Jiaxian Liu

LincRNa-p21: function and mechanism in cancer

AbstractIn view of the rapid development of gene chips and high-throughput sequencing technology, noncoding RNAs (ncRNas) form a high percentage of the mammalian genome. Two major subgroups of ncRNAs that have been identified are the long ncRNAs (lncRNas) and the microRNAs. A number of studies in the past few years have showed crucial functions for lncRNas in cancer. LincRNa-p21 as a p53-dependent transcriptional target gene and a potential diagnostic marker is involved in proliferation, cell cycle, metabolism and reprogramming. In addition, more researches revealed that lincRNa-p21 is associated with cancer progression and contributed to the treatment and prognosis of cancer. In this review, we briefly summarize the function and molecular mechanisms of lincRNa-p21 in cancer and its regulation for the genes expression .

Hydroquinone-induced malignant transformation of TK6 cells by facilitating SIRT1-mediated p53 degradation and up-regulating KRAS.

Hydroquinone (HQ), known as one of the metabolic products of benzene, causes a number of hematologic malignancies. The study evaluated the potential mechanism of Sirtuin 1 (SIRT1) in HQ-induced TK6 cell malignant transformation. The data of our study show that short term exposure of TK6 cells to HQ led to a decrease expression of SIRT1. Knockdown of SIRT1 sensitized to the HQ-induced apoptosis in vitro and increased the expression of p53, p21 and γ-H2AX. Furthermore, chronic HQ-treated (20μM once a week for 19 weeks) caused carcinogenic transformation and was confirmed by abnormal cell proliferation, matrix metalloproteinase 9(MMP9) and subcutaneous tumor formation in nude mice. SIRT1 increased KRAS expression, and decreased H3K9 and H3K18 acetylation, inhibited p53 signaling and the level of caspase-3 in HQ-induced transformation cells. Taken together, these data suggest that SIRT1 is involved in HQ-induced malignant transformation associated with suppressing p53 signaling and activation of KRAS.

Inhibition of autophagy enhances Hydroquinone-induced TK6 cell death

Hydroquinone (HQ), one of the metabolic products of benzene, is a carcinogen. It can induce apoptosis in lymphoma cells. However, whether HQ can induce autophagy and what roles autophagy plays in TK6 cells exposured to HQ remains unclear. In this study, we found that HQ could induce autophagy through techniques of qRT-PCR, Western blot, immunofluorescent assay of LC3 and transmission electron microscope. Furthermore, inhibiting autophagy using 3-methyladenine (3-MA) or chloroquine (CQ) significantly enhanced HQ-induced cell apoptosis, suggesting that autophagy may be a survival mechanism. Our study also showed that HQ activated PARP-1. Moreover, knockdown of PARP-1 strongly exhibited decreased autophagy related genes expression. In contrast, the absence of SIRT1 increased that. Altogether, our data provided evidence that HQ induced autophagy in TK6 cells and autophagy protected TK6 from HQ attack-induced injury in vitro, and the autophagy was partially mediated via activation of the PARP-1-SIRT1 signaling pathway.

Dichloroacetonitrile induces cytotoxicity through oxidative stress mediated and p53 dependent apoptosis pathway in LO2 cells

Abstract Dichloroacetonitrile (DCAN), one of the disinfection byproducts of water chlorination, induces cell proliferation and apoptosis; however, the detailed mechanism remains unclear. Oxidative stress participates in various biological processes, including DNA damage and cytotoxicity. To explore whether oxidative stress mediated DCAN-induced cell proliferation and apoptosis, we assessed the effect of redox imbalance and apoptosis in LO2 cells. We observed increase of reactive oxygen species and malondialdehyde and increased apoptosis by 13.6% in 500 μM DCAN compared with the control group. We also observed a decrease of antioxidant ability damage including glutathione, superoxide dismutase, and total antioxidant capacity depletion. Furthermore, DCAN might activate oxidative stress-mediated apoptosis pathway via up-regulation of p53 expression and caspase-3 activity. Therefore, we conclude that DCAN may activate apoptotic signals via p53 up-regulation and oxidative stress-mediated apoptosis in LO2 cells.

Rb silencing mediated by the down-regulation of MeCP2 is involved in cell transformation induced by long-term exposure to hydroquinone.

Hydroquinone (HQ), a metabolite of benzene, is a well‐known human carcinogen; however, its molecular mechanisms of action remain unclear. MeCP2 has been traditionally described as a transcriptional repressor, though growing evidence indicates that it also activates gene expression. Here, we investigated whether some epigenetic machinery genes are aberrantly expressed as target tumor suppressor genes in HQ‐transformed TK6 lymphoblastoid cells. Our results showed that treatment with 5‐Aza‐2′‐deoxycytidine or trichostatin A enhanced the expression of Rb, resulting in cell arrest in G1‐phase, and subsequently, an increase in apoptosis and a decrease in cell growth. Moreover, we hypothesised that Rb was silenced by the down‐regulation of MeCP2 in HQ‐transformed cells, resulting in the dynamic expression of Rb and epigenetic machinery proteins in HQ‐transformed cells at different time points. The expression of Rb and MeCP2 in patients with B‐cell non‐Hodgkins lymphoma (B‐NHL) showed that positive staining for MeCP2 or Rb was significantly lower in B‐NHL tumor tissues, and these changes were significantly and negatively correlated with the grade of B‐NHL. The restoration of MeCP2 in HQ‐transformed cells enhanced the expression of Rb, promoted cell apoptosis, and inhibited cell growth. The changes in the expression patterns of MeCP2 and Rb were inversely correlated with the degree of DNA methylation. A ChiP assay revealed that MeCP2 proteins were recruited to the Rb promoter with lower 5′‐methylcytosine levels. In conclusion, we demonstrated that the down‐regulation of MeCP2 silences Rb, a process involved in cell transformation resulting from long‐term exposure to HQ.

Long non-coding RNAs: The novel diagnostic biomarkers for leukemia

Long non-coding RNAs (LncRNAs) are a category of non-coding RNAs (ncRNAs) with a length of 200nt-100kb lacking a significant open reading frame. The study of lncRNAs is a newly established field, due in part to their capability to act as the novel biomarkers in disease. A growing body of research shows that lncRNAs may not only useful as biomarkers for the diagnosis and clinical typing and prognosis of cancers, but also as potential targets for novel therapies. Differential expression of lncRNAs has been found in leukemia in the last two years, however, the majority of the lncRNAs described here are transcripts of unknown function and their role in leukemogenesis is still unclear. Here, we summarize the lncRNAs associated with leukemia in order to find a potential classification tool for leukemia, and a new field of research is being explored.

Relationship between occupational stress and job burnout among rural-to-urban migrant workers in Dongguan, China: a cross-sectional study

Objectives In China, there have been an increasing number of migrant workers from rural to urban areas, and migrant workers have the highest incidence of occupational diseases. However, few studies have examined the impact of occupational stress on job burnout in these migrant workers. This study aimed to investigate the relationship between occupational stress and job burnout among migrant workers. Design This study used a cross-sectional survey. Setting This investigation was conducted in Dongguan city, Guangdong Province, China. Participants 3806 migrant workers, aged 18–60 years, were randomly selected using multistage sampling procedures. Primary and secondary outcome measures Multistage sampling procedures were used to examine demographic characteristics, behaviour customs and job-related data. Hierarchical linear regression and logistic regression models were constructed to explore the relationship between occupational stress and burnout. Results Demographics, behaviour customs and job-related characteristics significantly affected on burnout. After adjusting for the control variable, a high level of emotional exhaustion was associated with high role overload, high role insufficiency, high role boundary, high physical environment, high psychological strain, high physical strain, low role ambiguity, low responsibility and low vocational strain. A high level of depersonalisation was associated with high role overload, high role ambiguity, high role boundary, high interpersonal strain, high recreation, low physical environment and low social support. A low level of personal accomplishment was associated with high role boundary, high role insufficiency, low responsibility, low social support, low physical environment, low self-care and low interpersonal strain. Compared to the personal resources, the job strain and personal strain were more likely to explain the burnout of rural-to-urban migrant workers in our study. Conclusions The migrant workers have increased job burnouts in relation to occupational stress. Relieving occupational stress and maintaining an appropriate quantity and quality of work could be important measures for preventing job burnout among these workers.

Bcl-2 protects TK6 cells against hydroquinone-induced apoptosis through PARP-1 cytoplasm translocation and stabilizing mitochondrial membrane potential

B cell leukemia/lymphoma‐2 (Bcl‐2) suppresses apoptosis by binding the BH3 domain of proapoptotic factors and thereby regulating mitochondrial membrane potential (MMP). This study aimed to investigate the role of Bcl‐2 in controlling the mitochondrial pathway of apoptosis during hydroquinone (HQ)‐induced TK6 cytotoxicity. In this study, HQ, one metabolite of benzene, decreased the MMP in a concentration‐dependent manner and induced the generation of reactive oxygen species (ROS), the activation of the DNA damage marker γ‐H2AX, and production of the DNA damage‐responsive enzyme poly(ADP‐ribose)polymerase‐1 (PARP‐1). Exposure of TK6 cells to HQ leads to an increase in Bcl‐2 and co‐localization with PARP‐1 in the cytoplasm. Inhibition of Bcl‐2 using the BH3 mimetic, ABT‐737, suppressed the PARP‐1 nuclear to cytoplasm translocation and sensitized TK6 cells to HQ‐induced apoptosis through depolarization of the MMP. Western blot analysis indicated that ABT‐737 combined with HQ increased the levels of cleaved PARP and γ‐H2AX, but significantly decreased the level of P53. Thus, ABT‐737 can influence PARP‐1 translocation and induce apoptosis via mitochondria‐mediated apoptotic pathway, independently of P53. In addition, we found that knockdown of PARP‐1 attenuated the HQ‐induced production of cleaved PARP and P53. These results identify Bcl‐2 as a protective mediator of HQ‐induced apoptosis and show that upregulation of Bcl‐2 helps to localize PARP‐1 to the cytoplasm and stabilize MMP. Environ. Mol. Mutagen. 59:49–59, 2018.

Hydroquinone induces TK6 cell growth arrest and apoptosis through PARP‐1/p53 regulatory pathway

Hydroquinone (HQ), one of the most important metabolites derived from benzene, induces cell cycle arrest and apoptosis. Poly(ADP‐ribose) polymerase‐1 (PARP‐1) participates in various biological processes, including DNA repair and cell cycle regulation. To explore whether PARP‐1 regulatory pathway mediated HQ‐induced cell cycle arrest and apoptosis, we assessed the effect of PARP‐1 suppression on induction of apoptosis analyzed by FACSCalibur flow cytometer in PARP‐1 deficientTK6 cells (TK6‐shPARP‐1). We observed an increase in the fraction of cells in G1 phase by 7.6% and increased apoptosis by 4.5% in PARP‐1‐deficient TK6 cells (TK6‐shPARP‐1) compared to those negative control cells (TK6‐shNC cells) in response to HQ treatment. Furthermore, HQ might activate the extrinsic pathways of apoptosis via up‐regulation of Fas expression, followed by caspase‐3 activation, apoptotic body, and sub G1 accumulation. Enhanced p53 expression was observed in TK6‐shPARP‐1 cells than in TK6‐shNC cells after HQ treatment. In contrast, Fas expression was lower in TK6‐shPARP‐1 cells than in TK6‐shNC cells. Therefore, we conclude that HQ may activate apoptotic signals via Fas up‐regulation and p53‐mediated apoptosis in TK6‐shNC cells. The reduction of PARP‐1 expression further intensified up‐regulation of p53 in TK6‐shPARP‐1 cells, resulting in an increased G1→S phase cell arrest and apoptosis in TK6‐shPARP‐1 cells compared to TK6‐shNC cells.

miR-7-5p overexpression suppresses cell proliferation and promotes apoptosis through inhibiting the ability of DNA damage repair of PARP-1 and BRCA1 in TK6 cells exposed to hydroquinone

Hydroquinone (HQ), one of the major metabolic products of benzene, is a carcinogen, which induces apoptosis and inhibit proliferation in lymphoma cells. microRNA-7-5p (miR-7-5p), a tumor suppressor, participates in various biological processes including cell proliferation and apoptosis regulation by repressing expression of specific oncogenic target genes. To explore whether miR-7-5p is involved in HQ-induced cell proliferation and apoptosis, we assessed the effect of miR-7-5p overexpression on induction of apoptosis analyzed by FACSCalibur flow cytometer in transfection of TK6 cells with miR-7-5p mimic (TK6- miR-7-5p). We observed an increased apoptosis by 25.43% and decreased proliferation by 28.30% in TK6-miR-7-5p cells compared to those negative control cells (TK6-shNC) in response to HQ treatment. Furthermore, HQ might active the apoptotic pathway via partly downregulation the expression of BRCA1 and PARP-1, followed by p53 activation, in TK6-miR-7-5p cells. In contrast, attenuated p53 and BRCA1 expression was observed in shPARP-1 cells than in NC cells after HQ treatment. Therefore, we conclude that HQ may activate apoptotic signals via inhibiting the tumor suppressive effects of miR-7-5p, which may be mediated partly by upregulating the expression of PARP-1 and BRCA1 in control cells. The increase of miR-7-5p expression further intensified downregulation of PARP-1 and BRCA1 in TK6-miR-7-5p cells, resulting in an increase of apoptosis and proliferation inhibited.