GoSTR, a negative modulator of stem trichome formation in cotton.

Trichomes, the outward projection of plant epidermal tissue, provide an effective defense against stress and insect pests. Although numerous genes have been identified to be involved in trichome development, the molecular mechanism for trichome cell fate determination is not well enunciated. Here, we reported GoSTR functions as a master repressor for stem trichome formation, which was isolated by map-based cloning based on a large F2 segregating population derived from a cross between TM-1 (pubescent stem) and J220 (smooth stem). Sequence alignment revealed a critical G-to-T point mutation in GoSTR's coding region that converted codon 2 from GCA (Alanine) to TCA (Serine). This mutation occurred between the majority of Gossypium hirsutum with pubescent stem (GG-haplotype) and G. barbadense with glabrous stem (TT-haplotype). Silencing of GoSTR in J220 and Hai7124 via virus-induced gene silencing resulted in the pubescent stems but no visible change in leaf trichomes, suggesting stem trichomes and leaf trichomes are genetically distinct. Yeast two-hybrid assay and luciferase complementation imaging assay showed GoSTR interacts with GoHD1 and GoHOX3, two key regulators of trichome development. Comparative transcriptomic analysis further indicated that many transcription factors such as GhMYB109, GhTTG1, and GhMYC1/GhDEL65 which function as positive regulators of trichomes were significantly upregulated in the stem from the GoSTR-silencing plant. Taken together, these results indicate that GoSTR functions as an essential negative modulator of stem trichomes and its transcripts will greatly repress trichome cell differentiation and growth. This study provided valuable insights for plant epidermal hair initiation and differentiation research.

Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression.

TGF-ß signaling pathway plays a key role in breast cancer metastasis. Recent studies suggest that TGF-ß regulates tumor progression and invasion not only via transcriptional regulation, but also via translational regulation. Using both bioinformatics and experimental tools, we identified a micropeptide CIP2A-BP encoded by LINC00665, whose translation was downregulated by TGF-ß in breast cancer cell lines. Using TNBC cell lines, we showed that TGF-ß-activated Smad signaling pathway induced the expression of translation inhibitory protein 4E-BP1, which inhibited eukaryote translation initiation factor elF4E, leading to reduced translation of CIP2A-BP from LINC00665. CIP2A-BP directly binds tumor oncogene CIP2A to replace PP2A's B56γ subunit, thus releasing PP2A activity, which inhibits PI3K/AKT/NFκB pathway, resulting in decreased expression levels of MMP-2, MMP-9, and Snail. Downregulation of CIP2A-BP in TNBC patients was significantly associated with metastasis and poor overall survival. In the MMTV-PyMT model, either introducing CIP2A-BP gene or direct injection of CIP2A-BP micropeptide significantly reduced lung metastases and improved overall survival. In conclusion, we provide evidence that CIP2A-BP is both a prognostic marker and a novel therapeutic target for TNBC.

A facial strategy to efficiently improve catalytic performance of CoFe2O4 to peroxymonosulfate.

Cobalt iron spinel (CoFe2O4) has been considered as a good heterogeneous catalysis to peroxymonosulfate (PMS) in the degradation of persistent organic pollutants due to its magnetic properties and good chemical stability. However, its catalytic activity needs to be further improved. Here, a facial strategy, "in-situ substitution", was adopted to modify CoFe2O4 to improve its catalytic performance just by suitably increasing the Co/Fe ratio in synthesis process. Compared with CoFe2O4, the newly synthesized Co1.5Fe1.5O4, could not only significantly improve the degradation efficiency of phenol, from 50.69 to 93.6%, but also exhibited more effective mineralization ability and higher PMS utilization. The activation energy advantage for phenol degradation using Co1.5Fe1.5O4 was only 44.2 kJ/mol, much lower than that with CoFe2O4 (127.3 kJ/mol). A series of related representations of CoFe2O4 and Co1.5Fe1.5O4 were compared to explore the possible reasons for the outstanding catalytic activity of Co1.5Fe1.5O4. Results showed that Co1.5Fe1.5O4 as well represented spinel crystal as CoFe2O4 and the excess cobalt just partially replaced the position of iron without changing the original structure. Co1.5Fe1.5O4 had smaller particle size (8.7 nm), larger specific surface area (126.3 m2/g), which was more favorable for exposure of active sites. Apart from the superior physical properties, more importantly, more reactive centers Co (Ⅱ) and surface hydroxyl compounds generated on Co1.5Fe1.5O4, which might be the major reason. Furthermore, Co1.5Fe1.5O4 behaved good paramagnetism, wide range of pH suitability and strong resistance to salt interference, making it a new prospect in environmental application.

Efficient degradation of Rhodamine B by magnetically recoverable Fe3O4-modified ternary CoFeCu-layered double hydroxides via activating peroxymonosulfate.

Environment-friendly nano-catalysts capable of activating peroxymonosulfate (PMS) have received increasing attention recently. Nevertheless, traditional nano-catalysts are generally well dispersed and difficult to be separated from reaction system, so it is particularly important to develop nano-catalysts with both good catalytic activity and excellent recycling efficiency. In this work, magnetically recoverable Fe3O4-modified ternary CoFeCu-layered double hydroxides (Fe3O4/CoFeCu-LDHs) was prepared by a simple co-precipitation method and initially applied to activate PMS for the degradation of Rhodamine B (RhB). X-ray diffraction (XRD), fourier transform infrared spectrometer (FT-IR), scanning electron microscope (SEM), transmission electron microscopy (TEM), Brunauer-Emmett-Teller method (BET), and vibrating sample magnetometer (VSM) were applied to characterize morphology, structure, specific surface area and magnetism. In addition, the effects of several key parameters were evaluated. The Fe3O4/CoFeCu-LDHs exhibited high catalytic activity, and RhB degradation efficiency could reach 100% within 20 min by adding 0.2 g/L of catalyst and 1 mmol/L of PMS into 50 mg/L of RhB solution under a wide pH condition (3.0-7.0). Notably, the Fe3O4/CoFeCu-LDHs showed good super-paramagnetism and excellent stability, which could be effectively and quickly recovered under magnetic condition, and the degradation efficiency after ten cycles could still maintain 98.95%. Both radicals quenching tests and electron spin resonance (ESR) identified both HO• and SO4•- were involved and SO4•- played a dominant role on the RhB degradation. Finally, the chemical states of the sample's surface elements were measured by X-ray photoelectron spectroscopy (XPS), and the possible activation mechanism in Fe3O4/CoFeCu-LDHs/PMS system was proposed according to comprehensive analysis.

LMI1-like and KNOX1 genes coordinately regulate plant leaf development in dicotyledons.

KEY MESSAGE: This report reveals that the LMI1-like and KNOX1 genes coordinately control the leaf development and different combinations of those genes which produce diverse leaf shapes including broad, lobed and compound leaves. Class I KNOTTED1-like homeobox (KNOX1) genes are involved in compound leaf development and are repressed by the ASYMMETRIC LEAVES1 (AS1)-AS2 complex. Cotton plants have a variety of leaf shapes, including broad leaves and lobed leaves. GhOKRA, a LATE MERISTEM IDENTITY 1 (LMI1)-like gene, controls the development of an okra leaf shape. We cloned the corresponding cotton homologs of Arabidopsis thaliana AS1 and AS2 and seven KNOX1 genes. Through virus-induced gene silencing technology, we found that either GhAS1 or GhAS2-silenced cotton plants showed a great change in leaf shape from okra leaves to trifoliolate dissected leaves. In the shoot tips of these plants, the expression of the cotton ortholog of Knotted in A. thaliana 1 (KNAT1), GhKNOTTED1-LIKE2/3/4 (GhKNL2/3/4), was increased. However, GhKNOX1s-silenced plants maintained the wild-type okra leaves. A novel dissected-like leaf in A. thaliana was further generated by crossing plants constitutively expressing GhOKRA with either as1-101 or as2-101 mutant plants. The dissected-like leaves showed two different leaf vein patterns. This report reveals that the LMI1-like and KNOX1 genes coordinately control leaf development, and different combinations of these genes produce diverse leaf shapes including broad leaves, lobed leaves and compound leaves. This is the first report on the artificial generation of compound leaves from simple leaves in cotton.

Exosomal FMR1-AS1 facilitates maintaining cancer stem-like cell dynamic equilibrium via TLR7/NFκB/c-Myc signaling in female esophageal carcinoma.

BACKGROUND: Though esophageal cancer is three to four times more common among males than females worldwide, this type of cancer still ranks in the top incidence among women, even more than the female specific cancer types. The occurrence is currently attributed to extrinsic factors, including tobacco use and alcohol consumption. However, limited attention has been given to gender-specific intrinsic genetic factors, especially in female. METHODS: We re-annotated a large cohort of microarrays on 179 ESCC patients and identified female-specific differently expressed lncRNAs. The associations between FMR1-AS1 and the risk and prognosis of ESCC were examined in 206 diagnosed patients from eastern China and validated in 188 additional patients from southern China. The effects of FMR1-AS1 on the malignant phenotypes on female ESCC cells were detected in vitro and in vivo. ChIRP-MS, reporter gene assays and EMSA were conducted to identify the interaction and regulation among FMR1-AS1, TLR7 and NFκB. RESULTS: We found FMR1-AS1 expression is exclusively altered and closely associated with the level of sXCI in female ESCC patients, and its overexpression may correlate to poor clinical outcome. ChIRP-MS data indicate that FMR1-AS1 could be packaged into exosomes and released into tumor microenvironment. Functional studies demonstrated that FMR1-AS1 could bind to endosomal toll-like receptor 7 (TLR7) and activate downstream TLR7-NFκB signaling, promoting the c-Myc expression, thus inducing ESCC cell proliferation, anti-apoptosis and invasion ability. Exosome incubation and co-xenograft assay indicate that FMR1-AS1 exosomes may secreted from ESCC CSCs, transferring stemness phenotypes to recipient non-CSCs in tumor microenvironment. Furthermore, we also found a correlation between the serum levels of FMR1-AS1 and the overall survival (OS) of the female ESCC patients. CONCLUSIONS: Our results highlighted exosomal FMR1-AS1 in maintaining CSC dynamic interconversion state through the mechanism of activating TLR7-NFκB signaling, upregulating c-Myc level in recipient cells, which may be taken as an attractive target approach for advancing current precision cancer therapeutics in female patients.

X chromosome-linked long noncoding RNA lnc-XLEC1 regulates c-Myc-dependent cell growth by collaborating with MBP-1 in endometrial cancer.

LncRNAs (long noncoding RNAs) are noncoding transcripts that are more than 200 nt long and have been described as the largest subclass in the noncoding transcriptome in humans. Although studies of lncRNAs in cancer have been continuing for a long time, no much has been known about X chromosome-linked lncRNAs. Here, by using RNA-seq we report the identification of a new X chromosome-linked lncRNA (lnc-XLEC1) that is aberrantly downregulated during the development of endometrial carcinoma (EC). The overexpression of lnc-XLEC1 reduces the migration and proliferation of EC cells. Flow cytometry analysis indicated that lnc-XLEC1 overexpression resulted in a substantial accumulation of EC cells in the G1 phase. In addition, lnc-XLEC1 had inhibitive effects that may result from its collaboration with MBP-1 during the suppression of the c-Myc expression and the negative regulating of the Cdk/Rb/E2F pathway. The anti-tumor effects of lnc-XLEC1 on EC progression suggest that lnc-XLEC1 has some potential value in anti-carcinoma therapies and deserves further investigation. Our study reported for the first time that the lnc-XLEC1 might be related to the incidence and prognosis of EC. Moreover, we discovered that this process might be related to somatic X dosage compensation and skewed X chromosome inactivation (SXCI).

A CC-NBS-LRR gene induces hybrid lethality in cotton.

Hybrid lethality forms a reproductive barrier that has been found in many eukaryotes. Most cases follow the Bateson-Dobzhansky-Muller genetic incompatibility model and involve two or more loci. In this study, we demonstrate that a coiled-coil nucleotide-binding site leucine-rich repeat (CC-NBS-LRR) gene is the causal gene underlying the Le4 locus for interspecific hybrid lethality between Gossypium barbadense and G. hirsutum (cotton). Silencing this CC-NBS-LRR gene can restore F1 plants from a lethal to a normal phenotype. A total of 11 099 genes were differentially expressed between the leaves of normal and lethal F1 plants, of which genes related to autoimmune responses were highly enriched. Genes related to ATP-binding and ATPase were up-regulated before the lethal syndrome appeared; this may result in the conversion of Le4 into an active state and hence trigger immune signals in the absence of biotic/abiotic stress. We discuss our results in relation to the evolution and domestication of Sea Island cottons and the molecular mechanisms of hybrid lethality associated with autoimmune responses. Our findings provide new insights into reproductive isolation and may benefit cotton breeding.

Long non-coding RNA LINC00672 contributes to p53 protein-mediated gene suppression and promotes endometrial cancer chemosensitivity.

Thousands of long intergenic non-protein coding RNAs (lincRNAs) have been identified in mammals in genome-wide sequencing studies. Some of these RNAs have been consistently conserved during the evolution of species and could presumably function in important biologic processes. Therefore, we measured the levels of 26 highly conserved lincRNAs in a total of 176 pairs of endometrial carcinoma (EC) and surrounding non-tumor tissues of two distinct Chinese populations. Here, we report that a lincRNA, LINC00672, which possesses an ultra-conserved region, is aberrantly down-regulated during the development of EC. Nevertheless, LINC00672 is a p53-targeting lincRNA acting along with heterogeneous nuclear ribonucleoproteins as a suppressive cofactor, which locally reinforces p53-mediated suppression of LASP1, an evolutionarily conserved neighboring gene of LINC00672 and putatively associated with increased tumor aggressiveness, during anti-tumor processes. LINC00672 overexpression could lower the levels of LASP1 and slow the development of malignant phenotypes of EC both in vitro and in vivo Moreover, LINC00672 significantly increased the 50% inhibitory concentration of paclitaxel in EC cells and increased the sensitivity of xenograft mice to paclitaxel. These findings indicate that LINC00672 can influence LASP1 expression as a locus-restricted cofactor for p53-mediated gene suppression, thus impacting EC malignancies and chemosensitivity to paclitaxel.

A functional copy number variation in the WWOX gene is associated with lung cancer risk in Chinese.

WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that has been reported to lose function due to genetic alterations in several cancers. WWOX maps to the common chromosomal fragile site FRA16D and several copy number variations (CNVs) were found within this gene. In this study, we investigated the association between the CNVs of WWOX and lung cancer risk in four independent case-control studies, which are on 2942 lung cancer cases and 3074 cancer-free controls of southern, eastern and northern Chinese. A common CNV-67048 was genotyped by the Taqman real-time PCR, and its biological effect was accessed with protein expression and sequencing assays. We found that in comparison with the common 2-copy genotype, the carriers of loss variant genotypes (1-copy or 0-copy) had a significantly increased risk of lung cancer (adjusted OR = 1.39, 95% CI = 1.24-1.55, P = 9.01×10(-9)) in a dose-response manner (Ptrend = 1.12 × 10(-10)), and the WWOX protein expressions in lung cancer tissues were significantly lower (P = 0.036), accompanying a higher rate of exons absence (P = 0.021) in subjects with loss genotypes of CNV-67048. Our data suggest that the loss genotypes of CNV-67048 in WWOX predispose their carriers to lung cancer; this might be related with altered WWOX gene expression and exons absence in them.

Increased levels of the long intergenic non-protein coding RNA POU3F3 promote DNA methylation in esophageal squamous cell carcinoma cells.

BACKGROUND & AIMS: Thousands of long intergenic non-protein coding RNAs (lincRNAs) have been identified in mammals via genome-wide sequencing studies. Many are functional, but are expressed aberrantly by cancer cells. We investigated whether levels of lincRNAs are altered during the development of esophageal squamous cell carcinoma (ESCC). METHODS: We used quantitative real-time polymerase chain reaction to measure levels of 26 highly conserved lincRNAs in ESCC and surrounding nontumor tissues. A total of 182 ESCC and paired adjacent nontumor tissue samples were collected from patients undergoing tylectomy at The First Affiliate Hospital of Soochow University from 2001 through 2009; another 178 ESCC tissue pairs were collected from Guangzhou Medical University from 2002 through 2009. LincRNAs were expressed from lentiviral vectors or knocked down with small hairpin RNAs in Eca-109 and TE-1 cells. RESULTS: Levels of a lincRNA encoded by a gene located next to POU3F3 (linc-POU3F3) were significantly higher in ESCC than neighboring nontumor tissues. In RNA immunoprecipitation assays, linc-POU3F3 was associated with the EZH2 messenger RNA (mRNA). Overexpression of linc-POU3F3 in cell lines increased their proliferation and ability to form colonies, and reduced the expression of POU3F3 mRNA, whereas knockdown of linc-POU3F3 increased the levels of POU3F3 mRNA. CpG islands in POU3F3 were densely hypermethylated in cell lines that overexpressed linc-POU3F3; methylation at these sites was reduced by knockdown of linc-POU3F3. Pharmacologic inhibition of EZH2 increased the levels of POU3F3 mRNA and significantly reduced binding of DNA methyltransferase (DNMT)1, DNMT3A, and DNMT3B to POU3F3. ESCC cells with knockdown of linc-POU3F3 formed xenograft tumors more slowly in mice than control ESCC cells. CONCLUSIONS: Levels of linc-POU3F3 are increased in ESCC samples from patients compared with nontumor tissues. This noncoding RNA contributes to the development of ESCC by interacting with EZH2 to promote methylation of POU3F3, which encodes a transcription factor.

Functional polymorphisms in the CD44 gene and acute myeloid leukemia cancer risk in a Chinese population.

CD44 is such one adhesion molecule that mediates interactions between acute myeloid leukemia (AML) cells and stromal. It has been demonstrated that CD4 plays a critical role in AML development. However, studies of functional single nucleotide polymorphisms (SNPs) in CD44 gene have not touched upon AML. This case-control study probed the contribution of functional SNPs in CD44 gene to AML susceptibility in eastern Chinese population. Five representative SNPs of CD44 (rs10836347C>T, rs13347C>T, rs1425802A>G, rs11821102G>A, rs713330T>C) were opted and genotyped in 421 AML patients and 461 healthy subjects and the association with risk of AML was estimated by logistic regression. Moreover, the potential role of rs13347C > T in AML was further explored. Compared with the rs13347CC genotype, CT carriers had a significant increase in AML susceptibility (adjusted odds ratio [OR] = 1.76; 95% confidence interval [CI] = 1.32-2.34), TT carriers had a further increased risk of AML (OR = 2.67; 95% CI = 1.69-4.21). Furthermore, our transient transfection assay and Western blot results demonstrated that the presence of rs13347T allele led to more CD44 expression. Yet, there exists no significant difference in genotype frequencies of the other four sites between cases and controls. Above findings suggest that rs13347C>T in 3'UTR of CD44 may be a genetic modifier for developing AML.

Risk factors shared by COPD and lung cancer and mediation effect of COPD: two center case-control studies.

PURPOSE: To reveal the shared risk factors for chronic obstructive pulmonary disease (COPD) and lung cancer, and to analyze the mediation effect of COPD during lung carcinogenesis. METHODS: We conducted four independent case-control studies included 1,511 COPD patients and 1,677 normal lung function controls and 1,559 lung cancer cases and 1,679 cancer-free controls during 2002-2011 in southern and eastern Chinese. RESULTS: Eight factors were observed to be consistently associated with both diseases risk, including pre-existing tuberculosis, smoking, passive smoking, occupational exposure to metallic toxicant, poor housing ventilation, biomass burning, cured meat consumption, and seldom vegetables/fruits consumption. Furthermore, smoking and biomass burning conferred significantly higher risk effects on lung cancer in individuals with pre-existing COPD than those without. COPD also had significant mediation effects during lung carcinogenesis caused by smoking, passive smoking, and biomass burning, which explained about 12.0 % of effect, 3.8 % of effect, and 6.1 % of effect of these factors on lung tumorigenesis in turn. CONCLUSION: Our study mapped a shared spectrum of etiological factors for both COPD and lung cancer in Chinese, and COPD acts as a mediator during lung cancer development. These observations should be in consideration for the prevention of both diseases.

Effects of a functional variant c.353T>C in snai1 on risk of two contextual diseases. Chronic obstructive pulmonary disease and lung cancer.

RATIONALE: Epithelial-mesenchymal transition (EMT) plays a key role in the development of chronic obstructive pulmonary disease (COPD) and lung cancer. OBJECTIVES: There are five major EMT regulatory genes (Snai1, Slug, Zeb1, Zeb2, and Twist1) involved in EMT. We hypothesized that germline variants in these genes may influence the development of both diseases. METHODS: Seven genetic variants were genotyped in two two-stage case-control studies with 2,072 lung cancer cases and 2,077 control subjects, and 1,791 patients with COPD and 1,940 control subjects to show their associations with development of both diseases. MEASUREMENTS AND MAIN RESULTS: An exon variant c.353T>C(p.Val118Ala) of Snai1 harbored decreased risks of lung cancer (CT/CC vs. TT: odds ratio [OR], 0.76; 95% confidence interval [CI], 0.65-0.90) and COPD (CC vs. CT vs. TT: OR, 0.75; 95% CI, 0.63-0.89), and c.353T>C affected lung cancer risk indirectly through COPD (COPD accounted for 6.78% of effect that the variant had on lung cancer). Moreover, c.353T>C was correlated with lung cancer stages in smoking patients (P = 0.013), and those with the c.353C genotypes were less likely to have metastasis at diagnosis than those with the c.353TT genotype (OR, 0.60; 95% CI, 0.41-0.88). The c.353C allele encoding p.118Ala attenuated Snai1's ability to up-regulate mesenchymal biomarkers (i.e., fibronectin and vimentin) expression, and to promote EMT-like changes, including morphologic changes, cell migration, and invasion. However, these effects were not observed for the other variants. CONCLUSIONS: The functional germline variant c.353T>C (p.Val118Ala) of Snai1 confers consistently decreased risks of lung cancer and COPD, and this variant affects lung cancer risk through a mediation effect of COPD.

Identification of chimeric TSNAX-DISC1 resulting from intergenic splicing in endometrial carcinoma through high-throughput RNA sequencing.

Gene fusion is among the primary processes that generate new genes and has been well characterized as potent pathway of oncogenesis. Here, by high-throughput RNA sequencing in nine paired human endometrial carcinoma (EC) and matched non-cancerous tissues, we obtained that chimeric translin-associated factor X-disrupted-in-schizophrenia 1 (TSNAX-DISC1) occurred significantly upregulated in multiple EC samples. Experimental investigation showed that TSNAX-DISC1 appears to be formed by splicing without chromosomal rearrangement. The chimera expression inversely correlated with the binding of CCCTC-binding factor (CTCF) to the insulators. Subsequent investigations indicate that long intergenic non-coding RNA lincRNA-NR_034037, separating TSNAX from DISC1, regulates TSNAX -DISC1 production and TSNAX/DISC1 expression levels by extricating CTCF from insulators. Dysregulation of TSNAX influences steroidogenic factor-1-stimulated transcription on the StAR promoter, altering progesterone actions, implying the association with cancer. Together, these results advance our understanding of the mechanism in which lincRNA-NR_034037 regulates TSNAX-DISC1 formation programs that tightly regulate EC development.

The effect of functional MAPKAPK2 copy number variation CNV-30450 on elevating nasopharyngeal carcinoma risk is modulated by EBV infection.

UNLABELLED: Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) is recognized as oncogenic and simulative role on tumorigenesis by virtue of abnormal expression in cancer including nasopharyngeal carcinoma (NPC). We hypothesized that the copy number variation (CNV)-30450, which duplicates the MAPKAPK2 promoter, may affect MAPKAPK2 expression and be associated with NPC risk. In two independent case-control panels of southern and eastern Chinese with a total of 1590 NPC patients and 1979 cancer-free controls, we investigated the association between CNV-30450 and NPC risk by genotyping the CNV-30450 with the TaqMan assay, and tested its biological effect. Consistent findings were observed in the two populations, that the increased copy number of CNV-30450 was associated with increased risk of NPC (3/4-copy versus 2-copy: odds ratio = 1.28, 95% confidence interval = 1.10-1.49), in which lies a biological mechanism that the adverse genotypes enhanced the promoter activity of MAPKAPK2 and elevated MAPKAPK2 expression. Moreover, the CNV-30450 adverse genotypes significantly interacted with Epstein-Barr virus (EBV) infection on increasing NPC risk (P = 0.035), and the genotype-phenotype correlation was only significant in EBV-positive cases (P = 0.037) but not in EBV-negative ones (P = 0.366). These data suggest that the functional CNV-30450 in the MAPKAPK2 promoter elevates the NPC risk with a modulation by EBV infection, which may be an indicator of susceptibility to NPC. SUMMARY: This case-control study suggests that the functional CNV-30450 in the MAPKAPK2 promoter elevates the NPC risk with a modulation by EBV infection, which may be an indicator of susceptibility to NPC.

Genetic variant in the 3'-untranslated region of VEGFR1 gene influences chronic obstructive pulmonary disease and lung cancer development in Chinese population.

Lung inflammation and epithelial to mesenchymal transition (EMT) are two pathogenic features for the two contextual diseases: chronic obstructive pulmonary disease (COPD) and lung cancer. VEGFR1 (or FLT1) plays a certain role in promoting tumour growth, inflammation and EMT. To simultaneously test the association between the single nucleotide polymorphisms (SNPs) in VEGFR1 and risk of COPD and lung cancer would reveal genetic mechanisms shared by these two diseases and joint aetiology. We conducted a two-population hospital-based case-control study. Three potential functional SNPs (rs664393, rs7326277 and rs9554314) were genotyped in southern Chinese and validated in eastern Chinese to explore their associations with COPD risk in 1511 COPD patients and 1677 normal lung function controls, and with lung cancer risk in 1559 lung cancer cases and 1679 cancer-free controls. We also detected the function of the promising SNP. Individuals carrying the rs7326277C (CT+CC) variant genotypes of VEGFR1 had a significant decrease in risk of both COPD (OR = 0.78; 95% CI = 0.68-0.90) and lung cancer (OR = 0.79; 95% CI = 0.64-0.98), compared with those carrying the rs7326277TT genotype. Functional assays further showed that the rs7326277C genotypes had lower transcriptional activity and caused decreased VEGFR expression, compared with the rs7326277TT genotype. However, no significant association was observed for the other two SNPs (rs664393 and rs9554314) and either COPD or lung cancer risk. Our data suggested that the rs7326277C variant of VEGFR1 could reduce both COPD and lung cancer risk by lowering VEGFR1 mRNA expression; the SNP might be a common susceptible locus for both COPD and lung cancer.

GHCU, a Molecular Chaperone, Regulates Leaf Curling by Modulating the Distribution of KNGH1 in Cotton.

Leaf shape is considered to be one of the most significant agronomic traits in crop breeding. However, the molecular basis underlying leaf morphogenesis in cotton is still largely unknown. In this study, through genetic mapping and molecular investigation using a natural cotton mutant cu with leaves curling upward, the causal gene GHCU is successfully identified as the key regulator of leaf flattening. Knockout of GHCU or its homolog in cotton and tobacco using CRISPR results in abnormal leaf shape. It is further discovered that GHCU facilitates the transport of the HD protein KNOTTED1-like (KNGH1) from the adaxial to the abaxial domain. Loss of GHCU function restricts KNGH1 to the adaxial epidermal region, leading to lower auxin response levels in the adaxial boundary compared to the abaxial. This spatial asymmetry in auxin distribution produces the upward-curled leaf phenotype of the cu mutant. By analysis of single-cell RNA sequencing and spatiotemporal transcriptomic data, auxin biosynthesis genes are confirmed to be expressed asymmetrically in the adaxial-abaxial epidermal cells. Overall, these findings suggest that GHCU plays a crucial role in the regulation of leaf flattening through facilitating cell-to-cell trafficking of KNGH1 and hence influencing the auxin response level.

Heterozygous genetic variations of FOXP3 in Xp11.23 elevate breast cancer risk in Chinese population via skewed X-chromosome inactivation.

FOXP3 (forkhead box P3: also known as IPEX, XPID) is not only a hallmark of immunosuppressive regulatory T cells (Tregs), but also an X-linked breast cancer suppressor gene expressed in tumor cells. A two-stage investigation was conducted in individuals from northern, southern and eastern China. Individuals carrying a FOXP3 rs2294021CT genotype showed about 1.5-fold increased risk of breast cancer compared with TT carriers. In a related biochemical assay, the rs2294021C allele was found to significantly enhance transcription activity, leading to higher mRNA levels of FOXP3 compared with T allele. Moreover, the number of Tregs and its corresponding interleukin-10 (IL-10) secretion were elevated whereas the proliferation of antitumor T cells was decreased in the C-allele carriers. The breast cancer oncogenes Her-2/ErbB2 and Skp2 were also found to be significantly inhibited in C-allele carriers. Moreover, skewed X-chromosome inactivation (SXCI) analysis showed that rs2294021CT carriers with SXCI showed higher risk than the homozygous carriers and CT carriers without SXCI, suggesting a possible interaction between the rs2294021CT genotype and SXCI. Taken together, these findings indicate that the rs2294021CT genotype may increase an individual's susceptibility to breast cancer by breaking the balance between Treg-mediated immune tolerance and FOXP3-controlled tumor-suppressive effect.

A genetic polymorphism in lincRNA-uc003opf.1 is associated with susceptibility to esophageal squamous cell carcinoma in Chinese populations.

The development of esophageal squamous cell carcinoma (ESCC) is a multifactorial process, and associations between genetic variants and ESCC have been identified in genome-wide association studies. The aim of this study was to evaluate the effects of single nucleotide polymorphisms (SNPs) of long intergenic non-coding RNAs (lincRNAs) on ESCC susceptibility in Chinese populations. We scoured exons of lincRNAs located in ESCC susceptibility loci for all probable functional SNPs. These 52 SNPs were opted for and genotyped in 1493 ESCC patients and 1553 cancer-free controls from eastern and southern Chinese populations, and their associations with the risk for ESCC were estimated using logistic regression. Functional relevance was further examined by biochemical assays. Significant differences were found between patients and controls in the genotype frequencies for the rs11752942A>G site in the lincRNA-uc003opf.1 exon. Compared with the rs11752942AA genotype, AG and GG genotypes had a significantly reduced risk of ESCC (adjusted odds ratio = 0.73; 95% confidence interval = 0.63-0.84). Biochemical analysis demonstrated that, when compared with the A allele, the rs11752942G allele could markedly attenuate the level of lincRNA-uc003opf.1 both in vivo and in vitro by binding micro-RNA-149*, thereby affecting cell proliferation and tumor growth. These findings indicated that functional polymorphism rs11752942A>G in lincRNA-uc003opf.1 exon might be a genetic modifier for the development of ESCC.