Publications by authors named "Pingting Ying"

12 Publications

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A genetic variant conferred high expression of CAV2 promotes pancreatic cancer progression and associates with poor prognosis.

Eur J Cancer 2021 Jul 8;151:94-105. Epub 2021 May 8.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China. Electronic address:

Aim: This study aimed to identify the functional genes and genetic variants associated with the prognosis of pancreatic ductal adenocarcinoma (PDAC) and reveal the mechanism underlying their prognostic roles.

Methods: First, we implement a two-stage exome-wide association study in a total of 1070 patients to identify the genetic variant correlated with PDAC prognosis. Then we performed fine mapping through bioinformatics analysis and dual-luciferase reporter assays to reveal the causal functional variant and prognostic gene. Next, we established the gene knockdown, knockout, and overexpression cell lines with small interfering RNA, CRISPR/Cas9, and lentivirus, respectively, and investigated the gene function on cell proliferation and migration in vivo and in vitro. Finally, we performed the RNA-seq to elucidate downstream genes and mechanisms altering PDAC prognosis.

Results: We identified the CAV1-CAV2 locus tagged by rs8940 was significantly associated with PDAC prognosis, and rs10249656 in the 3'untranslated region of CAV2 was the real functional variant, which upregulated CAV2 expression through abolishing miR-548s binding. We observed upregulated CAV2 in PDAC and the higher expression correlated with worse prognosis. Transient knockdown of CAV2 inhibited PDAC migration without affecting proliferation rate. Knockout of CAV2 suppressed PDAC progression and metastasis, whereas stable overexpression of CAV2 promoted. Overexpressed CAV2 promoted the PDAC progression and metastasis via perturbing genes in the focal adhesion (CCND1, IGTA1, and ZYX) and extracellular matrix organisation (PLOD2, CAST, and ITGA1) pathways mechanically.

Conclusion: These findings shed light on an important role of CAV2 on PDAC progression and the prognostic impact of its genetic variation.
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http://dx.doi.org/10.1016/j.ejca.2021.04.008DOI Listing
July 2021

Identification of genetic variants in mA modification genes associated with pancreatic cancer risk in the Chinese population.

Arch Toxicol 2021 03 21;95(3):1117-1128. Epub 2021 Jan 21.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

N6-Methyladenosine (mA) is the most prevalent modification of RNA in eukaryotes, and is associated with many cellular processes and even the development of cancers. We hypothesized that single-nucleotide polymorphisms (SNPs) in mA modification genes, including its "writers", "erasers" and "readers", might affect the mA functions and associate with the susceptibility to pancreatic ductal adenocarcinoma (PDAC). We first conducted a two-stage case-control study in Chinese population to interrogate all SNPs in 22 mA modification genes. In the discovery stage, a total of 2735 SNPs were genotyped in 980 patients and 1991 controls. Then, the promising SNP was replicated in another independent population consisting of 858 cases and 2084 controls. As a result, we found the rs7495 in 3'UTR of hnRNPC was significantly associated with increased risk of PDAC in both stages (combined odds ratio = 1.22, 95% confidence interval = 1.12-1.32, P = 2.39 × 10). To further reveal the biological function of rs7495 and hnRNPC, we performed a series of biochemical experiments. Luciferase reporter assays indicated that rs7495G allele promoted hnRNPC expression through disrupting a putative binding site for has-miR-183-3p. Cell viability assay demonstrated that knockdown of hnRNPC suppressed the proliferation of PDAC cells. RNA-seq analysis suggested that as an mA "reader", hnRNPC played an important role in RNA biological processes. In conclusion, our findings elucidated that rs7495G could confer higher risk of PDAC via promoting the expression of hnRNPC through a miRNA-mediated manner. These results provided a novel insight into the critical role of mA modification in tumorigenesis.
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http://dx.doi.org/10.1007/s00204-021-02978-5DOI Listing
March 2021

CancerImmunityQTL: a database to systematically evaluate the impact of genetic variants on immune infiltration in human cancer.

Nucleic Acids Res 2021 01;49(D1):D1065-D1073

Department of Epidemiology and Biostatistics, Key Laboratory of Environmental Health of Ministry of Education, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.

Tumor-infiltrating immune cells as integral component of the tumor microenvironment are associated with tumor progress, prognosis and responses to immunotherapy. Genetic variants have been demonstrated to impact tumor-infiltrating, underscoring the heritable character of immune landscape. Therefore, identification of immunity quantitative trait loci (immunQTLs), which evaluate the effect of genetic variants on immune cells infiltration, might present a critical step toward fully understanding the contribution of genetic variants in tumor development. Although emerging studies have demonstrated the determinants of germline variants on immune infiltration, no database has yet been developed to systematically analyze immunQTLs across multiple cancer types. Using genotype data from TCGA database and immune cell fractions estimated by CIBERSORT, we developed a computational pipeline to identify immunQTLs in 33 cancer types. A total of 913 immunQTLs across different cancer types were identified. Among them, 5 immunQTLs are associated with patient overall survival. Furthermore, by integrating immunQTLs with GWAS data, we identified 527 immunQTLs overlapping with known GWAS linkage disequilibrium regions. Finally, we constructed a user-friendly database, CancerImmunityQTL (http://www.cancerimmunityqtl-hust.com/) for users to browse, search and download data of interest. This database provides an informative resource to understand the germline determinants of immune infiltration in human cancer and benefit from personalized cancer immunotherapy.
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http://dx.doi.org/10.1093/nar/gkaa805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778991PMC
January 2021

Functional characterization of a low-frequency V1937I variant in FASN associated with susceptibility to esophageal squamous cell carcinoma.

Arch Toxicol 2020 06 9;94(6):2039-2046. Epub 2020 May 9.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Metabolic reprogramming has been regarded as one of the core hallmarks of cancer and increased de novo fatty acid synthesis has been documented in multiple tumors including esophageal squamous cell carcinoma (ESCC). Our previous exome-wide analyses found a Val1937Ile variant (rs17848945) in the 34th exon of fatty acid synthase (FASN) that showed a strong association with the risk of ESCC. In this study, we performed a series of functional assays to investigate the biological functions underlying this variant in the development of ESCC. We demonstrated that FASN was upregulated in ESCC and both knockdown and knockout of FASN significantly inhibited ESCC cell proliferation, suggesting a tumor promoter role for this gene in ESCC. Furthermore, the results showed that overexpression of FASN[I] in the ESCC cells substantially enhanced cell proliferation, compared with overexpression of FASN[V], or the control vector. Intriguingly, we found that the FASN[I] variant can enhance the enzyme activity of FASN, and, thus, increase the amount of the FASN end-product, palmitate in the ESCC cells. We also observed elevated palmitate levels in the plasma of the FASN[I] genotype carriers among a total of 632 healthy Chinese adults. In conclusion, our results suggested that the FASN V1937I variant influenced ESCC cell proliferation and susceptibility by altering the catabolic activity of FASN on palmitate. These findings may highlight an important role of palmitate metabolism in the development of ESCC and may contribute to the personalized medicine of this disease.
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http://dx.doi.org/10.1007/s00204-020-02738-xDOI Listing
June 2020

N-methyladenosine mRNA methylation of regulates AKT signalling to promote PTEN-deficient pancreatic cancer progression.

Gut 2020 12 20;69(12):2180-2192. Epub 2020 Apr 20.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China

Objective: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Thus far, most drugs have failed to significantly improve patient survival. N-methyladenosine (mA) plays an important role in the progression of PDAC, but its aberrant regulation driven by germline variants in human diseases remains unclear.

Design: We first performed an exome-wide association analysis in 518 PDAC patients with overall survival and replicated in an independent population containing 552 PDAC patients. Then, a series of biochemical experiments in vitro and in vivo were conducted to investigate potential mechanisms of the candidate variant and its target gene underlying the PDAC progression. Moreover, the PIK3CB-selective inhibitor KIN-193 was used to block PDAC tumour growth.

Results: We identified a missense variant rs142933486 in that is significantly associated with the overall survival of PDAC by reducing the mA level, which facilitated its mRNA and protein expression levels mediated by the mA 'writer' complex (METTL13/METTL14/WTAP) and the mA 'reader' YTHDF2. The upregulation of is widely found in PDAC tumour tissues and significantly correlated with the poor prognosis of PDAC, especially in PTEN-deficient patients. We further demonstrated that overexpression substantially enhanced the proliferation and migration abilities of PTEN-deficient PDAC cells and activated AKT signalling pathway. Remarkably, KIN-193, a PIK3CB-selective inhibitor, is shown to serve as an effective anticancer agent for blocking PTEN-deficient PDAC.

Conclusions: These findings demonstrate aberrant mA homoeostasis as an oncogenic mechanism in PDAC and highlight the potential of as a therapeutic target for this disease.
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http://dx.doi.org/10.1136/gutjnl-2019-320179DOI Listing
December 2020

Genetic variants in m6A modification genes are associated with esophageal squamous-cell carcinoma in the Chinese population.

Carcinogenesis 2020 07;41(6):761-768

Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

N 6-methyladenosine (m6A) is an abundant modification in RNAs that affects RNA metabolism, and it is reported to be closely related to cancer occurrence and metastasis. In this study, we focused on evaluating the associations between genetic variants in m6A modification genes and the risk of esophageal squamous-cell carcinoma (ESCC). By integrating data of our previous genome-wide association studies and the predictions of several annotation tools, we identified a single nucleotide polymorphism, rs2416282 in the promoter of YTHDC2, that was significantly associated with the susceptibility of ESCC (odds ratio = 0.84, 95% CI: 0.77-0.92, P = 2.81 × 10-4). Through further functional experiments in vitro, we demonstrated that rs2416282 regulated YTHDC2 expression. Knockdown of YTHDC2 substantially promoted the proliferation rate of ESCC cells by affecting several cancer-related signaling pathways. Our results suggested that rs2416282 contributed to ESCC risk by regulating YTHDC2 expression. This study provided us a valuable insight into the roles of genetic variants in m6A modification genes for ESCC susceptibility and may contribute to the prevention of this disease in the future.
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http://dx.doi.org/10.1093/carcin/bgaa012DOI Listing
July 2020

Genetic Predisposition to Colon and Rectal Adenocarcinoma Is Mediated by a Super-enhancer Polymorphism Coactivating and .

Cancer Epidemiol Biomarkers Prev 2020 04 27;29(4):850-859. Epub 2020 Jan 27.

State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment & Health (Ministry of Education), Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Genome-wide association studies (GWAS) have identified dozens of loci associated with colon and rectal adenocarcinoma risk. As tissue-specific super-enhancers (SE) play important roles in tumorigenesis, we systematically investigate SEs and inner variants in established GWAS loci to decipher the underlying biological mechanisms.

Methods: Through a comprehensive bioinformatics analysis on multi-omics data, we screen potential single-nucleotide polymorphisms (SNP) in cancer-specific SEs, and then subject them to a two-stage case-control study containing 4,929 cases and 7,083 controls from the Chinese population. A series of functional assays, including reporter gene assays, electrophoretic mobility shift assays (EMSA), CRISPR-Cas9 genome editing, chromosome conformation capture (3C) assays, and cell proliferation experiments, are performed to characterize the variant's molecular consequence and target genes.

Results: The SNP rs11064124 in 12p13.31 is found significantly associated with the risk of colon and rectal adenocarcinoma with an odds ratio (OR) of 0.87 [95% confidence interval (CI), 0.82-0.92, = 8.67E-06]. The protective rs11064124-G weakens the binding affinity with vitamin D receptor (VDR) and increases the enhancer's activity and interactions with two target genes' promoters, thus coactivating the transcription of and , which are both putative tumor suppressor genes for colon and rectal adenocarcinoma.

Conclusions: Our integrative study highlights an SE polymorphism rs11064124 and two susceptibility genes and in 12p13.31 for colon and rectal adenocarcinoma.

Impact: These findings suggest a novel insight for genetic pathogenesis of colon and rectal adenocarcinoma, involving transcriptional coactivation of diverse susceptibility genes via the SE element as a gene regulation hub.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1116DOI Listing
April 2020

Evaluation of polymorphisms in microRNA-binding sites and pancreatic cancer risk in Chinese population.

J Cell Mol Med 2020 02 27;24(3):2252-2259. Epub 2019 Dec 27.

State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment & Health (Ministry of Education), Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

As promising biomarkers and therapy targets, microRNAs (miRNAs) are involved in various physiological and tumorigenic processes. Genetic variants in miRNA-binding sites can lead to dysfunction of miRNAs and contribute to disease. However, systematic investigation of the miRNA-related single nucleotide polymorphisms (SNPs) for pancreatic cancer (PC) risk remains elusive. We performed integrative bioinformatics analyses to select 31 SNPs located in miRNA-target binding sites using the miRNASNP v2.0, a solid database providing miRNA-related SNPs for genetic research, and investigated their associations with risk of PC in two large case-control studies totally including 1847 cases and 5713 controls. We observed that the SNP rs3802266 is significantly associated with increased risk of PC (odds ratio (OR) = 1.21, 95% confidence intervals (CI) = 1.11-1.31, P = 1.29E-05). Following luciferase reporter gene assays show that rs3802266-G creates a stronger binding site for miR-181a-2-3p in 3' untranslated region (3'UTR) of the gene ZHX2. Expression quantitative trait loci (eQTL) analysis suggests that ZHX2 expression is lower in individuals carrying rs3802266-G with increased PC risk. In conclusion, our findings highlight the involvement of miRNA-binding SNPs in PC susceptibility and provide new clues for PC carcinogenesis.
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http://dx.doi.org/10.1111/jcmm.14906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011162PMC
February 2020

ANKLE1 N -Methyladenosine-related variant is associated with colorectal cancer risk by maintaining the genomic stability.

Int J Cancer 2020 06 6;146(12):3281-3293. Epub 2019 Nov 6.

Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.

The N -Methyladenosine (m A) modification plays an important role in many biological processes, especially tumor development. However, little is still known about how it affects colorectal cancer (CRC) carcinogenesis. Here, we first systematically investigate the association of variants related to m A modification with the CRC risk in 1,062 CRC cases and 2,184 controls by using our exome-wide association data and followed by two replication sets including 7,341 CRC cases and 7,902 controls. The variant rs8100241 located in ANKLE1 was significantly associated with CRC risk (odds ratio = 0.88, 95% confidence interval = 0.84-0.92, p = 4.85 × 10 ) in 8,403 cases and 10,086 controls. This variant was previously identified to be associated with the susceptibility of breast cancer with BRCA1 mutation triple negative breast cancer. Further functional analysis indicated that overexpression of the rs8100241[A] allele significantly increased the ANKLE1 m A level and facilitated the ANKLE1 protein expression compared to that of rs8100241[G] allele. We further found the ANKLE1 m A modification was catalyzed by the "writer" complex (METTL3, METTL14, or WTAP) and recognized by the "reader" YTHDF1. Mechanistically, we found that the ANKLE1 functions as a potential tumor suppressor that inhibits cell proliferation and facilitates the genomic stability. An elevated frequency of micronucleated cells, increased cell proliferation, and colony formation ability were observed when ANKLE1 knockdown. Our study illustrated that the germline missense variant can increase CRC risk by influencing ANKLE1 m A level, highlighting a clinical potential of variants-associated m A modification as a risk marker for CRC prevention.
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http://dx.doi.org/10.1002/ijc.32677DOI Listing
June 2020

A functional variant in the boundary of a topological association domain is associated with pancreatic cancer risk.

Mol Carcinog 2019 10 24;58(10):1855-1862. Epub 2019 Jun 24.

State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment & Health (Ministry of Education), Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

As the proper binding of CCCTC-binding factor (CTCF) in the boundaries of topological association domains (TADs) was important for chromatin structures and gene regulation, we hypothesized that single nucleotide polymorphisms (SNPs) affecting CTCF binding in TAD boundaries might contribute to pancreatic cancer (PC) susceptibility. We first genome widely screened out potential SNPs via bioinformatics analysis on Hi-C data, ChIP-seq data, and CTCF binding motif, then tested their associations with PC risk in a previous genome-wide association studies (GWASs) data set (981 cases and 1,991 controls), followed by another independent replication set (1,208 cases and 1,465 controls). Electrophoretic mobility shift assays (EMSAs), expression Quantitative Trait Loci (eQTL) analyses and cell proliferation experiments were performed to uncover the biological mechanisms. The positive SNP rs2001389 was found significantly associated with PC risk with odds ratio (OR) being 1.166 (95% confidence interval (CI) = 1.075-1.264, P = 2.143E-04) in the combined study. The allele G of rs2001389 weakened the binding activity with CTCF, and it was related to the lower expression of a putative antioncogene MFSD13A whose knockdown promoted proliferation of PC cells. By integrating analysis on multiomics data, association studies and functional assays, we proposed that the common variant rs2001389 and the gene MFSD13A might be genetic modifiers of PC tumorigenesis.
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http://dx.doi.org/10.1002/mc.23077DOI Listing
October 2019

A genetic variant in PIK3R1 is associated with pancreatic cancer survival in the Chinese population.

Cancer Med 2019 07 6;8(7):3575-3582. Epub 2019 May 6.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.

Pancreatic cancer is one of the deadliest malignancies with few early detection tests or effective therapies. PI3K-AKT signaling is recognized to modulate cancer progression. We previously identified that a genetic variant in PKN1 increased pancreatic cancer risk through the PKN1/FAK/PI3K/AKT pathway. In order to investigate the associations between genetic variations in that pathway and pancreatic cancer prognosis, we conducted a two-stage survival analysis in a total of 547 Chinese pancreatic cancer patients. Consequently, a variant, rs13167294 A>C in PIK3R1, was significantly associated with poor survival in both stages and with hazard ratio being 1.32 (95% CI = 1.13-1.56, P = 0.0007) in the combined analysis. Function annotation and prediction suggested that genetic variants in this locus might affect overall survival of pancreatic cancer patients by regulating PIK3R1 expression.
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http://dx.doi.org/10.1002/cam4.2228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601582PMC
July 2019

AWESOME: a database of SNPs that affect protein post-translational modifications.

Nucleic Acids Res 2019 01;47(D1):D874-D880

Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, 430030, China.

Protein post-translational modifications (PTMs), including phosphorylation, ubiquitination, methylation, acetylation, glycosylation et al, are very important biological processes. PTM changes in some critical genes, which may be induced by base-pair substitution, are shown to affect the risk of diseases. Recently, large-scale exome-wide association studies found that missense single nucleotide polymorphisms (SNPs) play an important role in the susceptibility for complex diseases or traits. One of the functional mechanisms of missense SNPs is that they may affect PTMs and leads to a protein dysfunction and its downstream signaling pathway disorder. Here, we constructed a database named AWESOME (A Website Exhibits SNP On Modification Event, http://www.awesome-hust.com), which is an interactive web-based analysis tool that systematically evaluates the role of SNPs on nearly all kinds of PTMs based on 20 available tools. We also provided a well-designed scoring system to compare the performance of different PTM prediction tools and help users to get a better interpretation of results. Users can search SNPs, genes or position of interest, filter with specific modifications or prediction methods, to get a comprehensive PTM change induced by SNPs. In summary, our database provides a convenient way to detect PTM-related SNPs, which may potentially be pathogenic factors or therapeutic targets.
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http://dx.doi.org/10.1093/nar/gky821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324025PMC
January 2019