Publications by authors named "Jiahui Si"

21 Publications

  • Page 1 of 1

Construction of a circRNA-miRNA-mRNA Regulated Pathway Involved in EGFR-TKI Lung Adenocarcinoma Resistance.

Technol Cancer Res Treat 2021 Jan-Dec;20:15330338211056809

Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), 12519Peking University Cancer Hospital and Institute, Beijing, People's Republic of China.

Epidermal growth factor receptor-tyrosine kinase inhibitors are widely used for lung epidermal growth factor receptor-positive lung adenocarcinomas, but acquired resistance is inevitable. Although non-coding RNAs, such as circular RNA and microRNA, are known to play vital roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance, comprehensive analysis is lacking. Thus, this study aimed to explore the circular RNA-microRNA-messenger RNA regulatory network involved in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. To identify differentially expressed genes between the epidermal growth factor receptor-tyrosine kinase inhibitor sensitive cell line PC9 and resistant cell line PC9/ epidermal growth factor receptor-tyrosine kinase inhibitor resistance(PC9/ER), circular RNA, microRNA and messenger RNA microarrays were performed. Candidates were then identified to construct a circular RNA-microRNA-messenger RNA network using bioinformatics. Additionally, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted to evaluate the network messenger RNA, setting up a protein-protein interaction network for hub-gene identification. Afterwards, RNA immunoprecipitation was performed to enrich microRNA, and quantitative real-time PCR was used to estimated gene expression levels. In total, 603, 377, and 1863 differentially expressed circular RNA, microRNA, messenger RNAs, respectively, were identified using microarray analysis, constructing a circular RNA-microRNA-messenger RNA network containing 18 circular RNAs, 17 microRNAs and 175 messenger RNAs. Moreover, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the most enriched biological process terms and pathways were related to epidermal growth factor receptor-tyrosine kinase inhibitor resistance, including Wnt and Hippo signaling pathways. Based on the competing endogenous RNA and protein-protein interaction network, circ-0007312 was showed to interact with miR-764 and both circ-0003748 and circ-0001398 were shown to interact with miR-628; both these microRNAs targeted MAPK1. Furthermore, circ-0007312, circ-0003748, circ-0001398, and MAPK1 were up-regulated, whereas miR-764 and miR-628 were downregulated in PC9/ER cells as compared to parental PC9 cells. We also found that circ-0007312 and miR-764 were positively expressed in plasma. Our original study associated with mechanism of target therapy in lung cancer provided a systematic and comprehensive regulation of circular RNA, microRNA and messenger RNA in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. It was found that circ-0007312- miR-764-MAPK1, circ-0003748-miR-628-MAPK1, and circ-0001398-miR-628-MAPK1 axis may play key roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance.
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http://dx.doi.org/10.1177/15330338211056809DOI Listing
November 2021

HIF1A-AS2 induces osimertinib resistance in lung adenocarcinoma patients by regulating the miR-146b-5p/IL-6/STAT3 axis.

Mol Ther Nucleic Acids 2021 Dec 14;26:613-624. Epub 2021 Sep 14.

Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing 100142, China.

Although epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) show efficacy in lung adenocarcinoma (LUAD) patients, TKI resistance inevitably develops, limiting long-term results. Thus, there is an urgent need to address drug resistance in LUAD. Long non-coding RNA (lncRNA) HIF1A-AS2 could be a critical mediator in the progression of various tumor types. We examined the function of HIF1A-AS2 in modifying tumor aggravation and osimertinib resistance in lung adenocarcinoma. Using clinical samples, we showed that HIF1A-AS2 was upregulated in LUAD specimens, predicting poorer overall survival and disease-free survival. HIF1A-AS2 silencing inhibited the proliferation, migration, and tumorigenesis of LUAD cells and therapeutic efficacy of osimertinib against tumor cells and . RNA precipitation assays, western blotting, luciferase assays, and rescue experiments demonstrated that HIF1A-AS2 sponged microRNA-146b-5p (miR-146b-5p), promoting interleukin-6 (IL-6) expression, activating the IL-6/STAT3 pathway, and leading to LUAD progression. miR-146b-5p and IL-6 levels were correlated with the prognosis of LUAD patients. Our results indicated that HIF1A-AS2 functions as an oncogenic factor in adenocarcinoma cells by targeting the miR-146b-5p/IL-6/STAT3 axis and may be a prognostic indicator of survival. Moreover, it can be a potential therapeutic target to enhance the efficacy of osimertinib in LUAD patients.
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http://dx.doi.org/10.1016/j.omtn.2021.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517096PMC
December 2021

Epigenome-wide analysis of DNA methylation and coronary heart disease: a nested case-control study.

Elife 2021 Sep 13;10. Epub 2021 Sep 13.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.

Background: Identifying environmentally responsive genetic loci where DNA methylation is associated with coronary heart disease (CHD) may reveal novel pathways or therapeutic targets for CHD. We conducted the first prospective epigenome-wide analysis of DNA methylation in relation to incident CHD in the Asian population.

Methods: We did a nested case-control study comprising incident CHD cases and 1:1 matched controls who were identified from the 10 year follow-up of the China Kadoorie Biobank. Methylation level of baseline blood leukocyte DNA was measured by Infinium Methylation EPIC BeadChip. We performed the single cytosine-phosphate-guanine (CpG) site association analysis and network approach to identify CHD-associated CpG sites and co-methylation gene module.

Results: After quality control, 982 participants (mean age 50.1 years) were retained. Methylation level at 25 CpG sites across the genome was associated with incident CHD (genome-wide false discovery rate [FDR] < 0.05 or module-specific FDR < 0.01). One SD increase in methylation level of identified CpGs was associated with differences in CHD risk, ranging from a 47 % decrease to a 118 % increase. Mediation analyses revealed 28.5 % of the excessed CHD risk associated with smoking was mediated by methylation level at the promoter region of gene (P for mediation effect = 0.036). Methylation level at the promoter region of was associated with blood pressure and subsequent risk of CHD, with the mediating proportion to be 7.7 % ( = 0.003) via systolic blood pressure and 6.4 % ( = 0.006) via diastolic blood pressure. Network analysis revealed a co-methylation module associated with CHD.

Conclusions: We identified novel blood methylation alterations associated with incident CHD in the Asian population and provided evidence of the possible role of epigenetic regulations in the smoking- and blood pressure-related pathways to CHD risk.

Funding: This work was supported by National Natural Science Foundation of China (81390544 and 91846303). The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (202922/Z/16/Z, 088158/Z/09/Z, 104085/Z/14/Z), grant (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) from the National Key R&D Program of China, and Chinese Ministry of Science and Technology (2011BAI09B01).
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http://dx.doi.org/10.7554/eLife.68671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8585480PMC
September 2021

A large-scale genome-wide association analysis of lung function in the Chinese population identifies novel loci and highlights shared genetic aetiology with obesity.

Eur Respir J 2021 10 14;58(4). Epub 2021 Oct 14.

Program in Genetic Epidemiology and Statistical Genetics, Dept of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Lung function is a heritable complex phenotype with obesity being one of its important risk factors. However, knowledge of their shared genetic basis is limited. Most genome-wide association studies (GWASs) for lung function have been based on European populations, limiting the generalisability across populations. Large-scale lung function GWASs in other populations are lacking.

Methods: We included 100 285 subjects from the China Kadoorie Biobank (CKB). To identify novel loci for lung function, single-trait GWAS analyses were performed on forced expiratory volume in 1 s (FEV), forced vital capacity (FVC) and FEV/FVC in the CKB. We then performed genome-wide cross-trait analysis between lung function and obesity traits (body mass index (BMI), BMI-adjusted waist-to-hip ratio and BMI-adjusted waist circumference) to investigate the shared genetic effects in the CKB. Finally, polygenic risk scores (PRSs) of lung function were developed in the CKB and their interaction with BMI's association on lung function were examined. We also conducted cross-trait analysis in parallel with the CKB using up to 457 756 subjects from the UK Biobank (UKB) for replication and investigation of ancestry-specific effects.

Results: We identified nine genome-wide significant novel loci for FEV, six for FVC and three for FEV/FVC in the CKB. FEV and FVC showed significant negative genetic correlation with obesity traits in both the CKB and UKB. Genetic loci shared between lung function and obesity traits highlighted important biological pathways, including cell proliferation, embryo, skeletal and tissue development, and regulation of gene expression. Mendelian randomisation analysis suggested significant negative causal effects of BMI on FEV and on FVC in both the CKB and UKB. Lung function PRSs significantly modified the effect of change in BMI on change in lung function during an average follow-up of 8 years.

Conclusion: This large-scale GWAS of lung function identified novel loci and shared genetic aetiology between lung function and obesity. Change in BMI might affect change in lung function differently according to a subject's polygenic background. These findings may open new avenues for the development of molecular-targeted therapies for obesity and lung function improvement.
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http://dx.doi.org/10.1183/13993003.00199-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513692PMC
October 2021

Small Cell Size Circulating Aneuploid Cells as a Biomarker of Prognosis in Resectable Non-Small Cell Lung Cancer.

Front Oncol 2021 3;11:590952. Epub 2021 Mar 3.

Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.

Objective: The size distribution of circulating aneuploid cells (CACs) and its clinical significance were investigated in resectable non-small cell lung cancer (NSCLC).

Patients And Methods: A total of 50 patients with resectable NSCLC were enrolled in this study. Blood samples (50 pre-surgery and 35 post-surgery) were collected and used for the detection of CAC chromosome 8 heteroploidy through the subtraction enrichment and immunostaining fluorescence hybridization (SE-iFISH) method.

Results: Less than 20% small cell size and more than 80% large cell size CACs were detected. Karyotypes, including triploid, tetraploid, and multiploid, had varying distributions. The triploid subtype accounted for the majority of small cell size CACs, whereas the multiploid subtype accounted for the majority of large cell size CACs. We found that total small cell size and triploid small cell size CACs, but not large cell size CACs, derived from pre-surgery samples, were associated with shorter disease-free survival. Moreover, total small cell size and triploid small cell size CACs were associated with higher TNM stage and recurrence. Nevertheless, the variation between pre- and post-surgery CACs was not related to survival among patients with resectable NSCLC.

Conclusions: Pre-surgery small cell size CACs, especially the triploid subtype, could be regarded as a potential prognostic biomarker for patients with resectable NSCLC.
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http://dx.doi.org/10.3389/fonc.2021.590952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968455PMC
March 2021

A transdisciplinary approach to understand the epigenetic basis of race/ethnicity health disparities.

Epigenomics 2021 Nov 10;13(21):1761-1770. Epub 2021 Mar 10.

Program in Genetic Epidemiology & Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

Health disparities correspond to differences in disease burden and mortality among socially defined population groups. Such disparities may emerge according to race/ethnicity, socioeconomic status and a variety of other social contexts, and are documented for a wide range of diseases. Here, we provide a transdisciplinary perspective on the contribution of epigenetics to the understanding of health disparities, with a special emphasis on disparities across socially defined racial/ethnic groups. Scientists in the fields of biological anthropology, bioinformatics and molecular epidemiology provide a summary of theoretical, statistical and practical considerations for conducting epigenetic health disparities research, and provide examples of successful applications from cancer research using this approach.
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http://dx.doi.org/10.2217/epi-2020-0080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579937PMC
November 2021

Improved lipidomic profile mediates the effects of adherence to healthy lifestyles on coronary heart disease.

Elife 2021 Feb 9;10. Epub 2021 Feb 9.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.

Adherence to healthy lifestyles is associated with reduced risk of coronary heart disease (CHD), but uncertainty persists about the underlying lipid pathway. In a case-control study of 4681 participants nested in the prospective China Kadoorie Biobank, 61 lipidomic markers in baseline plasma were measured by targeted nuclear magnetic resonance spectroscopy. Baseline lifestyles included smoking, alcohol consumption, dietary habit, physical activity, and adiposity levels. Genetic instrument was used to mimic the lipid-lowering effect of statins. We found that 35 lipid metabolites showed statistically significant mediation effects in the pathway from healthy lifestyles to CHD reduction, including very low-density lipoprotein (VLDL) particles and their cholesterol, large-sized high-density lipoprotein (HDL) particle and its cholesterol, and triglyceride in almost all lipoprotein subfractions. The statins genetic score was associated with reduced intermediate- and low-density lipoprotein, but weak or no association with VLDL and HDL. Lifestyle interventions and statins may improve different components of the lipid profile.
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http://dx.doi.org/10.7554/eLife.60999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872516PMC
February 2021

Shisa3 brakes resistance to EGFR-TKIs in lung adenocarcinoma by suppressing cancer stem cell properties.

J Exp Clin Cancer Res 2019 Dec 4;38(1):481. Epub 2019 Dec 4.

Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, People's Republic of China.

Background: Although EGFR tyrosine kinase inhibitors (EGFR-TKIs) are beneficial to lung adenocarcinoma patients with sensitive EGFR mutations, resistance to these inhibitors induces a cancer stem cell (CSC) phenotype. Here, we clarify the function and molecular mechanism of shisa3 as a suppressor that can reverse EGFR-TKI resistance and inhibit CSC properties.

Methods: The suppresser genes involved in EGFR-TKI resistance were identified and validated by transcriptome sequencing, quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Biological function analyses, cell half maximal inhibitory concentration (IC50), self-renewal, and migration and invasion capacities, were detected by CCK8, sphere formation and Transwell assays. Tumorigenesis and therapeutic effects were investigated in nonobese diabetic/severe combined immunodeficiency (nod-scid) mice. The underlying mechanisms were explored by Western blot and immunoprecipitation analyses.

Results: We found that low expression of shisa3 was related to EGFR-TKI resistance in lung adenocarcinoma patients. Ectopic overexpression of shisa3 inhibited CSC properties and the cell cycle in the lung adenocarcinoma cells resistant to gefitinib/osimertinib. In contrast, suppression of shisa3 promoted CSC phenotypes and the cell cycle in the cells sensitive to EGFR-TKIs. For TKI-resistant PC9/ER tumors in nod-scid mice, overexpressed shisa3 had a significant inhibitory effect. In addition, we verified that shisa3 inhibited EGFR-TKI resistance by interacting with FGFR1/3 to regulate AKT/mTOR signaling. Furthermore, combinational administration of inhibitors of FGFR/AKT/mTOR and cell cycle signaling could overcome EGFR-TKI resistance associated with shisa3-mediated CSC capacities in vivo.

Conclusion: Taken together, shisa3 was identified as a brake to EGFR-TKI resistance and CSC characteristics, probably through the FGFR/AKT/mTOR and cell cycle pathways, indicating that shisa3 and concomitant inhibition of its regulated signaling may be a promising therapeutic strategy for reversing EGFR-TKI resistance.
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http://dx.doi.org/10.1186/s13046-019-1486-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894286PMC
December 2019

Early famine exposure and adult disease risk based on a 10-year prospective study of Chinese adults.

Heart 2020 02 8;106(3):213-220. Epub 2019 Nov 8.

Department of Epidemiology and Biostatistics, Peking University Health Science Center, Beijing, China

Objective: To comprehensively examine the potential impacts of prenatal experience of the Chinese Great Famine on chronic disease risks in the middle age.

Methods: This study included 92 284 participants aged 39-51 years from China Kadoorie Biobank born around the famine period and without major chronic diseases at baseline. We categorised participants into non-famine births (born between 1 October 1956 and 30 September 1958, and 1 October 1962 and 30 September 1964) and famine births (born between 1 October 1959 and 30 September 1961). The outcomes were incident cardiovascular disease, cancer and respiratory system disease. Cox regression was used to estimate adjusted HR and 95% CI for famine exposure. Subgroup analyses were performed according to baseline characteristics.

Results: During a median 10.1 years of follow-up, we identified 4626 incident ischaemic heart disease (IHD) cases, 7332 cerebrovascular disease cases, 3111 cancer cases and 16 081 respiratory system disease cases. In the whole population, prenatal famine exposure was not statistically associated with the risks of developing any chronic diseases in adulthood. However, for urban participants, compared with non-famine births, famine births had a higher risk of cerebrovascular disease (HR 1.18; 95% CI 1.09 to 1.28); such association was not shown for rural participants (p for interaction <0.001). Also, we observed the associations of prenatal famine exposure with IHD (HR 1.15; 95% CI 1.05 to 1.26) and cerebrovascular disease (HR 1.13; 95% CI 1.05 to 1.21) in participants with lower physical activity level, but not in those with higher ones (all p for interaction=0.003).

Conclusion: Our findings indicate that prenatal exposure to the Chinese famine might be associated with an increased cardiovascular risk and such risk may be modified by adult lifestyle.
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http://dx.doi.org/10.1136/heartjnl-2019-315750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6968949PMC
February 2020

Long non-coding RNA H19 confers resistance to gefitinib via miR-148b-3p/DDAH1 axis in lung adenocarcinoma.

Anticancer Drugs 2020 01;31(1):44-54

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital and Institute, Beijing, China.

Epidermal growth factor receptor tyrosine kinase inhibitors therapy, such as gefitinib, have proven to be effective for lung adenocarcinoma with epidermal growth factor receptor-sensitive mutations. However, drug resistance remains inevitable and the underlying mechanisms are still elusive and poorly understood. In order to explore the mechanisms underlying tyrosine kinase inhibitors resistance, we used long non-coding RNA microarray analysis and found that long non-coding RNA H19 was highly expressed in gefitinib-resistant cell lines. In addition, knockdown of long non-coding RNA H19 was found to be able to decrease cell proliferation, half maximal inhibitory concentration (IC50) of gefitinib, migration and invasion. Mechanistically, we demonstrated that long non-coding RNA H19 positively regulated dimethylarginine dimethylaminohydrolase-1 expression via sponging miR-148b-3p. Furthermore, overexpression or inactivation of miR-148b-3p could enhance or reverse the inhibitory effect of long non-coding RNA H19 inhibition in lung adenocarcinoma cells, respectively. High expression of either long non-coding RNA H19 or dimethylarginine dimethylaminohydrolase-1 was associated with poorer overall survival in patients with lung adenocarcinoma, while high expression of miR-148b was associated with better overall survival. Overall, our data revealed that long non-coding RNA H19 confers resistance to gefitinib via miR-148b/dimethylarginine dimethylaminohydrolase-1 axis in lung adenocarcinoma, which offers a new insight into the epidermal growth factor receptor tyrosine kinase inhibitors therapy resistance.
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http://dx.doi.org/10.1097/CAD.0000000000000831DOI Listing
January 2020

Chronic hepatitis B virus infection and total and cause-specific mortality: a prospective cohort study of 0.5 million people.

BMJ Open 2019 04 9;9(4):e027696. Epub 2019 Apr 9.

Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.

Objectives: Chronic hepatitis B virus (HBV) infection is associated with a higher risk of liver diseases. Substantial uncertainty remains, however, about the associations of HBV infection with mortality from extrahepatic causes, especially from subtypes of cardiovascular diseases. We prospectively examined the association of chronic HBV infection with total and cause-specific mortality.

Design: Population-based prospective cohort study.

Setting: China Kadoorie Biobank in which participants from 10 geographically diverse areas across China were enrolled between 2004 and 2008.

Participants: 475 801 participants 30-79 years of age without reporting major chronic diseases at baseline were enrolled. Hepatitis B surface antigen (HBsAg) was tested using an on-site rapid test strip at baseline.

Primary And Secondary Outcome Measures: Total and cause-specific mortality.

Results: A total of 35 822 deaths were recorded during ~10 years of follow-up. In multivariable-adjusted analyses, compared with HBsAg-negative participants, HBsAg-positive participants had an increased risk of total mortality (HR=2.01, 95% CI: 1.91 to 2.12), which was higher in men (HR=2.16, 95% CI: 2.01 to 2.31) than in women (HR=1.74, 95% CI: 1.60 to 1.90). Presence of HBsAg was associated with increased mortality from liver cancer (1339 deaths, HR=13.95, 95% CI: 12.46 to 15.62), infections (410 deaths, HR=10.30, 95% CI: 8.21 to 12.94), digestive diseases (688 deaths, HR=6.83, 95% CI: 5.49 to 8.50), intracerebral haemorrhage (4077 deaths, HR=1.38, 95% CI: 1.14 to 1.68) and ischaemic heart diseases (4624 deaths, HR=1.31, 95% CI: 1.09 to 1.58). The positive association between HBsAg status and risk of death was stronger in participants younger than 50 years, smokers, physically active or non-hypertensive participants.

Conclusions: Among Chinese adults, chronic HBV infection was associated with increased mortality from a range of hepatic and extrahepatic diseases.
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http://dx.doi.org/10.1136/bmjopen-2018-027696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500223PMC
April 2019

Long-term survival of patients with locally advanced esophageal squamous cell carcinoma receiving esophagectomy following neoadjuvant chemotherapy: a cohort study.

Cancer Manag Res 2019 8;11:1299-1308. Epub 2019 Feb 8.

Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing 100142, China,

Purpose: The role of neoadjuvant chemotherapy and subsequent adjuvant therapy in the treatment of patients with locally advanced esophageal squamous cell carcinomas (ESCC) is not well established.

Patients And Methods: We retrospectively reviewed 228 patients with locally advanced ESCC receiving esophagectomy following neoadjuvant chemotherapy from January 2007 through December 2016. The probabilities of disease-free survival (DFS) and overall survival (OS) were estimated by means of the Kaplan-Meier method and were compared with the use of the log-rank test. Univariate and multivariate analyses of predictors of DFS and OS were performed using a Cox proportional-hazards model. Propensity score matching analysis was performed for further analysis regarding the benefit of adjuvant therapy.

Results: The pathological complete response of neoadjuvant chemotherapy was achieved in 13 of 228 patients (5.7%). With a median follow-up of 59.6 months, the median DFS and OS were 35.4 and 45.4 months, respectively. The multivariate Cox model determined chemotherapy regimens (=0.003) and ypT category (=0.006) were significant independent predictors of DFS; and chemotherapy regimens (=0.001), ypT category (<0.001), and ypN category (=0.013) were significant independent predictors of OS. Furthermore, patients who received adjuvant therapy seemed to be associated with poorer survival (both DFS and OS) compared with those who did not in full cohort (=0.001 and =0.184, respectively) and matched cohort (=0.251 and =0.374, respectively).

Conclusion: Surgery following neoadjuvant chemotherapy was applicable. Chemotherapy regimens and ypT category were significant independent predictors of both DFS and OS and ypN category was also a significant independent predictor of OS. However, these patients did not seem to benefit from subsequent adjuvant therapy. The necessity of adjuvant therapy requires further investigation.
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http://dx.doi.org/10.2147/CMAR.S195355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371923PMC
February 2019

BPI-9016M, a c-Met inhibitor, suppresses tumor cell growth, migration and invasion of lung adenocarcinoma via miR203-DKK1.

Theranostics 2018 12;8(21):5890-5902. Epub 2018 Nov 12.

Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.

Activation of c-Met plays a critical role in tumorigenesis, migration and invasion in lung cancer. Here, we explored the therapeutic efficacy of a novel small-molecule c-Met inhibitor (BPI-9016M) in lung adenocarcinoma and investigated the underlying molecular mechanisms. BPI-9016M, a c-Met tyrosine kinase receptor inhibitor, was used to treat patient-derived xenografts (PDX) from lung adenocarcinoma in NOD/SCID mice. Immunohistochemistry and Western blot analysis were used to determine the expression of c-Met and its downstream signaling molecules. CCK8, wound healing, and trans-well assays were used to analyze cell proliferation, spreading, migration and invasion. RNA sequencing and quantitative real-time PCR (qPCR) was used to screen and validate the expression of downstream genes in lung adenocarcinoma cells treated with BPI-9016M. Luciferase reporter assay was used to detect the interaction between miRNA and the targeted gene. : BPI-9016M significantly suppressed growth in three out of four lung adenocarcinoma PDX models, particularly in the tumors with high expression of c-Met. In lung adenocarcinoma cell lines, BPI-9016M treatment resulted in increased miR203, which reduced migration and invasion and also repressed Dickkopf-related protein 1 (DKK1) expression. Forced overexpression of DKK1 or down-regulation of miR203 reversed the inhibitory effect of BPI-9016M on migration and invasion. C-Met was verified to positively and negatively associate with DKK1 and miR203, respectively. High expression of c-Met/DKK1 or low expression of miR203 related to poor outcome of lung adenocarcinoma patients. Furthermore, we observed significantly enhanced tumor cell growth inhibition upon combining BPI-9016M treatment with miR203 mimics or DKK1 siRNA. Our data indicated that BPI-9016M is an effective agent against lung adenocarcinoma, particularly in tumors with c-Met activation, and likely functions through upregulation of miR203 leading to reduced DKK1 expression.
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http://dx.doi.org/10.7150/thno.27667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299440PMC
September 2019

Genomic sequencing and editing revealed the GRM8 signaling pathway as potential therapeutic targets of squamous cell lung cancer.

Cancer Lett 2019 02 27;442:53-67. Epub 2018 Oct 27.

Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing, Peking University Cancer Hospital and Institute, Beijing, China. Electronic address:

The study sought to explore novel genetic aberration driving squamous cell lung carcinoma (LUSC). The whole exome (WES), whole genome (WGS) and target region (TS) sequencings and CRISPR-Cas9 genome editing techniques were integrated to explore and validate novel targeting candidates from LUSC primary tumors and corresponding patient-derived xenografts (PDXs). Seven genes (FGFR2, GRM1,PIK3CG, PIK3CA,ZFHX4, CSMD3, GRM8) with high frequencies of both single nucleotide variants (SNVs) and copy number variants (CNVs), and two genes (CLDN1 and RIT1) only with CNVs were identified by bioinformatics analysis. The functions of these candidates were validated through CRISPR-Cas9 system in primary PDX cells. Furthermore, we focused on the genetic and functional analysis of Metabotropic glutamate receptor 8 (GRM8), whose transcriptional activation was elucidated to promote the survival of LUSC tumor cell through inhibiting cAMP pathway and activating MAPK pathway. The SNV identified in GRM8, A112G, activated downstream signaling pathway and induced cell proliferation, which could be reversed by cAMP stimulator and MEK inhibitor. In conclusion, the components of GRM8 signaling pathway could serve as potential targets of squamous cell lung cancer carrying GRM8 activating variants.
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http://dx.doi.org/10.1016/j.canlet.2018.10.035DOI Listing
February 2019

Chronic hepatitis B virus infection and risk of chronic kidney disease: a population-based prospective cohort study of 0.5 million Chinese adults.

BMC Med 2018 06 18;16(1):93. Epub 2018 Jun 18.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, China.

Background: Existing evidence remains inconclusive as to the association between chronic hepatitis B virus (HBV) infection and the risk of chronic kidney disease (CKD). We prospectively examined the association between chronic HBV infection and CKD risk, and the joint associations of HBV infection with established risk factors of several lifestyle factors and prevalent diseases on CKD risk.

Methods: Participants from the China Kadoorie Biobank were enrolled during 2004-2008 and followed up until 31 December 2015. After excluding participants with previously diagnosed CKD, cancer, heart disease, and stroke at baseline, the present study included 469,459 participants. Hepatitis B surface antigen (HBsAg) was qualitatively tested at baseline. Incident CKD cases were identified mainly through the health insurance system and disease and death registries.

Results: During a median follow-up of 9.1 years (4.2 million person-years), we documented 4555 incident cases of CKD. Cox regression yielded multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Compared with HBsAg-negative participants, the multivariable-adjusted HR (95% CI) for CKD was 1.37 (1.18, 1.60) for HBsAg-positive participants. The association was stronger in men (HR = 1.77; 95% CI: 1.43, 2.20) than in women (HR = 1.10; 95% CI: 0.88, 1.36). HBsAg-positive participants, with or without hepatitis or cirrhosis, whether or not under treatment, all showed increased risk of developing CKD. We observed positive additive interactions of HBsAg positivity with smoking, physical inactivity, or diabetes on CKD risk. Compared with HBsAg-negative participants who were nonsmokers, more physically active, or did not have diabetes at baseline, the greatest CKD risk for HBsAg-positive participants was for those who were smokers (HR = 1.85; 95% CI: 1.44, 2.38), physically inactive (HR = 1.91; 95% CI: 1.52, 2.40), or diabetic (HR = 6.11; 95% CI: 4.47, 8.36).

Conclusions: In countries with a high endemicity of HBV infection, kidney damage associated with chronic HBV infection should be a non-negligible concern. Our findings also highlight the importance of health advice on quitting smoking, increasing physical activity, improving glucose control, and early screening for CKD in people with chronic HBV infection.
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http://dx.doi.org/10.1186/s12916-018-1084-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004660PMC
June 2018

Associations of egg consumption with cardiovascular disease in a cohort study of 0.5 million Chinese adults.

Heart 2018 11 21;104(21):1756-1763. Epub 2018 May 21.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.

Objective: To examine the associations between egg consumption and cardiovascular disease (CVD), ischaemic heart disease (IHD), major coronary events (MCE), haemorrhagic stroke as well as ischaemic stroke.

Methods: During 2004-2008, over 0.5 million adults aged 30-79 years were recruited from 10 diverse survey sites in China. Participants were asked about the frequency of egg consumption and were followed up via linkages to multiple registries and active investigation. Among 461 213 participants free of prior cancer, CVD and diabetes, a total of 83 977 CVD incident cases and 9985 CVD deaths were documented, as well as 5103 MCE. Stratified Cox regression was performed to yield adjusted hazard ratios for CVD endpoints associated with egg consumption.

Results: At baseline, 13.1% of participants reported daily consumption (usual amount 0.76 egg/day) and 9.1% reported never or very rare consumption (usual amount 0.29 egg/day). Compared with non-consumers, daily egg consumption was associated with lower risk of CVD (HR 0.89, 95% CI 0.87 to 0.92). Corresponding multivariate-adjusted HRs (95% CI) for IHD, MCE, haemorrhagic stroke and ischaemic stroke were 0.88 (0.84 to 0.93), 0.86 (0.76 to 0.97), 0.74 (0.67 to 0.82) and 0.90 (0.85 to 0.95), respectively. There were significant dose-response relationships of egg consumption with morbidity of all CVD endpoints (P for linear trend <0.05). Daily consumers also had an 18% lower risk of CVD death and a 28% lower risk of haemorrhagic stroke death compared to non-consumers.

Conclusion: Among Chinese adults, a moderate level of egg consumption (up to <1 egg/day) was significantly associated with lower risk of CVD, largely independent of other risk factors.
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http://dx.doi.org/10.1136/heartjnl-2017-312651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241631PMC
November 2018

CMTM1_v17 is associated with chemotherapy resistance and poor prognosis in non-small cell lung cancer.

World J Surg Oncol 2017 Jan 28;15(1):34. Epub 2017 Jan 28.

Department of Thoracic Surgery II, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, 100142, China.

Background: Considering neoadjuvant chemotherapy (NAC) prior to surgery could shrink and reduce the primary tumor and distant micro-metastases to reduce the high relapses rates, NAC has been an accepted therapeutic management for patients with non-small cell lung cancer (NSCLC). CMTM1_v17 is highly expressed in human testis tissues and solid tumor tissues but relatively low expression was obtained in the corresponding normal tissues. This study aims to investigate the significance of CMTM1_v17 in NSCLC and its association with platinum-based NAC efficacy.

Methods: 31 pairs of tumor tissues before and after NAC and 78 resected tumor tissues after NAC were utilized for immunohistochemistry (IHC) staining of CMTM1_v17 protein. The correlation between CMTM1_v17 expression and chemotherapy efficacy was analyzed. The prognostic value of CMTM1_v17 index for disease-free survival (DFS) and overall survival (OS) was analyzed using Kaplan-Meier survival and multivariable Cox regression.

Results: CMTM1_v17 expression was related to treatment effect and outcome in tumor tissues after NAC not before NAC from 31 cases of NSCLC. We identified that high CMTM1_v17 expression was associated with low objective remission rate (ORR) (P = 0.008) and poor prognosis (the median OS: 35.1 months vs 65.6 months, P = 0.0045; the median DFS: 17.27 months vs 35.54 months, P = 0.0207) in the 31 patients. Next, we detected CMTM1_v17 expression to confirm correlation between this protein status and clinical characteristics in 78 NSCLC patients with NAC treatment. The upregulation of CMTM1_v17 had a higher SD rate (P = 0.007) and worse outcome (the median OS: 41.0 months vs 80.6 months, P = 0.0028; the median DFS: 33.4 vs 64.8 months, P = 0.0032). COX multivariate analysis indicated that CMTM1_v17 is an independent prognostic risk factor on patients who have received NAC (OS: HR = 3.642, P = 0.002; DFS:HR = 3.094, P = 0.002).

Conclusions: CMTM1_v17 expression is significantly associated with chemoresistance and poor prognosis of the early stage NSCLC patients who have received NAC.
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http://dx.doi.org/10.1186/s12957-016-1094-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5273821PMC
January 2017

Tea consumption and risk of ischaemic heart disease.

Heart 2017 05 11;103(10):783-789. Epub 2017 Jan 11.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China.

Objective: To prospectively examine the association between tea consumption and the risk of ischaemic heart disease (IHD).

Methods: Prospective study using the China Kadoorie Biobank; participants from 10 areas across China were enrolled during 2004-2008 and followed up until 31 December 2013. After excluding participants with cancer, heart disease and stroke at baseline, the present study included 199 293 men and 288 082 women aged 30-79 years at baseline. Information on IHD incidence was collected through disease registries and the new national health insurance databases.

Results: During a median follow-up of 7.2 years, we documented 24 665 (7.19 cases/1000 person-years) incident IHD cases and 3959 (1.13 cases/1000 person-years) major coronary events (MCEs). Tea consumption was associated with reduced risk of IHD and MCE. In the whole cohort, compared with participants who never consumed tea during the past 12 months, the multivariable-adjusted HRs and 95% CIs for less than daily and daily tea consumers were 0.97 (0.94 to 1.00) and 0.92 (0.88 to 0.95) for IHD, 0.92 (0.85 to 1.00) and 0.90 (0.82 to 0.99) for MCE. No linear trends in the HRs across the amount of tea were observed in daily consumers for IHD and MCE (P >0.05). The inverse association between tea consumption and IHD was stronger in rural (P 0.006 for IHD, <0.001 for MCE), non-obese (P 0.012 for MCE) and non-diabetes participants (P 0.004 for IHD).

Conclusions: In this large prospective study, daily tea consumption was associated with a reduced risk of IHD.
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http://dx.doi.org/10.1136/heartjnl-2016-310462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529974PMC
May 2017

Season of birth and the risk of type 2 diabetes in adulthood: a prospective cohort study of 0.5 million Chinese adults.

Diabetologia 2017 05 7;60(5):836-842. Epub 2017 Jan 7.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, 38 Xueyuan Road, Beijing, 100191, People's Republic of China.

Aims/hypothesis: Season of birth as a surrogate for potential environmental exposure during fetal development and early postnatal life has shown an inconsistent association with adult type 2 diabetes in white populations living in high-latitude regions. The present study aimed to examine the association between birth seasonality and risk of adult type 2 diabetes in Chinese individuals living across wide regions of low latitude and lower to middle latitude.

Methods: Participants from the China Kadoorie Biobank were enrolled during 2004-2008 and followed up until 31 December 2013. After excluding participants with cancer, heart disease, stroke and diabetes at baseline, the present study included 189,153 men and 272,058 women aged 30-79 years. We used multivariable Cox proportional hazards model to estimate the HR and 95% CI.

Results: During a median follow-up of 7.2 years (3.3 million person-years), we documented 8784 incident cases of type 2 diabetes. In the whole cohort, compared with summer-born participants, the adjusted HRs (95% CIs) were 1.09 (1.02, 1.16), 1.08 (1.02, 1.15) and 1.09 (1.02, 1.15) for those who were born in Spring, Autumn and Winter, respectively. The association was consistent in both men and women and across subgroups defined by residence and lifestyle factors later in life.

Conclusions/interpretation: In this large prospective study, participants born in summer had a lower risk of adult type 2 diabetes compared with other seasons of birth, suggesting exposures in early life with some degree of seasonal variation might influence the risk of adult diabetes.
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http://dx.doi.org/10.1007/s00125-016-4200-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521727PMC
May 2017

Induction of Patient-Derived Xenograft Formation and Clinical Significance of Programmed Cell Death Ligand 1 (PD-L1) in Lung Cancer Patients.

Med Sci Monit 2016 Oct 27;22:4017-4025. Epub 2016 Oct 27.

Department of Thoracic Surgery II, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China (mainland).

BACKGROUND The immune checkpoint of programmed cell death ligand 1 (PD-L1) commonly expressed in solid cancers, and the blockade of this molecule show promising results in advanced cancers, including lung cancer. The relevance of PD-L1 to patient-derived xenograft (PDX) formation and clinicopathological characteristics in early stage lung cancer have not been fully elucidated. MATERIAL AND METHODS Cell counting kit-8 and flow cytometry were carried out to examine proliferation and apoptosis in PC9 and H520 cells transfected with siRNAs. Nod-scid mice were used to establish PDX. Immunohistochemistry was done to investigate PD-L1 expression in tumor tissues. RESULTS PD-L1 was detected in lung cancer cell lines and 45.45% of primary tumor tissues from a cohort of 209 lung cancer patients. Cell growth was restrained and apoptosis was induced when PD-L1 was inhibited in PC9 and H520 cells. In addition, we successfully established 16 PDX models from tissues from 43 cases of primary lung cancer. Higher PD-L1 expression rates (75%) was observed in primary tumors with PDX formation compared to protein expression rate (44.44%) in tumors without PDX formation. Consistently, a 1.9-fold increase of PDX formation frequency was identified in the PD-L1 positive tumors than in the PD-L1 negative tumors. Moreover, PD-L1 was found to be related to smoking, histological type, and pathological stage. Importantly, PD-L1 overexpression was associated with shorter overall survival (OS) of lung cancer patients. CONCLUSIONS This study suggests that overexpression of PD-L1 could induce PDX formation and is related to poor outcome for the lung cancer patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087670PMC
http://dx.doi.org/10.12659/msm.900661DOI Listing
October 2016

Blockade of Notch3 inhibits the stem-like property and is associated with ALDH1A1 and CD44 via autophagy in non-small lung cancer.

Int J Oncol 2016 Jun 30;48(6):2349-58. Epub 2016 Mar 30.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Surgery II, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China.

Acquired resistance to standard chemotherapy causes treatment failure in patients with local advanced and advanced non-small lung cancer (NSCLC). Cancer stem cells (CSCs) are a small subpopulation within cancer that is thought to be resistant to conventional chemotherapy. The Notch pathway is one of the most intensively studied for putative therapeutic targets of CSCs in solid tumors. In our study, suppression of Notch3 decreased colony and sphere formation of stem-like property in lung cancer cells. In addition, Notch3 expression was demonstrated to be upregulated in the patients with chemoresistance and related to poor prognosis of NSCLC patients. Our results also showed that CSC markers ALDH1A1 and CD44 were highly expressed in NSCLC patients with chemoresistance and these two markers were positively correlated with Notch3 expression in lung cancer specimens from TCGA database. Furthermore, the lung cancer cells with drug resistance were shown to be associated with activation of autophagy. All the data support a crucial role of Notch3 in the increase of stem-like property in NSCLC cells that might be associated with upregulation of ALDH1A1 and CD44 and activation of autophagy.
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http://dx.doi.org/10.3892/ijo.2016.3464DOI Listing
June 2016
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