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.

LncRNA-Encoded Micropeptide ACLY-BP Drives Lipid Deposition and Cell Proliferation in Clear Cell Renal Cell Carcinoma via Maintenance of ACLY Acetylation.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of lethal kidney cancer. Reprogramming of fatty acid and glucose metabolism resulting in the accumulation of lipids and glycogen in the cytoplasm is a hallmark of ccRCC. Here, we identified a micropeptide ACLY-BP encoded by the GATA3-suppressed LINC00887, which regulated lipid metabolism and promoted cell proliferation and tumor growth in ccRCC. Mechanistically, the ACLY-BP stabilizes the ATP citrate lyase (ACLY) by maintaining ACLY acetylation and preventing ACLY from ubiquitylation and degradation, thereby leading to lipid deposition in ccRCC and promoting cell proliferation. Our results may offer a new clue for the therapeutic approaches and the diagnostic assessment for ccRCC. IMPLICATIONS: This study identifies ACLY-BP encoded by LINC00887 as a lipid-related micropeptide that stabilizes ACLY to generate acetyl-CoA, driving lipid deposition and promoting cell proliferation in ccRCC.

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.

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.

A micropeptide XBP1SBM encoded by lncRNA promotes angiogenesis and metastasis of TNBC via XBP1s pathway.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) with a poor prognosis. To date, the mechanism of TNBC's aggressive phenotype is still unclear. Based on metabolome analysis, we found that glutamine (Gln) metabolism plays a key role in the difference between TNBC and non-TNBC. We identified a 21-amino-acid survival-associated micropeptide XBP1SBM, encoded by the lncRNA MLLT4-AS1, which was upregulated in TNBC tissues and Gln-deprived TNBC cell lines. We showed that XBP1SBM expression was upregulated by Gln-deprivation-induced XBP1s transcriptional promotion, and in turn retained XBP1s in the nuclear to enhance the expression of VEGF. Using human endothelial cells, mouse xenograft models and mouse spontaneous BC models, we found that XBP1SBM improved Gln levels and promoted angiogenesis and metastasis in TNBC. Our study showed that a TNBC-specific nutrient deficiency adaption results in aggressive TNBC, and this mechanism provides a novel potential prognostic biomarker and therapeutic target in TNBC.

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.

A Novel Micropeptide Encoded by Y-Linked LINC00278 Links Cigarette Smoking and AR Signaling in Male Esophageal Squamous Cell Carcinoma.

Long noncoding RNAs (lncRNA) have been shown to play critical roles in many diseases, including esophageal squamous cell carcinoma (ESCC). Recent studies have reported that some lncRNA encode functional micropeptides. However, the association between ESCC and micropeptides encoded by lncRNA remains largely unknown. In this study, we characterized a Y-linked lncRNA, LINC00278, which was downregulated in male ESCC. LINC00278 encoded a Yin Yang 1 (YY1)-binding micropeptide, designated YY1BM. YY1BM was involved in the ESCC progression and inhibited the interaction between YY1 and androgen receptor (AR), which in turn decreased expression of eEF2K through the AR signaling pathway. Downregulation of YY1BM significantly upregulated eEF2K expression and inhibited apoptosis, thus conferring ESCC cells more adaptive to nutrient deprivation. Cigarette smoking decreased m6A modification of LINC00278 and YY1BM translation. In conclusion, these results provide a novel mechanistic link between cigarette smoking and AR signaling in male ESCC progression. SIGNIFICANCE: Posttranscriptional modification of a micropeptide-encoding lncRNA is negatively impacted by cigarette smoking, disrupting negative regulation of the AR signaling pathway in male ESCC. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/13/2790/F1.large.jpg.See related commentary by Banday et al., p. 2718.

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.

LncRNA-encoded polypeptide ASRPS inhibits triple-negative breast cancer angiogenesis.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) with the most aggressive phenotype and poor overall survival. Using bioinformatics tools, we identified LINC00908 encoding a 60-aa polypeptide and differentially expressed in TNBC tissues. We named this endogenously expressed polypeptide ASRPS (a small regulatory peptide of STAT3). ASRPS expression was down-regulated in TNBCs and associated with poor overall survival. We showed that LINC00908 was directly regulated by ERα, which was responsible for the differential down-regulation of LINC00908 in TNBCs. ASRPS directly bound to STAT3 through the coiled coil domain (CCD) and down-regulated STAT3 phosphorylation, which led to reduced expression of VEGF. In human endothelial cells, a mouse xenograft breast cancer model, and a mouse spontaneous BC model, ASRPS expression reduced angiogenesis. In a mouse xenograft breast cancer model, down-regulation of ASRPS promoted tumor growth, and ASRPS acted as an antitumor peptide. We presented strong evidence that LINC00908-encoded polypeptide ASRPS represented a TNBC-specific target for treatment.

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.

Gossypium barbadense and Gossypium hirsutum genomes provide insights into the origin and evolution of allotetraploid cotton.

Allotetraploid cotton is an economically important natural-fiber-producing crop worldwide. After polyploidization, Gossypium hirsutum L. evolved to produce a higher fiber yield and to better survive harsh environments than Gossypium barbadense, which produces superior-quality fibers. The global genetic and molecular bases for these interspecies divergences were unknown. Here we report high-quality de novo-assembled genomes for these two cultivated allotetraploid species with pronounced improvement in repetitive-DNA-enriched centromeric regions. Whole-genome comparative analyses revealed that species-specific alterations in gene expression, structural variations and expanded gene families were responsible for speciation and the evolutionary history of these species. These findings help to elucidate the evolution of cotton genomes and their domestication history. The information generated not only should enable breeders to improve fiber quality and resilience to ever-changing environmental conditions but also can be translated to other crops for better understanding of their domestication history and use in improvement.

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).

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.

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.

Circular RNA ITCH has inhibitory effect on ESCC by suppressing the Wnt/ß-catenin pathway.

Circular RNAs with exonic sequences represent a special form of non-coding RNAs, discovered by analyzing a handful of transcribed genes. It has been observed that circular RNAs function as microRNA sponges. In the present study, we investigated whether the expression of circular RNAs is altered during the development of esophageal squamous cell carcinoma (ESCC). Using a TaqMan-based reverse transcriptase polymerase chain reaction assay, the relationship between cir-ITCH and ESCC was analyzed in a total of 684 ESCC and paired adjacent non-tumor tissue samples from eastern and southern China. We found that cir-ITCH expression was usually low in ESCC compared to the peritumoral tissue. The functional relevance of cir-ITCH was further examined by biochemical assays. As sponge of miR-7, miR-17, and miR-214, cir-ITCH might increase the level of ITCH. ITCH hyper expression promotes ubiquitination and degradation of phosphorylated Dvl2, thereby inhibiting the Wnt/ß-catenin pathway. These results indicate that cir-ITCH may have an inhibitory effect on ESCC by regulating the Wnt pathway.

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.

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.

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.

A Newfound association between MDC1 functional polymorphism and lung cancer risk in Chinese.

Mediator of DNA damage checkpoint protein 1 (MDC1) plays an early and core role in Double-Strand Break Repair (DDR) and ataxia telangiectasia-mutated (ATM) mediated response to DNA double-strand breaks (DSBs), and thus involves the pathogenesis of several DNA damage-related diseases such as cancer. We hypothesized that the single nucleotide polymorphisms (SNPs) of MDC1 which have potencies on affecting MDC1 expression or function were associated with risk of lung cancer. In a two-stage case-control study, we tested the association between 5 putatively functional SNPs of MDC1 and lung cancer risk in a southern Chinese population, and validated the promising association in an eastern Chinese population. We found the SNP rs4713354A>C that is located in the 5'-untranslated region of MDC1 was significantly associated with lung cancer risk in both populations (P = 0.001), with an odds ratio as 1.33(95% confidence interval = 1.14­1.55) for the rs4713354C (CA+CC) genotypes compared to the rs4713354AA genotype. The correct sixth sentence is: The gene-based analysis rested with these SNPs suggested the MDC1 as a susceptible gene for lung cancer (P = 0.057) [corrected]. Moreover, by querying the gene expression database, we further found that the rs4713354C genotypes confer a significantly lower mRNA expression of MDC1 than the rs4713354AA genotype in 260 cases of lymphoblastoid cells (P = 0.002). Our data suggested that the SNP rs4713354A>C of MDC1 may be a functional genetic biomarker for susceptibility to lung cancer in Chinese.