Publications by authors named "Siyuan Niu"

7 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

Sudden death of COVID-19 patients in Wuhan, China: A retrospective cohort study.

J Glob Health 2021 Mar 27;11:05006. Epub 2021 Mar 27.

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.

Background: In December 2019, coronavirus disease 2019 (COVID-19) emerged in Wuhan city and rapidly spread throughout China. So far, it has caused ~ 4000 deaths in this country. We aimed to systematically characterize clinical features and determine risk factors of sudden death for COVID-19 patients.

Methods: Deceased patients with COVID-19 in Tongji hospital from January 22 to March 23, 2020 were extracted. Patients who died within 24 hours after admission were identified as sudden deaths, and the others formed non-sudden deaths. The differences in clinical characteristics between the two groups were estimated. Risk factors associated with sudden deaths were explored by logistic regression.

Results: 281 deceased patients were enrolled in this study. Sudden death occurred in 28 (10.0%) patients, including 4 (14.3%) admitted to the intensive care unit. Fatigue was more common in sudden deaths (11, 47.8%) than in non-sudden deaths (40, 17.2%). Both the count and percentage of eosinophils were lower in sudden deaths than that in non-sudden deaths ( = 0.006 and  = 0.004). Compared with non-sudden deaths, sudden deaths had higher plasma levels of procalcitonin, C-reactive protein, D-dimer, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, lactate dehydrogenase, alkaline phosphatase and N-terminal pro-brain natriuretic peptide. There were not significant differences in gender, age, chest CT image features and comorbidities observed.

Conclusions: The differences between the two groups suggested more severe systemic inflammation, multi-organ dysfunction, especially impaired liver and heart function in COVID-19 patients who died suddenly after admission. More researches are needed to verify these points.
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http://dx.doi.org/10.7189/jogh.11.05006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005311PMC
March 2021

Clinical characteristics and risk factors associated with COVID-19 disease severity in patients with cancer in Wuhan, China: a multicentre, retrospective, cohort study.

Lancet Oncol 2020 07 29;21(7):893-903. Epub 2020 May 29.

Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: COVID-19 has spread globally. Epidemiological susceptibility to COVID-19 has been reported in patients with cancer. We aimed to systematically characterise clinical features and determine risk factors of COVID-19 disease severity for patients with cancer and COVID-19.

Methods: In this multicentre, retrospective, cohort study, we included all adult patients (aged ≥18 years) with any type of malignant solid tumours and haematological malignancy who were admitted to nine hospitals in Wuhan, China, with laboratory-confirmed COVID-19 between Jan 13 and March 18, 2020. Enrolled patients were statistically matched (2:1) with patients admitted with COVID-19 who did not have cancer with propensity score on the basis of age, sex, and comorbidities. Demographic characteristics, laboratory examinations, illness severity, and clinical interventions were compared between patients with COVID-19 with or without cancer as well as between patients with cancer with non-severe or severe COVID-19. COVID-19 disease severity was defined on admission on the basis of the WHO guidelines. Univariable and multivariable logistic regression, adjusted for age, sex, comorbidities, cancer type, tumour stage, and antitumour treatments, were used to explore risk factors associated with COVID-19 disease severity. This study was registered in the Chinese Clinical Trial Register, ChiCTR2000030807.

Findings: Between Jan 13 and March 18, 2020, 13 077 patients with COVID-19 were admitted to the nine hospitals in Wuhan and 232 patients with cancer and 519 statistically matched patients without cancer were enrolled. Median follow-up was 29 days (IQR 22-38) in patients with cancer and 27 days (20-35) in patients without cancer. Patients with cancer were more likely to have severe COVID-19 than patients without cancer (148 [64%] of 232 vs 166 [32%] of 519; odds ratio [OR] 3·61 [95% CI 2·59-5·04]; p<0·0001). Risk factors previously reported in patients without cancer, such as older age; elevated interleukin 6, procalcitonin, and D-dimer; and reduced lymphocytes were validated in patients with cancer. We also identified advanced tumour stage (OR 2·60, 95% CI 1·05-6·43; p=0·039), elevated tumour necrosis factor α (1·22, 1·01-1·47; p=0·037), elevated N-terminal pro-B-type natriuretic peptide (1·65, 1·03-2·78; p=0·032), reduced CD4+ T cells (0·84, 0·71-0·98; p=0·031), and reduced albumin-globulin ratio (0·12, 0·02-0·77; p=0·024) as risk factors of COVID-19 severity in patients with cancer.

Interpretation: Patients with cancer and COVID-19 were more likely to deteriorate into severe illness than those without cancer. The risk factors identified here could be helpful for early clinical surveillance of disease progression in patients with cancer who present with COVID-19.

Funding: China National Natural Science Foundation.
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http://dx.doi.org/10.1016/S1470-2045(20)30309-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259911PMC
July 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

CpG-methylation-based risk score predicts progression in colorectal cancer.

Epigenomics 2020 04 17;12(7):605-615. Epub 2020 Mar 17.

Department of Epidemiology & Biostatistics & Ministry of Education Key Lab of Environment & Health, School of Public Health, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei 430030, PR China.

To identify patients with colorectal cancer (CRC) who are at a truly higher risk of progression, which is key for individualized approaches to precision therapy. We developed a predictor associated with progression-free interval (PFI) using The Cancer Genome Atlas CRC methylation data. The risk score was associated with PFI in the whole cohort (p < 0.001). A nomogram consisting of the risk score and other significant clinical features was generated to predict the 3- and 5-year PFI in the whole set (area under the curve: 0.79 and 0.71, respectively). The risk score based on 23 DNA-methylation sites may serve as the basis for improved prediction of progression in patients with CRC in future clinical practice.
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http://dx.doi.org/10.2217/epi-2019-0300DOI Listing
April 2020

Risk SNP-Mediated Enhancer-Promoter Interaction Drives Colorectal Cancer through Both and .

Cancer Res 2020 05 3;80(9):1804-1818. Epub 2020 Mar 3.

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.

Although genome-wide association studies (GWAS) have identified more than 100 colorectal cancer risk loci, most of the biological mechanisms associated with these loci remain unclear. Here we first performed a comprehensive expression quantitative trait loci analysis in colorectal cancer tissues adjusted for multiple confounders to test the determinants of germline variants in established GWAS susceptibility loci on mRNA and long noncoding RNA (lncRNA) expression. Combining integrative functional genomic/epigenomic analyses and a large-scale population study consisting of 6,024 cases and 10,022 controls, we then prioritized rs174575 with a C>G change as a potential causal candidate for colorectal cancer at 11q12.2, as its G allele was associated with an increased risk of colorectal cancer (OR = 1.26; 95% confidence interval = 1.17-1.36; = 2.57 × 10). rs174575 acted as an allele-specific enhancer to distally facilitate expression of both FADS2 and lncRNA AP002754.2 via long-range enhancer-promoter interaction loops, which were mediated by E2F1. AP002754.2 further activated a transcriptional activator that upregulated FADS2 expression. FADS2, in turn, was overexpressed in colorectal cancer tumor tissues and functioned as a potential oncogene that facilitated colorectal cancer cell proliferation and xenograft growth and by increasing the metabolism of PGE2, an oncogenic molecule involved in colorectal cancer tumorigenesis. Our findings represent a novel mechanism by which a noncoding variant can facilitate long-range genome interactions to modulate the expression of multiple genes including not only mRNA, but also lncRNA, which provides new insights into the understanding of colorectal cancer etiology. SIGNIFICANCE: This study provides an oncogenic regulatory circuit among several oncogenes including , and underlying the association of rs174575 with colorectal cancer risk, which is driven by long-range enhancer-promoter interaction loops. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/9/1804/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2389DOI Listing
May 2020

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