Exploring the source, migration and environmental risk of perfluoroalkyl acids and novel alternatives in groundwater beneath fluorochemical industries along the Yangtze River, China.

The widely used legacy perfluoroalkyl acids (PFAAs) with serious environmental hazards are gradually restricted and being replaced by novel alternatives. Here, for an efficient control of emerging environmental risks in groundwater, we systematically studied the source apportionment, spatial attenuation, composition change and risk zoning of 12 PFAAs and five novel alternatives within a region of ~200 km2 around a mega fluorochemical industrial park (FIP) along the Yangtze River, and in-depth explored potential association between groundwater and soil pollution as well as influencing factors on contaminant migration and risk distribution in the aquifer. Short-chain PFAAs and novel alternatives together accounted for over 70% in groundwater, revealing their prevalence in replacing legacy perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Novel alternatives for PFOA were mainly hexafluoropropylene oxide dimer acid (GenX) and hexafluoropropylene oxide trimer acid (HFPO-TA), while those for PFOS were 6:2 chlorinated polyfluorinated ether sulfonic acid (6:2 Cl-PFESA) and 6:2 fluorotelomer sulfonic acid (6:2 FTS). PFAAs (maximum total: 1339 ng/L) and novel alternatives (maximum total: 208 ng/L) in groundwater were mostly derived from the FIP, and exhibited an exponentially decreasing trend with increasing distance. Compared with those in groundwater, more diverse sources of PFAAs and novel alternatives in surface soil were identified. The transport of these chemicals may be retarded by clayed surface soils with high organic matter contents. High aquifer permeability could generally promote the dilution and migration of PFAAs and novel alternatives in groundwater, as well as reduce the differences in their spatial distribution. Shorter-chain components with smaller molecules and higher hydrophilicity exhibited greater migration capacities in the aquifer. In addition, different levels of health risk from PFOS and PFOA were zoned based on drinking groundwater, and high risks tended to be distributed in areas with relatively poor aquifer water yield due to higher pollutant accumulation.

Promoter hypermethylation of SOX11 promotes the progression of cervical cancer in vitro and in vivo.

The development of cervical cancer (CC) is a multi­gene, multi­step carcinogenic process that involves complex genetic and epigenetic mechanisms. SRY­related HMG­box gene 11 (SOX11) is a member of the SOX family of transcription factors with an emerging crucial role in the development of various tumor types. To elucidate the function of SOX11 in cervical carcinogenesis, the expression level of SOX11 during the development of human CC was analyzed by immunohistochemistry and western blot analysis. Additionally, the methylation status of the SOX11 was examined using bisulfite sequencing and methylation­specific polymerase chain reaction. The SOX11 expression and promoter methylation in human CC cell lines were also determined. The effect of SOX11 expression restoration after 5­aza­2'­deoxycytidine (5­Aza­dC) treatment on the CC cell proliferation ability was evaluated in CC cell lines. SOX11 was highly expressed in normal cervix (NC) and precancerous low­grade squamous intraepithelial lesions, but weakly expressed or virtually absent in precancerous high­grade squamous intraepithelial lesions and CC, which is consistent with the result of the western blot analysis. Hypermethylation of the SOX11 promoter was detected in CC, which was significantly higher than that in NC samples at each CpG site. The expression level of SOX11 in the CC cell lines was downregulated compared with the positive control, Tera­1human teratoma cell line. Upon 5­Aza­dC treatment, SOX11 expression was significantly upregulated in the CC cell lines at the mRNA and protein levels, and cell proliferation was inhibited. The results indicated that the downregulation of SOX11 in CC is due to the hypermethylation of the SOX11 promoter region. Thus, SOX11 methylation may have a role in the growth of CC cells and cervical carcinogenesis.

Human GPR4 and the Notch signaling pathway in endothelial cell tube formation.

G protein-coupled receptor 4 (GPR4) is hypothesized to function as a pH sensor and is important in the regulation of proliferation, migration and angiogenesis of vascular endothelial cells (ECs). Furthermore, the Notch signaling pathway is significant in the regulation of the angiogenic behavior of ECs. However, whether GPR4 regulates angiogenesis via the Notch signaling pathway remains unclear. The present study evaluated the effect of Notch signaling in human GPR4­induced angiogenesis in HMEC­1 cells. The results revealed that GPR4 increased Notch1 expression in a time­dependent manner. In addition, the inhibition of Notch1 expression using small interfering RNA or the Notch receptor inhibitor, γ-secretase inhibitor I, significantly blocked GPR4­induced HMEC­1 tube formation and lymphocyte transendothelial migration. Furthermore, the inhibition of Notch1 blocked GPR4­induced vascular endothelial growth factor and hypoxia-inducible factor 1α expression. Thus, it was demonstrated that GPR4 affects ECs by regulating Notch1, a function that may be important for physiological and pathological angiogenesis.

The polycomb group protein enhancer of zeste 2 is a novel therapeutic target for cervical cancer.

Enhancer of zeste 2 (EZH2), a polycomb histone methyltransferase, is overexpressed in various cancers, including cervical cancer. Gene expression analysis revealed that increased expression of EZH2 is associated with cervical cancer progression, particularly the progression to invasive squamous cell carcinoma. Enhancer of zeste 2 is known to trimethylate lysine 27 on histone H3, leading to gene silencing that contributes to the progression of tumours into a more aggressive form of cancer. However, the specific molecular mechanisms by which EZH2 contributes to the development of cervical cancer remain largely unknown. Recently, an EZH2 inhibitor was reported to selectively inhibit trimethylated lysine 27 on histone H3 and to reactivate silenced genes in cancer cells. In this study, we found that GSK343 (a specific inhibitor of EZH2 methyltransferase) induces phenotypic reprogramming of cancer cells from mesenchymal to epithelial cells, reducing proliferation and cell motility and blocking the invasion of cervical cancer cell lines both in vitro and in vivo. Treatment with the EZH2 inhibitor led to increased levels of the epithelial marker E-cadherin and decreased levels of mesenchymal markers such as N-cadherin and vimentin. The observed reprogramming is associated with restrained cervical cancer progression and provides direct evidence in support of EZH2 as a therapeutic target.

RNAi targeting GPR4 influences HMEC-1 gene expression by microarray analysis.

G-protein coupled receptor 4 (GPR4) belongs to a protein family comprised of 3 closely related G protein-coupled receptors. Recent studies have shown that GPR4 plays important roles in angiogenesis, proton sensing, and regulating tumor cells as an oncogenic gene. How GPR4 conducts its functions? Rare has been known. In order to detect the genes related to GPR4, microarray technology was employed. GPR4 is highly expressed in human vascular endothelial cell HMEC-1. Small interfering RNA against GPR4 was used to knockdown GPR4 expression in HMEC-1. Then RNA from the GPR4 knockdown cells and control cells were analyzed through genome microarray. Microarray results shown that among the whole genes and expressed sequence tags, 447 differentially expressed genes were identified, containing 318 up-regulated genes and 129 down-regulated genes. These genes whose expression dramatically changed may be involved in the GPR4 functions. These genes were related to cell apoptosis, cytoskeleton and signal transduction, cell proliferation, differentiation and cell-cycle regulation, gene transcription and translation and cell material and energy metabolism.