot analyses of the apoptosis, inflammation and metastasis genes and proteins in Kuding tea-treated cancer cells were performed. Kuding tea significantly induced apoptosis in TCA8113 cancer cells (P<0.05) by upregulating Bax, caspase-3 and caspase-9 expression, and downregulating Bcl-2 expression. Expression of the NF-κB, iNOS and COX-2 genes that are associated with inflammation was significantly downregulated by Kuding tea, which demonstrated its anti-inflammatory properties. Kuding tea also exerted an anti-metastatic effect on cancer cells. This was demonstrated by the decreased expression of matrix metalloproteases (MMPs) and the increased expression of tissue inhibitors of metalloproteinases (TIMPs), and confirmed by the inhibition of the metastasis of U14 squamous cell carcinoma cells in imprinting control region (ICR) mice. The ICR mouse buccal mucosa cancer model was established by injecting the mice with U14 cells. Following injection, the wound at the injection site was topically treated with Kuding tea. It was observed that the tumor volumes for the group treated with Kuding tea were smaller than those from the control mice. Analysis of the sections of buccal mucosa cancer tissue demonstrated that the buccal mucosa cancer degrees of the Kuding tea-treated mice were weaker than that in the control mice. Similar results were observed in the lesion sections of the cervical lymph nodes. Based on these results, Kuding tea exhibited successful in vitro anticancer effects in TCA8113 cells and in vivo buccal mucosa cancer preventive activity.

BackgroundRhythm abnormalities are crucial for diverse diseases. However, their role in disease progression induced by Helicobacter pylori (H. pylori) remains elusive.MethodsH. pylori infection was used in in vivo and in vitro experiments to examine its effect on rhythmic genes. The GEO database was used to screen H. pylori affecting rhythm genes, and the effect of rhythm genes on inflammatory factors. Chromatin immunoprecipitation and dual luciferase assays were used to further find out the regulation between molecules. Animal models were used to confirm the relationship between rhythm genes and H. pylori-induced inflammation.FindingsBMAL1 disorders aggravate inflammation induced by H. pylori. Specifically, H. pylori induce BMAL1 expression in vitro and in vivo through transcriptional activation of LIN28A, breaking the circadian rhythm. Mechanistically, LIN28A binds to the promoter region of BMAL1 and directly activates its transcription under H. pylori infection. BMAL1 in turn functions as a transcription factor and enhances the expression of proinflammatory cytokine TNF-α, thereby promoting inflammation. Of note, BMAL1 dysfunction in the rhythm disorder animal model aggravates inflammatory response induced by H. pylori infection in vivo.InterpretationThese findings in this study imply the pathogenic relationship between BMAL1 and H. pylori. BMAL1 may serve as a potential diagnostic marker and therapeutic target for the early diagnosis and treatment of diseases related to H. pylori infection.FundNational Natural Science Foundation of China.

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BackgroundThe infiltrative nature and lymphatic metastasis of head and neck squamous cell carcinoma (HNSCC) are the main reasons leading to its poor prognosis.MethodsA multimodal surface-enhanced resonance Raman spectroscopy (SERRS) and magnetic resonance (MR) nanoprobe, in which paramagnetic chelators and heptamethine cyanine-based Raman reporter molecules were functionalized on a gold nanostar (AuS) surface was developed. Preoperative MRI and intraoperative SERRS-guided surgery were performed on rabbits bearing head and neck VX2 tumours to determine feasibility of the MR/SERRS probe in defining tumour marginal infiltration and lymph nodes metastasis.FindingsPreoperative T1-weighted MRI (T1W-MRI) unambiguously delineated the orthotopic head and neck VX2 tumour xenograft and detected the metastatic lymph nodes in rabbit models after intravenous administration of the probe. With the assistance of a hand-held Raman detector, the probe not only intra-operatively demarcated invasive tumour margins but also successfully distinguished metastatic lymph nodes via a remarkable attenuated Raman signal. Importantly, the group of rabbits subjected to the SERRS-guided surgery exhibited prolonged median survival time (78 days) compared with that of the control group without surgical intervention (29 days) or the group treated with conventional white-light-guided surgery (42 days) (P < 0.0001).Interpretationwe developed a novel AuS-based multimodal MR/SERRS probe. The capability of this probe to identify both a tumour xenograft and metastatic lymph nodes preoperatively by MRI and intra-operatively by SERRS not only avoids the need for unnecessary resection of neurological structures but also provides a new opportunity to improve the surgical prognosis of head and neck carcinoma of infiltrative nature.