Publications by authors named "Roger Kai-Cheong Ngan"

24 Publications

  • Page 1 of 1

Dietary fiber intake from fresh and preserved food and risk of nasopharyngeal carcinoma: observational evidence from a Chinese population.

Nutr J 2021 02 2;20(1):14. Epub 2021 Feb 2.

School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, G/F, Patrick Manson Building (North Wing), 7 Sassoon Road, Pok Fu Lam, Hong Kong, SAR, China.

Background: The role of dietary fiber intake on risk of nasopharyngeal carcinoma (NPC) remains unclear. We examined the associations of dietary fiber intake on the risk of NPC adjusting for a comprehensive list of potential confounders.

Methods: Using data from a multicenter case-control study, we included 815 histologically confirmed NPC incident cases and 1502 controls in Hong Kong, China recruited in 2014-2017. Odds ratios (ORs) of NPC (cases vs controls) for dietary fiber intake from different sources at different life periods (age 13-18, age 19-30, and 10 years before recruitment) were evaluated using unconditional logistic regression, adjusting for sex, age, socioeconomic status, smoking and drinking status, occupational hazards, family history of cancer, salted fish, and total energy intake in Model 1, Epstein-Barr virus viral capsid antigen serological status in Model 2, and duration of sun exposure and circulating 25-hydroxyvitamin D in Model 3.

Results: Higher intake of total dietary fiber 10 years before recruitment was significantly associated with decreased NPC risk, with demonstrable dose-response relationship (P-values for trend = 0.001, 0.020 and 0.024 in Models 1-3, respectively). The adjusted ORs (95% CI) in the highest versus the lowest quartile were 0.51 (0.38-0.69) in Model 1, 0.48 (0.33-0.69) in Model 2, and 0.48 (0.33-0.70) in Model 3. However, the association was less clear after adjustment of other potential confounders (e.g. EBV) in the two younger periods (age of 13-18 and 19-30 years). Risks of NPC were significantly lower for dietary fiber intake from fresh vegetables and fruits and soybean products over all three periods, with dose-response relationships observed in all Models (P-values for trend for age 13-18, age 19-30 and 10 years before recruitment were, respectively, 0.002, 0.009 and 0.001 for Model1; 0.020, 0.031 and 0.003 for Model 2; and 0.022, 0.037 and 0.004 for Model 3). No clear association of NPC risk with dietary fiber intake from preserved vegetables, fruits and condiments was observed.

Conclusion: Our study has shown the protective role of dietary fiber from fresh food items in NPC risk, but no association for total dietary fiber intake was observed, probably because total intake also included intake of preserved food. Further studies with detailed dietary information and in prospective settings are needed to confirm this finding, and to explore the possible underlying biological mechanisms.
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http://dx.doi.org/10.1186/s12937-021-00667-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856716PMC
February 2021

Nasopharyngeal carcinoma MHC region deep sequencing identifies HLA and novel non-HLA TRIM31 and TRIM39 loci.

Commun Biol 2020 12 11;3(1):759. Epub 2020 Dec 11.

Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China.

Despite pronounced associations of major histocompatibility complex (MHC) regions with nasopharyngeal carcinoma (NPC), causal variants underlying NPC pathogenesis remain elusive. Our large-scale comprehensive MHC region deep sequencing study of 5689 Hong Kong Chinese identifies eight independent NPC-associated signals and provides mechanistic insight for disrupted transcription factor binding, altering target gene transcription. Two novel protective variants, rs2517664 (T = 4.6%, P = 6.38 × 10) and rs117495548 (G = 3.0%, P = 4.53 × 10), map near TRIM31 and TRIM39/TRIM39-RPP21; multiple independent protective signals map near HLA-B including a previously unreported variant, rs2523589 (P = 1.77 × 10). The rare HLA-B*07:05 allele (OR < 0.015, P = 5.83 × 10) is absent in NPC, but present in controls. The most prevalent haplotype lacks seven independent protective alleles (OR = 1.56) and the one with additional Asian-specific susceptibility rs9391681 allele (OR = 2.66) significantly increased NPC risk. Importantly, this study provides new evidence implicating two non-human leukocyte antigen (HLA) genes, E3 ubiquitin ligases, TRIM31 and TRIM39, impacting innate immune responses, with NPC risk reduction, independent of classical HLA class I/II alleles.
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http://dx.doi.org/10.1038/s42003-020-01487-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733486PMC
December 2020

Solar Ultraviolet Radiation and Vitamin D Deficiency on Epstein-Barr Virus Reactivation: Observational and Genetic Evidence From a Nasopharyngeal Carcinoma-Endemic Population.

Open Forum Infect Dis 2020 Oct 12;7(10):ofaa426. Epub 2020 Sep 12.

School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region (SAR), China.

Background: We investigated the relationship of Epstein-Barr virus viral capsid antigen (EBV VCA-IgA) serostatus with ambient and personal ultraviolet radiation (UVR) and vitamin D exposure.

Methods: Using data from a multicenter case-control study, we included 1026 controls subjects in 2014-2017 in Hong Kong, China. Odds ratios (ORs) and 95% confidence intervals (CIs) of the association between UVR exposure and EBV VCA-IgA (seropositivity vs seronegativity) were calculated using unconditional logistic regression models adjusted for potential confounders.

Results: We observed a large increase in seropositivity of EBV VCA-IgA in association with duration of sunlight exposures at both 10 years before recruitment and age 19-30 years (adjusted OR = 3.59, 95% CI = 1.46-8.77; and adjusted OR = 2.44, 95% CI = 1.04-5.73 for ≥8 vs <2 hours/day; for trend = .005 and .048, respectively). However, no association of EBV VCA-IgA serostatus with other indicators of UVR exposure was found. In addition, both circulating 25-hydroxyvitamin D (25OHD) and genetic predicted 25OHD were not associated with EBV VCA-IgA serostatus.

Conclusions: Our results suggest that personal UVR exposure may be associated with higher risk of EBV reactivation, but we did not find clear evidence of vitamin D exposure (observational or genetic), a molecular mediator of UVR exposure. Further prospective studies in other populations are needed to confirm this finding and to explore the underlying biological mechanisms. Information on photosensitizing agents, and serological markers of EBV, and biomarkers related to systemic immunity and inflammation should be collected and are also highly relevant in future studies.
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http://dx.doi.org/10.1093/ofid/ofaa426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585328PMC
October 2020

Role of miR-96/EVI1/miR-449a Axis in the Nasopharyngeal Carcinoma Cell Migration and Tumor Sphere Formation.

Int J Mol Sci 2020 Jul 31;21(15). Epub 2020 Jul 31.

Department of Biology, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.

The Wnt signaling pathway is one of the major signaling pathways used by cancer stem cells (CSC). Ecotropic Viral Integration Site 1 (EVI1) has recently been shown to regulate oncogenic development of tumor cells by interacting with multiple signaling pathways, including the Wnt signaling. In the present study, we found that the Wnt modulator ICG-001 could inhibit the expression of EVI1 in nasopharyngeal carcinoma (NPC) cells. Results from loss-of-function and gain-of-function studies revealed that EVI1 expression positively regulated both NPC cell migration and growth of CSC-enriched tumor spheres. Subsequent studies indicated ICG-001 inhibited EVI1 expression via upregulated expression of miR-96. Results from EVI1 3'UTR luciferase reporter assay confirmed that EVI1 is a direct target of miR-96. Further mechanistic studies revealed that ICG-001, overexpression of miR-96, or knockdown of EVI1 expression could restore the expression of miR-449a. The suppressive effect of miR-449a on the cell migration and tumor sphere formation was confirmed in NPC cells. Taken together, the miR-96/EVI1/miR-449a axis is a novel pathway involved in ICG-001-mediated inhibition of NPC cell migration and growth of the tumor spheres.
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http://dx.doi.org/10.3390/ijms21155495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432346PMC
July 2020

Clinical utility of serial analysis of circulating tumour cells for detection of minimal residual disease of metastatic nasopharyngeal carcinoma.

Br J Cancer 2020 07 6;123(1):114-125. Epub 2020 May 6.

Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China.

Background: Nasopharyngeal carcinoma (NPC) is an important cancer in Hong Kong. We aim to utilise liquid biopsies for serial monitoring of disseminated NPC in patients to compare with PET-CT imaging in detection of minimal residual disease.

Method: Prospective serial monitoring of liquid biopsies was performed for 21 metastatic patients. Circulating tumour cell (CTC) enrichment and characterisation was performed using a sized-based microfluidics CTC chip, enumerating by immunofluorescence staining, and using target-capture sequencing to determine blood mutation load. PET-CT scans were used to monitor NPC patients throughout their treatment according to EORTC guidelines.

Results: The longitudinal molecular analysis of CTCs by enumeration or NGS mutational profiling findings provide supplementary information to the plasma EBV assay for disease progression for good responders. Strikingly, post-treatment CTC findings detected positive findings in 75% (6/8) of metastatic NPC patients showing complete response by imaging, thereby demonstrating more sensitive CTC detection of minimal residual disease. Positive baseline, post-treatment CTC, and longitudinal change of CTCs significantly associated with poorer progression-free survival by the Kaplan-Meier analysis.

Conclusions: We show the potential usefulness of application of serial analysis in metastatic NPC of liquid biopsy CTCs, as a novel more sensitive biomarker for minimal residual disease, when compared with imaging.
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http://dx.doi.org/10.1038/s41416-020-0871-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341819PMC
July 2020

Crucifera sulforaphane (SFN) inhibits the growth of nasopharyngeal carcinoma through DNA methyltransferase 1 (DNMT1)/Wnt inhibitory factor 1 (WIF1) axis.

Phytomedicine 2019 Oct 29;63:153058. Epub 2019 Jul 29.

Department of Biology, Hong Kong Baptist University, Kowloon, Hong Kong, China. Electronic address:

Background: Sulforaphane (SFN), a natural compound present in cruciferous vegetable, has been shown to possess anti-cancer activities. Cancer stem cell (CSC) in bulk tumor is generally considered as treatment resistant cell and involved in cancer recurrence. The effects of SFN on nasopharyngeal carcinoma (NPC) CSCs have not yet been explored.

Purpose: The present study aims to examine the anti-tumor activities of SFN on NPC cells with CSC-like properties and the underlying mechanisms.

Methods: NPC cells growing in monolayer culture, CSCs-enriched NPC tumor spheres, and also the NPC nude mice xenograft were used to study the anti-tumor activities of SFN on NPC. The population of cells expressing CSC-associated markers was evaluated using flow cytometry and aldehyde dehydrogenase (ALDH) activity assay. The effect of DNA methyltransferase 1 (DNMT1) on the growth of NPC cells was analyzed by using small interfering RNA (siRNA)-mediated silencing method.

Results: SFN was found to inhibit the formation of CSC-enriched NPC tumor spheres and reduce the population of cells with CSC-associated properties (SRY (Sex determining Region Y)-box 2 (SOX2) and ALDH). In the functional study, SFN was found to restore the expression of Wnt inhibitory factor 1 (WIF1) and the effect was accompanied with the downregulation of DNMT1. The functional activities of WIF1 and DNMT1 were confirmed using exogenously added recombinant WIF1 and siRNA knockdown of DNMT1. Moreover, SFN was found to inhibit the in vivo growth of C666-1 cells and enhance the anti-tumor effects of cisplatin.

Conclusion: Taken together, we demonstrated that SFN could suppress the growth of NPC cells via the DNMT1/WIF1 axis.
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http://dx.doi.org/10.1016/j.phymed.2019.153058DOI Listing
October 2019

Milk Consumption Across Life Periods in Relation to Lower Risk of Nasopharyngeal Carcinoma: A Multicentre Case-Control Study.

Front Oncol 2019 10;9:253. Epub 2019 Apr 10.

School of Public Health, The University of Hong Kong, Hong Kong, China.

The much higher incidence of nasopharyngeal carcinoma (NPC) in men suggests sex hormones as a risk factor, and dairy products contain measurable amounts of steroid hormones. Milk consumption has greatly increased in endemic regions of NPC. We investigated the association between NPC and milk consumption across life periods in Hong Kong. A multicentre case-control study included 815 histologically confirmed NPC incident cases and 1,502 controls who were frequency-matched on age and sex at five major hospitals in Hong Kong in 2014-2017. Odds ratios (ORs) of NPC (cases vs. controls) for milk consumption at different life periods were estimated by unconditional logistic regression, adjusting for sex, age, socioeconomic status score, smoking and alcohol drinking status, exposure to occupational hazards, family history of cancer, IgA against Epstein-Barr virus viral capsid antigen, and total energy intake. Compared with abstainers, lower risks of NPC were consistently observed in regular users (consuming ≥5 glasses of milk [fresh and powdered combined] per month) across four life periods of age 6-12 (adjusted OR 0.74, 95% CI 0.54-0.86), 13-18 (0.68, 0.55-0.84), 19-30 (0.68, 0.55-0.84), and 10 years before recruitment (0.72, 0.59-0.87). Long-term average milk consumption of ≤2.5, >2.5, and ≤12.5, >12.5 glasses per month yielded adjusted OR (95% CI) of 1.00 (0.80-1.26), 0.98 (0.81-1.18), 0.95 (0.76-1.18), and 0.55 (0.43-0.70), respectively (all -values for trend < 0.05). Consumption of milk across life periods was associated with lower risks of NPC. If confirmed to be causal, this has important implications for dairy product consumption and prevention of NPC.
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http://dx.doi.org/10.3389/fonc.2019.00253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467951PMC
April 2019

The Wnt modulator ICG‑001 mediates the inhibition of nasopharyngeal carcinoma cell migration in vitro via the miR‑150/CD44 axis.

Int J Oncol 2019 Mar 12;54(3):1010-1020. Epub 2018 Dec 12.

Department of Biology, Hong Kong Baptist University, Hong Kong, P.R. China.

The Wnt signaling pathway is known to serve an important role in the control of cell migration. The present study analyzed the mechanisms underlying the in vitro modulation of the migration of nasopharyngeal carcinoma (NPC) cells by the CREB‑binding protein/catenin antagonist and Wnt modulator ICG‑001. The results revealed that ICG‑001‑mediated inhibition of tumor cell migration involved downregulated mRNA and protein expression of the Wnt target gene cluster of differentiation (CD)44. It was also demonstrated that ICG‑001 downregulated the expression of CD44, and this effect was accompanied by restored expression of microRNA (miRNA)‑150 in various NPC cell lines. Using a CD44 3'‑untranslated region luciferase reporter assay, miR‑150 was confirmed to be a novel CD44‑targeting miRNA, which could directly target CD44 and subsequently regulate the migration of NPC cells. The present study provides further insight into the inhibition of tumor cell migration through the modulation of miRNA expression by the Wnt modulator ICG‑001.
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http://dx.doi.org/10.3892/ijo.2018.4664DOI Listing
March 2019

Leukocyte telomere length associates with nasopharyngeal carcinoma risk and survival in Hong Kong Chinese.

Int J Cancer 2018 11 7;143(9):2289-2298. Epub 2018 Aug 7.

Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China.

Telomere shortening occurs as an early event in tumorigenesis. The TERT-CLPTM1L locus associates with nasopharyngeal carcinoma (NPC) risk. It remains unknown if leukocyte telomere length (LTL) associates with NPC risk and survival. The relative LTL (rLTL) was measured by quantitative-PCR in 2,996 individuals comprised of 1,284 NPC cases and 1712 matched controls. The odds ratio (OR) and 95% confidence intervals (CI) were calculated by logistic regression. The hazard ratio (HR) and 95% CI were calculated by Cox regression for survival analysis with rLTL and other clinical parameters in 1,243 NPC with a minimum follow-up period of 25 months. NPC patients had significantly shorter telomere length than controls. Shorter rLTL significantly associated with increased NPC risk, when the individuals were dichotomized into long and short telomeres based on median-split rLTL in the control group (OR = 2.317; 95% CI = 1.989-2.700, p = 4.10 × 10 ). We observed a significant dose-response association (p  = 3.26 × 10 ) between rLTL and NPC risk with OR being 3.555 (95% CI = 2.853-4.429) for the individuals in the first quartile (shortest) compared with normal individuals in the fourth quartile (longest). A multivariate Cox regression analysis adjusted by age demonstrated an independent effect of rLTL on NPC survival for late-stage NPC patients, when the individuals were categorized into suboptimal rLTL versus the medium rLTL based on a threshold set from normal (HR = 1.471, 95% CI = 1.056-2.048, p = 0.022). Shorter blood telomeres may be markers for higher susceptibility for NPC risk. Suboptimal rLTL may be a poor prognostic factor for advanced NPC patients, as it associates independently with poor survival.
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http://dx.doi.org/10.1002/ijc.31617DOI Listing
November 2018

Test-retest reliability of a computer-assisted self-administered questionnaire on early life exposure in a nasopharyngeal carcinoma case-control study.

Sci Rep 2018 05 4;8(1):7052. Epub 2018 May 4.

School of Public Health, The University of Hong Kong, Hong Kong S.A.R., China.

We evaluated the reliability of early life nasopharyngeal carcinoma (NPC) aetiology factors in the questionnaire of an NPC case-control study in Hong Kong during 2014-2017. 140 subjects aged 18+ completed the same computer-assisted questionnaire twice, separated by at least 2 weeks. The questionnaire included most known NPC aetiology factors and the present analysis focused on early life exposure. Test-retest reliability of all the 285 questionnaire items was assessed in all subjects and in 5 subgroups defined by cases/controls, sex, time between 1 and 2 questionnaire (2-29/≥30 weeks), education (secondary or less/postsecondary), and age (25-44/45-59/60+ years) at the first questionnaire. The reliability of items on dietary habits, body figure, skin tone and sun exposure in early life periods (age 6-12 and 13-18) was moderate-to-almost perfect, and most other items had fair-to-substantial reliability in all life periods (age 6-12, 13-18 and 19-30, and 10 years ago). Differences in reliability by strata of the 5 subgroups were only observed in a few items. This study is the first to report the reliability of an NPC questionnaire, and make the questionnaire available online. Overall, our questionnaire had acceptable reliability, suggesting that previous NPC study results on the same risk factors would have similar reliability.
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http://dx.doi.org/10.1038/s41598-018-25046-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935670PMC
May 2018

MicroRNA profiling study reveals miR-150 in association with metastasis in nasopharyngeal carcinoma.

Sci Rep 2017 09 20;7(1):12012. Epub 2017 Sep 20.

Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong, China.

MicroRNAs (miRNAs) are small non-coding RNAs that play a crucial role in pathogenesis of human cancers. Several miRNAs have been shown to involve in nasopharyngeal carcinoma (NPC) pathogenesis through alteration of gene networks. A global view of the miRNA expression profile of clinical specimens would be the best way to screen out the possible miRNA candidates that may be involved in disease pathogenesis. In this study, we investigated the expression profiles of miRNA in formalin-fixed paraffin-embedded tissues from patients with undifferentiated NPC versus non-NPC controls using a miRNA real-time PCR platform, which covered a total of 95 cancer-related miRNAs. Hierarchical cluster analysis revealed that NPC and non-NPC controls were clearly segregated. Promisingly, 10 miRNA candidates were differentially expressed. Among them, 9 miRNAs were significantly up-regulated of which miR-205 and miR-196a showed the most up-regulated in NPC with the highest incidence percentage of 94.1% and 88.2%, respectively, while the unique down-regulated miR-150 was further validated in patient sera. Finally, the in vitro gain-of-function and loss-of-function assays revealed that miR-150 can modulate the epithelial-mesenchymal-transition property in NPC/HK-1 cells and led to the cell motility and invasion. miR-150 may be a potential biomarker for NPC and plays a critical role in NPC tumourigenesis.
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http://dx.doi.org/10.1038/s41598-017-10695-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607379PMC
September 2017

Disparities of time trends and birth cohort effects on invasive breast cancer incidence in Shanghai and Hong Kong pre- and post-menopausal women.

BMC Cancer 2017 05 23;17(1):362. Epub 2017 May 23.

JC School of Public Health and Primary Care, the Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China.

Background: Breast cancer is the leading cause of cancer morbidity among Shanghai and Hong Kong women, which contributes to 20-25% of new female cancer incidents. This study aimed to describe the temporal trend of breast cancer and interpret the potential effects on the observed secular trends.

Methods: Cancer incident data were obtained from the cancer registries. Age-standardized incidence rate was computed by the direct method using the World population of 2000. Average annual percentage change (AAPC) in incidence rate was estimated by the Joinpoint regression. Age, period and cohort effects were assessed by using a log-linear model with Poisson regression.

Results: During 1976-2009, an increasing trend of breast cancer incidence was observed, with an AAPC of 1.73 [95% confidence interval (CI): 1.54-1.92)] for women in Hong Kong and 2.83 (95% CI, 2.26-3.40) in Shanghai. Greater upward trends were revealed in Shanghai women aged 50 years old or above (AAPC = 3.09; 95% CI, 1.48-4.73). Using age at 50 years old as cut-point, strong birth cohort effects were shown in both pre- and post-menopausal women, though a more remarkable effect was suggested in Shanghai post-menopausal women. No evidence for a period effect was indicated.

Conclusions: Incidence rate of breast cancer has been more speedy in Shanghai post-menopausal women than that of the Hong Kong women over the past 30 years. Decreased birth rate and increasing environmental exposures (e.g., light-at-night) over successive generations may have constituted major impacts on the birth cohort effects, especially for the post-menopausal breast cancer; further analytic studies are warranted.
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http://dx.doi.org/10.1186/s12885-017-3359-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442698PMC
May 2017

Metastasis-suppressing NID2, an epigenetically-silenced gene, in the pathogenesis of nasopharyngeal carcinoma and esophageal squamous cell carcinoma.

Oncotarget 2016 Nov;7(48):78859-78871

Department of Clinical Oncology, The University of Hong Kong, Hong Kong (SAR), People's Republic of China.

Nidogen-2 (NID2) is a key component of the basement membrane that stabilizes the extracellular matrix (ECM) network. The aim of the study is to analyze the functional roles of NID2 in the pathogenesis of nasopharyngeal carcinoma (NPC) and esophageal squamous cell carcinoma (ESCC). We performed genome-wide methylation profiling of NPC and ESCC and validated our findings using the methylation-sensitive high-resolution melting (MS-HRM) assay. Results showed that promoter methylation of NID2 was significantly higher in NPC and ESCC samples than in their adjacent non-cancer counterparts. Consistently, down-regulation of NID2 was observed in the clinical samples and cell lines of both NPC and ESCC. Re-expression of NID2 suppresses clonogenic survival and migration abilities of transduced NPC and ESCC cells. We showed that NID2 significantly inhibits liver metastasis. Mechanistic studies of signaling pathways also confirm that NID2 suppresses the EGFR/Akt and integrin/FAK/PLCγ metastasis-related pathways. This study provides novel insights into the crucial tumor metastasis suppression roles of NID2 in cancers.
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http://dx.doi.org/10.18632/oncotarget.12889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346683PMC
November 2016

Whole-exome sequencing identifies multiple loss-of-function mutations of NF-κB pathway regulators in nasopharyngeal carcinoma.

Proc Natl Acad Sci U S A 2016 10 19;113(40):11283-11288. Epub 2016 Sep 19.

Department of Clinical Oncology, The University of Hong Kong, Hong Kong, People's Republic of China; Center for Nasopharyngeal Carcinoma Research, The University of Hong Kong, Hong Kong, People's Republic of China;

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with a unique geographical distribution. The genomic abnormalities leading to NPC pathogenesis remain unclear. In total, 135 NPC tumors were examined to characterize the mutational landscape using whole-exome sequencing and targeted resequencing. An APOBEC cytidine deaminase mutagenesis signature was revealed in the somatic mutations. Noticeably, multiple loss-of-function mutations were identified in several NF-κB signaling negative regulators NFKBIA, CYLD, and TNFAIP3 Functional studies confirmed that inhibition of NFKBIA had a significant impact on NF-κB activity and NPC cell growth. The identified loss-of-function mutations in NFKBIA leading to protein truncation contributed to the altered NF-κB activity, which is critical for NPC tumorigenesis. In addition, somatic mutations were found in several cancer-relevant pathways, including cell cycle-phase transition, cell death, EBV infection, and viral carcinogenesis. These data provide an enhanced road map for understanding the molecular basis underlying NPC.
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http://dx.doi.org/10.1073/pnas.1607606113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056105PMC
October 2016

Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma.

Proc Natl Acad Sci U S A 2016 Mar 7;113(12):3317-22. Epub 2016 Mar 7.

Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China; Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China;

Multiple factors, including host genetics, environmental factors, and Epstein-Barr virus (EBV) infection, contribute to nasopharyngeal carcinoma (NPC) development. To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. The gene-based burden test discovered an association between macrophage-stimulating 1 receptor (MST1R) and NPC. We identified 13 independent cases carrying the MST1R pathogenic heterozygous germ-line variants, and 53.8% of these cases were diagnosed with NPC aged at or even younger than 20 y, indicating that MST1R germline variants are relevant to disease early-age onset (EAO) (age of ≤20 y). In total, five MST1R missense variants were found in EAO cases but were rare in controls (EAO vs. control, 17.9% vs. 1.2%, P = 7.94 × 10(-12)). The validation study, including 2,160 cases and 2,433 controls, showed that the MST1R variant c.G917A:p.R306H is highly associated with NPC (odds ratio of 9.0). MST1R is predominantly expressed in the tissue-resident macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Importantly, MST1R expression is detected in the ciliated epithelial cells in normal nasopharyngeal mucosa and plays a role in the cilia motility important for host defense. Although no somatic mutation of MST1R was identified in the sporadic NPC tumors, copy number alterations and promoter hypermethylation at MST1R were often observed. Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of the MST1R-mediated signaling pathways.
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http://dx.doi.org/10.1073/pnas.1523436113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812767PMC
March 2016

NF-κB p65 Subunit Is Modulated by Latent Transforming Growth Factor-β Binding Protein 2 (LTBP2) in Nasopharyngeal Carcinoma HONE1 and HK1 Cells.

PLoS One 2015 14;10(5):e0127239. Epub 2015 May 14.

Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong (SAR), PR China; Center for Cancer Research, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong (SAR), PR China; Center for Nasopharyngeal Carcinoma Research, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong (SAR), PR China.

NF-κB is a well-characterized transcription factor, widely known as a key player in tumor-derived inflammation and cancer development. Herein, we present the functional and molecular relevance of the canonical NF-κB p65 subunit in nasopharyngeal carcinoma (NPC). Loss- and gain-of-function approaches were utilized to reveal the functional characteristics of p65 in propagating tumor growth, tumor-associated angiogenesis, and epithelial-to-mesenchymal transition in NPC cells. Extracellular inflammatory stimuli are critical factors that trigger the NF-κB p65 signaling; hence, we investigated the components of the tumor microenvironment that might potentially influence the p65 signaling pathway. This led to the identification of an extracellular matrix (ECM) protein that was previously reported as a candidate tumor suppressor in NPC. Our studies on the Latent Transforming Growth Factor-β Binding Protein 2 (LTBP2) protein provides substantial evidence that it can modulate the p65 transcriptional activity. Re-expression of LTBP2 elicits tumor suppressive effects that parallel the inactivation of p65 in NPC cells. LTBP2 was able to reduce phosphorylation of p65 at Serine 536, inhibit nuclear localization of active phosphorylated p65, and impair the p65 DNA-binding ability. This results in a consequential down-regulation of p65-related gene expression. Therefore, the data suggest that the overall up-regulation of p65 expression and the loss of this candidate ECM tumor suppressor are milestone events contributing to NPC development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127239PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431814PMC
February 2016

Comparative methylome analysis in solid tumors reveals aberrant methylation at chromosome 6p in nasopharyngeal carcinoma.

Cancer Med 2015 Jul 29;4(7):1079-90. Epub 2015 Apr 29.

Department of Clinical Oncology, University of Hong Kong, Hong Kong (SAR), China.

Altered patterns of DNA methylation are key features of cancer. Nasopharyngeal carcinoma (NPC) has the highest incidence in Southern China. Aberrant methylation at the promoter region of tumor suppressors is frequently reported in NPC; however, genome-wide methylation changes have not been comprehensively investigated. Therefore, we systematically analyzed methylome data in 25 primary NPC tumors and nontumor counterparts using a high-throughput approach with the Illumina HumanMethylation450 BeadChip. Comparatively, we examined the methylome data of 11 types of solid tumors collected by The Cancer Genome Atlas (TCGA). In NPC, the hypermethylation pattern was more dominant than hypomethylation and the majority of de novo methylated loci were within or close to CpG islands in tumors. The comparative methylome analysis reveals hypermethylation at chromosome 6p21.3 frequently occurred in NPC (false discovery rate; FDR=1.33 × 10(-9) ), but was less obvious in other types of solid tumors except for prostate and Epstein-Barr virus (EBV)-positive gastric cancer (FDR<10(-3) ). Bisulfite pyrosequencing results further confirmed the aberrant methylation at 6p in an additional patient cohort. Evident enrichment of the repressive mark H3K27me3 and active mark H3K4me3 derived from human embryonic stem cells were found at these regions, indicating both DNA methylation and histone modification function together, leading to epigenetic deregulation in NPC. Our study highlights the importance of epigenetic deregulation in NPC. Polycomb Complex 2 (PRC2), responsible for H3K27 trimethylation, is a promising therapeutic target. A key genomic region on 6p with aberrant methylation was identified. This region contains several important genes having potential use as biomarkers for NPC detection.
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http://dx.doi.org/10.1002/cam4.451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529346PMC
July 2015

Therapeutic targeting of CBP/β-catenin signaling reduces cancer stem-like population and synergistically suppresses growth of EBV-positive nasopharyngeal carcinoma cells with cisplatin.

Sci Rep 2015 Apr 21;5:9979. Epub 2015 Apr 21.

1] Department of Biology, Hong Kong Baptist University, P.R., China [2] Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, P.R., China.

Nasopharyngeal carcinoma (NPC) is an EBV-associated epithelial malignancy prevalent in southern China. Presence of treatment-resistant cancer stem cells (CSC) may associate with tumor relapse and metastasis in NPC. ICG-001 is a specific CBP/β-catenin antagonist that can block CBP/β-catenin-mediated transcription of stem cell associated genes and enhance p300/β-catenin-mediated transcription, thereby reducing the CSC-like population via forced differentiation. In this study, we aimed to evaluate the effect of ICG-001 on the CSC-like population, and the combination effect of ICG-001 with cisplatin in the C666-1 EBV-positive NPC cells. Results showed that ICG-001 inhibited C666-1 cell growth and reduced expression of CSC-associated proteins with altered expression of epithelial-mesenchymal transition (EMT) markers. ICG-001 also inhibited C666-1 tumor sphere formation, accompanied with reduced SOX2(hi)/CD44(hi) CSC-like population. ICG-001 was also found to restore the expression of a tumor suppressive microRNA-145 (miR-145). Ectopic expression of miR-145 effectively repressed SOX2 protein expression and inhibited tumor sphere formation. Combination of ICG-001 with cisplatin synergistically suppressed in vitro growth of C666-1 cells and significantly suppressed growth of NPC xenografts. These results suggested that therapeutically targeting of the CBP/β-catenin signaling pathway with ICG-001 can effectively reduce the CSC-like population and combination with cisplatin can effectively suppress the growth of NPC.
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http://dx.doi.org/10.1038/srep09979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404684PMC
April 2015

Female breast cancer incidence among Asian and Western populations: more similar than expected.

J Natl Cancer Inst 2015 Jul 13;107(7). Epub 2015 Apr 13.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (HS, PSR, WFA, XRY); National Office for Cancer Prevention and Control & National Central Cancer Registry, National Cancer Center, Beijing, China (WQC); Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden (MH); Saw Swee Hock School of Public Health, National University of Singapore, Singapore (MH, WYL, KSC); Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (MH); Hong Kong Cancer Registry, Hospital Authority, Hong Kong, China (OWKM, RKCN); Taiwan Cancer Registry and Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan (CJC); Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea (DK); Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong, China (RKCN); Division of Occupational and Environmental Health, JC School of Public Health and Primary Care, the Chinese University of Hong Kong, Hong Kong, China (LAT).

Background: Previous reports suggested that female breast cancer is associated with earlier ages at onset among Asian than Western populations. However, most studies utilized cross-sectional analyses that may be confounded by calendar-period and/or birth cohort effects. We, therefore, considered a longitudinal (forward-looking) approach adjusted for calendar-period changes and conditioned upon birth cohort.

Methods: Invasive female breast cancer data (1988-2009) were obtained from cancer registries in China, Hong Kong, South Korea, Taiwan, Singapore, and the United States. Age-period-cohort models were used to extrapolate longitudinal age-specific incidence rates for the 1920, 1944, and 1970 birth cohorts.

Results: Cross-sectional age-specific incidence rates rose continuously until age 80 years among US white women, but plateaued or decreased after age 50 years among Asian women. In contrast, longitudinal age-specific rates were proportional (similar) among all Asian countries and the United States with incidence rates rising continuously until age 80 years. The extrapolated estimates for the most recent cohorts in some Asian countries actually showed later ages at onset than in the United States. Additionally, over successive birth cohorts, the incidence rate ratios (IRRs) for the longitudinal curves converged (narrowed) between Asian and US white women.

Conclusions: Similar longitudinal age-specific incidence rates along with converging IRRs indicate that the age effects for invasive breast cancer are more similar among Asian and Western populations than might be expected from a solely cross-sectional analysis. Indeed, the Asian breast cancer rates in recent generations are even surpassing the historically high rates in the United States, highlighting an urgent need for efficient prevention and treatment strategies among Asian populations.
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http://dx.doi.org/10.1093/jnci/djv107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651040PMC
July 2015

miR-31 is consistently inactivated in EBV-associated nasopharyngeal carcinoma and contributes to its tumorigenesis.

Mol Cancer 2014 Aug 7;13:184. Epub 2014 Aug 7.

Department of Anatomical and Cellular Pathology, State Key Laboratory in Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, People's Republic of China.

Background: As a distinctive type of head and neck cancers, nasopharyngeal carcinoma (NPC) is genesis from the clonal Epstein-Barr virus (EBV)-infected nasopharyngeal epithelial cells accumulated with multiple genetic lesions. Among the recurrent genetic alterations defined, loss of 9p21.3 is the most frequent early event in the tumorigenesis of EBV-associated NPC. In addition to the reported CDKN2A/p16, herein, we elucidated the role of a miRNA, miR-31 within this 9p21.3 region as NPC-associated tumor suppressor.

Methods: The expression and promoter methylation of miR-31 were assessed in a panel of NPC tumor lines and primary tumors. Its in vitro and in vivo tumor suppression function was investigated through the ectopic expression of miR-31 in NPC cells. We also determined the miR-31 targeted genes and its involvement in the growth in NPC.

Results: Downregulation of miR-31 expression was detected in almost all NPC cell line, patient-derived xenografts (PDXs) and primary tumors. Both homozygous deletion and promoter hypermethylation were shown to be major mechanisms for miR-31 silencing in this cancer. Strikingly, loss of miR-31 was also obviously observed in the dysplastic lesions of nasopharynx. Restoration of miR-31 in C666-1 cells inhibited the cell proliferation, colony-forming and migratory capacities. Dramatic reduction of in vitro anchorage-independent growth and in vivo tumorigenic potential were demonstrated in the stable clones expressing miR-31. Furthermore, we proved that miR-31 suppressed the NPC cell growth via targeting FIH1 and MCM2.

Conclusions: The findings provide strong evidence to support miR-31 as a new NPC-associated tumor suppressor on 9p21.3 region. The inactivation of miR-31 may contribute to the early development of NPC.
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http://dx.doi.org/10.1186/1476-4598-13-184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127521PMC
August 2014

Multigene pathway-based analyses identify nasopharyngeal carcinoma risk associations for cumulative adverse effects of TERT-CLPTM1L and DNA double-strand breaks repair.

Int J Cancer 2014 Oct 4;135(7):1634-45. Epub 2014 Mar 4.

Department of Clinical Oncology, University of Hong Kong, Pokfulam, Hong Kong SAR, People's Republic of China.

The genetic etiology of nasopharyngeal carcinoma (NPC) and mechanisms for inherited susceptibility remain unclear. To examine genetic risk factors for NPC, we hypothesized that heritable risk is attributable to cumulative effects of multiple common low-risk variants. With the premise that individual SNPs only confer subtle effects for cancer risk, a multigenic pathway-based approach was used to systematically examine associations between NPC genetic susceptibility with SNPs in genes in DNA repair pathways and from previously identified cancer genome-wide association study analyses. This case-control study covers 161 genes/loci and focuses on pathway-based analyses in 2,349 Hong Kong individuals, allowing stratification according to NPC familial status for meaningful association analysis. Three SNPs (rs401681, rs6774494 and rs3757318) corresponding to TERT/CLPTM1L (OR 95% CI = 0.77, 0.68-0.88), MDS1-EVI1 (OR 95% CI=0.79 0.69-0.89) and CCDC170 (OR 95% CI = 0.76, 0.66-0.86) conferred modest protective effects individually for NPC risk by the logistic regression analysis after multiple testing adjustment (p(Bonferroni)  < 0.05). Stratification of NPC according to familial status identified rs2380165 in BLM (OR 95% CI = 1.49, 1.20-1.86, p(Bonferroni)  < 0.05) association with family history-positive NPC (FH+ NPC) patients. Multiple SNPs pathway-based analysis revealed that the combined gene dosage effects for increasing numbers of unfavorable genotypes in TERT-CLPTM1L and double-strand break repair (DSBR) conferred elevated risk in FH+ and sporadic NPC patients (ORs per allele, 95% CIs = 1.37, 1.22-1.55, p(Bonferroni)  = 5.00 × 10(-6); 1.17, 1.09-1.26, p(Bonferroni)  = 4.58 × 10(-4) , respectively, in TERT/NHEJ pathways). Our data suggested cumulative increased NPC risk associations with TERT-CLPTM1L and DSBR pathways contribute to genetic susceptibility to NPC and have potential translational relevance for patient stratification and therapeutics.
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http://dx.doi.org/10.1002/ijc.28802DOI Listing
October 2014

Integrated mRNA and microRNA transcriptome sequencing characterizes sequence variants and mRNA-microRNA regulatory network in nasopharyngeal carcinoma model systems.

FEBS Open Bio 2014 13;4:128-40. Epub 2014 Jan 13.

Center for Nasopharyngeal Cancer Research, The University of Hong Kong, PR China ; Department of Clinical Oncology, The University of Hong Kong, PR China.

Nasopharyngeal carcinoma (NPC) is a prevalent malignancy in Southeast Asia among the Chinese population. Aberrant regulation of transcripts has been implicated in many types of cancers including NPC. Herein, we characterized mRNA and miRNA transcriptomes by RNA sequencing (RNASeq) of NPC model systems. Matched total mRNA and small RNA of undifferentiated Epstein-Barr virus (EBV)-positive NPC xenograft X666 and its derived cell line C666, well-differentiated NPC cell line HK1, and the immortalized nasopharyngeal epithelial cell line NP460 were sequenced by Solexa technology. We found 2812 genes and 149 miRNAs (human and EBV) to be differentially expressed in NP460, HK1, C666 and X666 with RNASeq; 533 miRNA-mRNA target pairs were inversely regulated in the three NPC cell lines compared to NP460. Integrated mRNA/miRNA expression profiling and pathway analysis show extracellular matrix organization, Beta-1 integrin cell surface interactions, and the PI3K/AKT, EGFR, ErbB, and Wnt pathways were potentially deregulated in NPC. Real-time quantitative PCR was performed on selected mRNA/miRNAs in order to validate their expression. Transcript sequence variants such as short insertions and deletions (INDEL), single nucleotide variant (SNV), and isomiRs were characterized in the NPC model systems. A novel TP53 transcript variant was identified in NP460, HK1, and C666. Detection of three previously reported novel EBV-encoded BART miRNAs and their isomiRs were also observed. Meta-analysis of a model system to a clinical system aids the choice of different cell lines in NPC studies. This comprehensive characterization of mRNA and miRNA transcriptomes in NPC cell lines and the xenograft provides insights on miRNA regulation of mRNA and valuable resources on transcript variation and regulation in NPC, which are potentially useful for mechanistic and preclinical studies.
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http://dx.doi.org/10.1016/j.fob.2014.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3907684PMC
February 2014

Dosimetric difference amongst 3 techniques: TomoTherapy, sliding-window intensity-modulated radiotherapy (IMRT), and RapidArc radiotherapy in the treatment of late-stage nasopharyngeal carcinoma (NPC).

Med Dosim 2014 7;39(1):44-9. Epub 2013 Dec 7.

Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China.

To investigate the dosimetric difference amongst TomoTherapy, sliding-window intensity-modulated radiotherapy (IMRT), and RapidArc radiotherapy in the treatment of late-stage nasopharyngeal carcinoma (NPC). Ten patients with late-stage (Stage III or IV) NPC treated with TomoTherapy or IMRT were selected for the study. Treatment plans with these 3 techniques were devised according to departmental protocol. Dosimetric parameters for organ at risk and treatment targets were compared between TomoTherapy and IMRT, TomoTherapy and RapidArc, and IMRT and RapidArc. Comparison amongst the techniques was done by statistical tests on the dosimetric parameters, total monitor unit (MU), and expected delivery time. All 3 techniques achieved similar target dose coverage. TomoTherapy achieved significantly lower doses in lens and mandible amongst the techniques. It also achieved significantly better dose conformity to the treatment targets. RapidArc achieved significantly lower dose to the eye and normal tissue, lower total MU, and less delivery time. The dosimetric advantages of the 3 techniques were identified in the treatment of late-stage NPC. This may serve as a guideline for selection of the proper technique for different clinical cases.
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http://dx.doi.org/10.1016/j.meddos.2013.09.004DOI Listing
September 2014

Definitive radiotherapy for early stage glottic cancer by 6 MV photons.

Head Neck Oncol 2012 May 18;4:23. Epub 2012 May 18.

Department of Clinical Oncology, Queen Elizabeth Hospital, 30 Gascoigne Road, Kowloon, Hong Kong, China.

Purpose: To evaluate the clinical outcome of early glottic cancer (GC) treated by primary radiotherapy (RT) with 6 MV photons.

Methods And Materials: We retrospectively reviewed the medical records of 695 consecutive patients with T1N0 and T2N0 GC treated between 1983 and 2005 by RT in our institution. Clinical outcome in terms of local control (LC), overall survival (OS) and cause- specific survival (CSS) rate were evaluated.

Results: The median follow-up time was 10.5 years. The 10-year actuarial LC rates were as follows: T1A, 91%; T1B, 87%; T2, 77%. The 10-year OS were as follows: T1, 74.2%; T2, 70.7%. The 10-year CSS were as follows: T1, 97.7%; T2, 97.1%.Poorly differentiated histology and tumor biologically effective dose<65 Gy15 were adverse factors in both LC of T1 and T2 disease. Involvement of anterior commissure was an adverse factor in both LC and CSS of T1 disease. Subglottic extension was associated with poor LC in T2 disease whereas hemoglobin <13.0 was associated with poor LC and CSS of T2 disease.

Conclusion: Primary RT remains an option among the various standard treatments for early GC. Clinical treatment outcome by 6MV photons is similar and comparable to historic data of Cobalt-60 and 2 MV photons.
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http://dx.doi.org/10.1186/1758-3284-4-23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448507PMC
May 2012