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Avian leukosis virus subgroup J (ALV-J), a highly oncogenic retrovirus, causes leukemia-like proliferative diseases in chickens. microRNAs post-transcriptionally suppress targets and are involved in the development of various tumors. We previously showed that miR-221 is upregulated in ALV-J-induced tumors. In this study, we analyzed the possible function of miR-221 in ALV-J tumorigenesis. The target validation system showed that CDKN1B is a target of miR-221 and is downregulated in ALV-J infection. As CDKN1B arrests the cell cycle and regulates its progression, we analyzed the proliferation of ALV-J-infected DF-1 cells. ALV-J-infection-induced DF1 cell derepression of G1/S transition and overproliferation required high miR-221 expression followed by CDKN1B downregulation. Cell cycle pathway analysis showed that ALV-J infection induced DF-1 cell overproliferation via the CDKN1B-CDK2/CDK6 pathway. Thus, miR-221 may play an important role in ALV-J-induced aggressive growth of DF-1 cells; these findings have expanded our insights into the mechanism underlying ALV-J infection and tumorigenesis.

Zearalenone (ZEA) was a mycotoxin biosynthesized by a variety of Fusarium fungi via a polypeptide pathway. ZEA has significant toxic reaction on immune cells. Thymic epithelial cells (TECs) as a crucial constituent of thymic stroma can provide unique microenvironment for thymocyte maturation, but the mechanism of ZEA affecting the TECs is poorly understood. The basic data about gene expression differences for the ZEA on thymic epithelial cell line 1 (MTEC1) will help us to elucidate this mechanism. Here, cell viability and proliferation assay and transcriptome sequencing on MTEC1 treated with ZEA were performed. 4188 differentially expressed genes (DEGs) between ZEA treated and control groups were identified, confirmed and analyzed. Our results showed that 10-50μg/ml ZEA significantly inhibited MTEC1 proliferation and arrested cell cycle at G2/M phase. Gene ontology and KEGG pathway analysis revealed that Chemokine, JAK-STAT and Toll-like receptor signaling pathway, were involved in the cell cycle pathway. 16 key genes involved in the cell cycle processes were validated and the results suggested that Mitotic catastrophe (MC) may take part in ZEA inhibition of METC1 cell proliferation. These data highlighted the importance of cell cycle pathway in MTEC1 treated with ZEA, and will contribute to get the molecular mechanisms of ZEA inhibition of MTEC1 cell proliferation.

Solute carrier family 34 member 2 (SLC34A2), a family member of sodium-driven phosphate cotransporters, has been reported to facilitate cell proliferation and tumor growth. However, the functional mechanism by which SLC34A2 promotes cell growth and cell cycle progression remains poorly understood. Here, we reported that SLC34A2 was overexpressed in CRC by analysis of TCGA and GEO datasets. A total of 45 differentially expressed genes (DEGs) were identified from comparing SLC34A2-high or –low groups and functional enrichment analysis of these DEGs demonstrated that cell cycle pathway was enriched. Interestingly, we found a positive correlation between TMPRSS3 (transmembrane serine protease 3) and SLC34A2, which was confirmed by RT-qPCR and western blotting. Furthermore, TMPRSS3 was also upregulated in CRC tumor tissues compared to normal tissues. Patients with high TMPRSS3 expression had poor prognosis. Functionally, TMPRSS3 deficiency inhibited cell proliferation and colony formation in CRC cells. TMPRSS3 overexpression in SLC34A2-deficient cells antagonized siSLC34A2-mediated cell cycle inhibition by promoting cyclin E, cyclin A protein expression. Based on these results, our study suggests that SLC34A2 promotes cancer proliferation and cell cycle progression by targeting TMPRSS3 in colorectal cancer cells.

Ambient fine particulate matter (PM2.5) is a worldwide environmental problem and is posing a serious threat to human health. Until now, the molecular toxicological mechanisms and the crucial toxic components of PM2.5 remain to be clarified. This study investigated the whole transcriptomic changes in THP-1 derived macrophages treated with different types of PM2.5 extracts using RNA sequencing technique. Bioinformatics analyses covering biological functions, signal pathways, protein networks and node genes were performed to explore the candidate pathways and critical genes, and to find the potential molecular mechanisms. Results of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes pathway (KEGG), and protein-protein interaction (PPI) networks revealed that water extracts (WEs) of PM2.5 obviously influenced genes and molecular pathways responded to oxidative stress and inflammation. Dichloromethane extracts (DEs) specifically affected genes and signal cascades related to cell cycle progress process. Furthermore, compared with WEs collected in heating season, non-heating season WEs induced much higher expression levels of Ca-associated genes (including phosphodiesterase 4B and cyclooxygenase-2), which may consequently result in more severe inflammatory responses. While, for DEs exposure, the heating season (DH) group showed extensive induction of deferentially expressed genes (DEGs) related to cell cycle pathway, which may be caused by the higher polycyclic aromatic hydrocarbons (PAHs) contents in DH samples than those from non-heating season. In conclusion, the oxidative stress and inflammation response are closely correlated with cellular responses in THP-1 derived macrophages induced by water soluble components of PM2.5, and cell cycle dysregulation may play an important role in biological effects induced by organic components. The different transcriptomic changes induced by seasonal PM2.5 extracts may partially depend on the contents of PAHs and metal ions, respectively.

Background Hypoxia-inducible lipid droplet-associated (HILPDA) is considered to have tumorigenic activity, but its function in lung adenocarcinoma (LUAD) is rarely known. This work aimed to assess the regulatory functions as well as the in-depth mechanism of HILPDA in LUAD. Methods The expression of HILPDA in LUAD tissues was analyzed based on TCGA database, and then qRT-PCR was performed to confirm the HILPDA expression in LUAD cell lines. Kaplan-Meier analysis was used to measure the correlation of HILPDA expression and overall survival in patients with LUAD. Then, Cell-Counting Kit-8 (CCK-8), colony formation and transwell assays were performed to detect cell proliferation, invasion and migration. Moreover, the pathways closely related to the high HILPDA expression was analyzed by Kyoto Encyclopedia of genes and Genomes (KEGG) analysis. The levels of Cell cycle pathway-related proteins were assessed using western blotting. Results Herein, we revealed that HILPDA was expressed at high levels in LUAD tissues and cell lines, and LUAD patients with the higher HILPDA expression presented the shorter survival time. Down-regulation of HILPDA in Calu-3 cells can retard cell proliferation, migration and invasion as well as arrest cells in the G1 phase, whereas overexpression of HILPDA in A549 cells presented a marked promotion on these phenotypes. Moreover, we surveyed that knockdown of HILPDA restrained the activation of cell cycle pathway, while up-regulation of HILPDA led to opponent outcomes. Conclusions In summing, HILPDA may act as an oncogenic factor in LUAD cells via modulating cell cycle pathway, which represent a novel biomarker of tumorigenesis in LUAD patients.

Loss of neuron homeostasis in the arcuate nucleus (ARC) is responsible for diet-induced-obesity (DIO). We previously reported that loss of Rb1 gene compromised the homeostasis of anorexigenic POMC neurons in ARC and induced obesity in mice. To evaluate the development of DIO, we propose to analyze the transcriptomic alteration of POMC neurons in mice following high fat diet (HFD) feeding. We isolated these neurons from established DIO mice and performed transcriptomic profiling using RNA-seq. In total, 1066 genes (628 upregulated and 438 downregulated) were identified as differentially expressed genes (DEGs). Pathway enrichment analysis with these DEGs further revealed that "cell cycle," "apoptosis," "chemokine signaling," and "sphingolipid metabolism" pathways were correlated with DIO development. Moreover, we validated that the pRb protein, a key regulator of "cell cycle pathway," was inactivated by phosphorylation in POMC neurons by HFD feeding. Importantly, the reversal of deregulated cell cycle by stereotaxic delivering of the unphosphorylated pRbΔP in ARC significantly meliorated the DIO. Collectively, our study provides insights into the mechanisms related to the loss of homeostasis of POMC neurons in DIO, and suggests pRb phosphorylation as a potential intervention target to treat DIO.

DNA damage results in mutations and plays critical roles in cancer development, progression, and treatment. Targeting DNA damage response in cancers by inhibiting poly-(ADP-ribose) polymerases (PARPs) offers an important therapeutic strategy. However, the failure of PARP inhibitors to markedly benefit patients suggests the necessity for developing new strategies to improve their efficacy. Here, we show that the expression of cyclin dependent kinase 4/6 (CDK4/6) complex members significantly correlates with mutations (as proxies of DNA damages), and that the combination of CDK4/6 and PARP inhibitors shows synergy in both RB-proficient and RB-deficient breast cancer cells. As PARPs constitute sensors of DNA damage and are broadly involved in multiple DNA repair pathways, we hypothesized that the combined inhibition of PARPs and DNA repair (or repair-related) pathways critical for cancer (DRPCC) should show synergy. To identify druggable candidate DRPCC(s), we analyzed the correlation between the genome-wide expression of individual genes and the mutations for 27 different cancer types, assessing 7146 exomes and over 1,500,000 somatic mutations. Pathway enrichment analyses of the top ranked genes correlated with mutations indicated "cell cycle pathway" as the top candidate DRPCC. Additionally, among functional cell-cycle complexes, the CDK4/6 complex showed the most significant negative correlation with mutations, also suggesting that combined CDK4/6 and PARP inhibition might exhibit synergy. Furthermore, combination treatment showed synergy in not only RB-proficient but also RB-deficient breast cancer cells in a reactive oxygen species-dependent manner. These findings suggest a potential therapeutic strategy to improve the efficacy of PARP and CDK4/6 inhibitors in cancer treatment. Funding: This study was supported by grants from the National Natural Science Foundation of China (NSFC Nos. 31471328 and 81622040 to Q. Yang; 81502622 to L. Wang). Declaration of Interest: The authors declare that they have no competing interests. Ethical Approval: The animal-handling procedures were approved by the Animal Care and Use Committee of Dalian Medical University.

Plants have a wide array of colors in different parts of their body and have been used for multiple purposes. Several colored components (secondary metabolites) such as anthocyanins, carotenoids, apocarotenoids, anthraquinones, flavonoids, etc., were investigated for their potential therapeutic efficacy as antitumorigenic agents. These colored molecules have the ability to interfere and involved in multiple cell signaling pathway such as cell death, cell survival and cell cycle pathway. In this article, we review the different colorants and their role in killing cancer cells. In vitro molecular mechanism of colored components differs against multiple cancer cell line that provides a guide to produce a further step in in vivo cancer treatment studies. It has been observed that there are numerous colorants can be used against cancer cells. Though there is a large resource of plant colorants with antioxidant properties, very little has been exploited so far. The detailed study on colorants will improve our knowledge in cancer biology and also facilitate the use for cancer treatment in near future.

The balance between cell proliferation and cell quiescence is regulated delicately by a variety of mediators, in which cyclin-dependent kinases (CDK) and CDK inhibitors (CDKI) play a very important role. Heparin which inhibits pulmonary artery smooth muscle cell (PASMC) proliferation increases the levels of two CDKIs, p21 and p27, although only p27 is important in inhibition of PASMC growth in vitro and in vivo. In the present study we investigated the expression profile of all the cell cycle regulating genes, including all seven CDKIs (p21, p27, p57, p15, p16, p18, and p19), in the lungs of mice with hypoxia-induced pulmonary hypertension. A cell cycle pathway specific gene microarray was used to profile the 96 genes involved in cell cycle regulation. We also observed the effect of heparin on gene expression. We found that (a) hypoxic exposure for two weeks significantly inhibited p27 expression and stimulated p18 activity, showing a 98% decrease in p27 and 81% increase in p18; (b) other CDKIs, p21, p57, p15, p16, and p19 were not affected significantly in response to hypoxia; (c) heparin treatment restored p27 expression, but did not influence p18; (d) ERK1/2 and p38 were mediators in heparin upregulation of p27. This study provides an expression profile of cell cycle regulating genes under hypoxia in mice with hypoxia-induced pulmonary hypertension and strengthens the previous finding that p27 is the only CDKI involved in heparin regulation of PASMC proliferation and hypoxia-induced pulmonary hypertension.

knockdown seems to impair cell growth and alters cell cycle distribution. An experimental set up, using a RT-PCR based cell cycle pathway array showed a reproducible up regulation of LOC688900 in rMSC, which encodes Schlafen-1, a protein known as an inducer of cell cycle arrest in T-lymphocytes and murine fibroblasts. Conclusions: Based on these knockdown studies we hold a promising tool for further in vitro analyses and differentiation studies in MSC. According to the present data, we conclude an involvement of Sox9 in cell cycle progression and thus cell proliferation, and suggest an up regulation of LOC688900 as a consequence of Sox9 down regulation.