Xiaoxin Chen

North Carolina Central University | NCCU · Biomedical Biotechnical Research Institute (BBRI)

Esophageal squamous cell carcinoma (ESCC) ranks as the 7th most frequently diagnosed cancer and the 6th leading cause of cancer-related death worldwide. NRF2 is identified as a therapeutic target for human ESCC, with a mutation rate of approximately 10-22%. Hyperactive NRF2 promotes proliferation, metastasis, and resistance to radiation and chemoth...

Esophageal diseases such as gastroesophageal reflux disease (GERD) and esophageal cancer have a strong association with alcohol drinking. However, the molecular mechanisms of alcohol-induced esophageal pathology remain unclear. In our previous study, we identified acyl-CoA synthetase short-chain family member 2 (ACSS2) as a transcriptional target o...

Objective NRF2 is a master transcription factor that regulates the stress response. NRF2 is frequently mutated and activated in human esophageal squamous cell carcinoma (ESCC), which drives resistance to chemotherapy and radiation therapy. Therefore, a great need exists for NRF2 inhibitors for targeted therapy of NRF2high ESCC. Design We performed...

Esophageal squamous cell carcinoma (ESCC) is characterized by the development of cancer in the esophageal squamous epithelium through a step-by-step accumulation of genetic, epigenetic and histopathological alterations. Recent studies have demonstrated that cancer-associated gene mutations exist in histologically normal or precancerous clones of th...

Objective: NRF2 is a master transcription factor that regulates the stress response. NRF2 is frequently mutated and activated in human esophageal squamous cell carcinoma (ESCC), which drives resistance to chemotherapy and radiation therapy. Therefore, a great need exists for NRF2 inhibitors for targeted therapy of NRF2high ESCC. Design: We performe...

Background Lymphatic metastasis is commonly seen in patients with esophageal squamous cell carcinoma (ESCC). Both lymphatic metastasis and the number of involved nodes are prognostic for post-operative survival. To better understand lymphatic metastasis of ESCC, there is a need to develop proper animal models. Aims This study is aimed to character...

Limited efforts have been made in assessing the effect of genome-wide profiling of RNA splicing-related variation on lung cancer risk. In the present study, we first identified RNA splicing-related genetic variants linked to lung cancer in a genome-wide profiling analysis and then conducted a two-stage (discovery and replication) association study...

Paired box 9 (PAX9) is a transcription factor of the PAX family functioning as both a transcriptional activator and repressor. Its functional roles in the embryonic development of various tissues and organs have been well studied. However, its roles and molecular mechanisms in cancer development are largely unknown. Here, we review the current unde...

Background The cellular origin and molecular mechanisms of Barrett’s esophagus (BE) are still controversial. Trans-differentiation is a mechanism characterized by activation of the intestinal differentiation program and inactivation of the squamous differentiation program.AimsRenal capsule grafting (RCG) was used to elucidate whether CDX2 overexpre...

Esophageal squamous cell carcinoma (ESCC) is a deadly disease and one of the most aggressive cancers of the gastrointestinal tract. As a master transcription factor regulating the stress response, NRF2 is often mutated and becomes hyperactive, and thus causes chemo-radioresistance and poor survival in human ESCC. There is a great need to develop NR...

Prostate cancer constitutes a serious health challenge and remains one of the main causes of cancer-related death among men. The more aggressive form of the disease has been attributed to androgen independence; resulting in lack of response to androgen deprivation therapy and sustained activation of other growth pathways. The scaffold proteins β-ar...

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a member of TIPE/TNFAIP8 family, has been involved in the development and progression of various human cancers. We hypothesized that TNFAIP8 promotes prostate cancer (PCa) progression via regulation of oxidative phosphorylation (OXPHOS) and glycolysis. Ectopic expression of TNFAIP8 increased PC...

The most common form of esophageal cancer (EC), esophageal squamous cell carcinoma (ESCC), is prevalent in many unindustrialized societies, among people with lower socioeconomic status and those who frequently use tobacco and alcohol. In some areas, ESCC mortality ranked top among all cancer. In this review, we begin with discussions of the extensi...

Alcohol drinking has been established as a major risk factor for esophageal diseases. Our previous study showed that ethanol exposure inhibited PAX9 expression in human esophageal squamous epithelial cells in vitro and in vivo. In this study, we aimed to investigate the molecular pathways through which alcohol drinking suppresses PAX9 in esophageal...

Esophageal squamous cell carcinoma (ESCC) is a deadly disease that requires extensive research on its mechanisms, prevention, and therapy. Recent studies have shown that NOTCH mutations are commonly seen in human ESCC. This chapter summarizes our current understanding of the NOTCH pathway in normal esophagus and in ESCC. In normal esophagus, NOTCH...

Alcohol drinking is a leading risk factor for the development of esophageal squamous cell carcinoma (ESCC). However, the molecular mechanisms of alcohol-associated ESCC remain poorly understood. One of the most commonly mutated genes in ESCC is nuclear factor erythroid 2 like 2 (NFE2L2 or NRF2), which is a critical transcription factor regulating o...

Activation of the nuclear factor (erythroid‐derived 2)‐like 2 (NFE2L2 or NRF2) transcription factor is a critical and evolutionarily conserved cellular response to oxidative stress, metabolic stress, and xenobiotic insult. Deficiency of NRF2 results in hypersensitivity to a variety of stressors, whereas its aberrant activation contributes to severa...

Pancreatic cancer (PanC) is one of the most lethal solid malignancies, and metastatic PanC is often present at the time of diagnosis. Although several high‐ and low‐penetrance genes have been implicated in PanC, their roles in carcinogenesis remain only partially elucidated. Because the nuclear factor erythroid2‐related factor2 (NRF2) signaling pat...

Prostate cancer (PCa) is a leading cause of cancer death among men, with greater prevalence of the disease among the African American population in the USA. Activator of G-protein signaling 3 (AGS3/G-protein signaling modulator 1) was shown to be overexpressed in prostate adenocarcinoma relative to the prostate gland. In this study, we investigated...

Mutations in the genes encoding nuclear factor (erythroid-derived 2)-like 2 (NRF2), Kelch-like ECH-associated protein 1 (KEAP1), and cullin 3 (CUL3) are commonly observed in human esophageal squamous cell carcinoma (ESCC) and result in activation of the NRF2 signaling pathway. Moreover, hyperactivity of the transcription factor Nrf2 has been found...

Pax9 is a transcription factor of the Pax family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of Pax9 in squamous cell differentiation and carcinogenesis of oro-esophageal epithelium. However, its functional role in differentiation and carcinogenesis remains unclear. In this study, Pax9 deficiency i...

Background: The Nrf2/Keap1 pathway is critical for human cells to respond to oxidative stress. In basal conditions the Keap1 homodimer is bound to Nrf2 in the cytoplasm. When stressed, Keap1 releases Nrf2 which translocates into the nucleus, binds the antioxidant response element, and activate antioxidative genes. Somatic mutations of Nrf2 or Keap1...

Esophageal squamous cell carcinoma (ESCC) is a deadly disease that requires extensive research. Here, we review the current understanding of the functions of the nuclear factor erythroid‐derived 2–like 2 (NRF2) signaling pathway in the esophagus. Genomic data suggest that gene mutations and several other mechanisms result in NRF2 hyperactivation in...

Background: The advantage of neoadjuvant chemotherapy (NAC) followed by open esophagectomy for treatment of esophageal squamous cell carcinoma has been widely recognized. However, the safety and feasibility of NAC for patients receiving minimally invasive esophagectomy (MIE) remain controversial. The purpose of this study was to evaluate the poten...

PAX9 is a transcription factor of the PAX family characterized by a DNA-binding paired domain. Previous studies have suggested a potential role of PAX9 in squamous cell differentiation and carcinogenesis of the oro-esophageal epithelium. However, its functional roles in differentiation and carcinogenesis remain unclear. In this study, Pax9 deficien...

In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy, but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown. In the case of Barrett's oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, whe...

Oxidative stress is known to play a pivotal role in the development of oral squamous cell carcinoma (OSCC). We have demonstrated that activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway has chemopreventive effects against oxidative stress-associated OSCC. However, Nrf2 have dual roles in cancer development; while...

Kenya belongs to a high incidence region known as Africa’s esophageal cancer (EC) corridor. It has one of the highest incidence rates of EC worldwide, but research on EC in Kenya has gone highly unnoticed. EC in Kenya is unique in its high percentage of young cases (< 30 years of age). In this review, we show the current status of EC in the country...

Exfoliative cytology has been widely used for early diagnosis of oral squamous cell carcinoma. We have developed an oral cancer risk index using DNA index value to quantitatively assess cancer risk in patients with oral leukoplakia, but with limited success. In order to improve the performance of the risk index, we collected exfoliative cytology, h...

Oxidative stress is known to play an important role in oral cancer development. In this study we aimed to examine whether a chemical activator of NRF2, sulforaphane (SFN), may have chemopreventive effects on oxidative stress-associated oral carcinogenesis. We first showed that Nrf2 activation and oxidative damage were commonly seen in human samples...

Gastroesophageal reflux disease (GERD) has become the most commonly seen gastrointestinal disorder in outpatient clinics. In the United States, around 20% of the general population experience heartburn on a weekly basis. Although clinical complaints can be mild or moderate, patients with GERD may develop further complications, such as peptic strict...

Oxidative stress is known to play an important role in oral cancer development. In this study we aimed to examine whether a chemical activator of NRF2, sulforaphane (SFN), may have chemopreventive effects on oxidative stress-associated oral carcinogenesis. We first showed that Nrf2 activation and oxidative damage were commonly seen in human samples...

Esophageal squamous cell carcinoma (ESCC) is a deadly disease that requires extensive research. In this review, we update recent progress in the research area of targeted therapy for ESCC. SOX2 and its associated proteins (e.g., ΔNP63α), which regulate lineage survival of ESCC cells, are proposed as therapeutic targets. It is believed that targetin...

Oxidative stress is a central component of many chronic diseases. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2 p45-related factor 2 (Nrf2) system is a major regulatory pathway of cytoprotective genes against oxidative and electrophilic stress. Activation of the Nrf2 pathway plays crucial roles in the chemopreventive ef...

Background: Esophageal cancer (EC) occurs commonly, especially in Asia, and is the sixth leading cause of cancer deaths worldwide. Recently, great progress has been made in research on the etiology and prevention of EC. Summary: The major risk factors for esophageal squamous cell carcinoma (ESCC) are tobacco smoking and alcohol drinking, which a...

Mammalian esophagus exhibits a remarkable change in epithelial structure during the transition from embryo to adult. However, the molecular mechanisms of esophageal epithelial development are not well understood. Zebrafish (Danio rerio), a common model organism for vertebrate development and gene function, has not previously been characterized as a...

Quantitation of the esophageal squamous epithelium in developing zebrafish. Percentage of the zebrafish (A) and the number of sections per zebrafish (B) with ESQE in the upper digestive tract at different developmental stages. (JPG)

Survival curves and quantitation of P63 or Pax9 knockdown phenotypes. (A) Survival curves (up to 7dpf) after MO injection; (B) Pax9 morphants (malformed lower jaw) and P63 morphants (finless) at 7dpf; (C) Pax9 and P63 morphants with esophageal SQ epithelium at 7dpf; (D) Sections containing ESQE per fish at 7dpf after different MO injection. * P<0.0...

H&E staining on serial transverse sections containing all the esophageal squamous epithelium of 7dpf zebrafish. The sections show the histology of pharynx (A), esophagus (B-O) and intestine (P). There are 9 sections containing the stratified squamous epithelium (C-K). Scare bar:5μm. (TIF)

Multiple surgical procedures have been reported to induce gastroesophageal reflux in animals. Herein, we report three surgical models with mice aiming to induce reflux of gastric contents, duodenal contents or mixed contents. Surgical procedures and general principles have been described in detail. A researcher with surgical experience should be ab...

Regular aspirin use has been convincingly shown to reduce the risk of colorectal cancer. However, long-term use of aspirin leads to gastrotoxicity. Herein, we designed and synthesized a novel class of resveratrol-based aspirin prodrugs to simultaneously release aspirin and resveratrol to attenuate the side effects caused by aspirin. Prodrug RAH exe...

Esophageal squamous cell carcinoma continues to heavily burden clinicians worldwide. Researchers have discovered the genomic landscape of esophageal squamous cell carcinoma, which holds promise for an era of personalized oncology care. One of the most pressing problems facing this issue is to improve the understanding of the newly available genomic...

Exfoliative cytology has been widely used for early diagnosis of oral squamous cell carcinoma (OSCC). Test outcome is reported as "negative", "atypical" (defined as abnormal epithelial changes of uncertain diagnostic significance), and "positive" (defined as definitive cellular evidence of epithelial dysplasia or carcinoma). The major challenge is...

Alcohol drinking is a major etiological factor of oro-esophageal squamous cell carcinoma (OESCC). Both local and systemic effects of ethanol may promote carcinogenesis, especially among chronic alcoholics. However, molecular mechanisms of ethanol-associated OESCC are still not well understood. In this review, we summarize current understandings and...

Background & Aims: Distinguishing between eosinophilic esophagitis (EoE), gastroesophageal reflux disease (GERD), and proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is challenging. We assessed whether immunohistochemical analysis of esophageal tissues for major basic protein (MBP), eotaxin3, and tryptase can be used in diagnosis...

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on translational research on Barrett's esophagus that address evidence for genetic instability in esophageal cancer; the role of microsatellite instability; the use of histologic and serum Doublecortin-like kinase 1 expression for progression of Barr...

In this study, we identified Nrf2 as a molecular target of [6]-shogaol (6S), a bioactive compound isolated from ginger, in colon epithelial cells in vitro and in vivo. Following 6S treatment of HCT-116 cells, the intracellular GSH/GSSG ratio was initially diminished but then elevated above the basal level. Intracellular reactive oxygen species (ROS...

The stratified squamous epithelium of the esophagus forms a tight protective barrier. Defects of the barrier function contribute to gastroesophageal reflux disease (GERD), which is manifested as damage to the esophageal epithelium due to exposure to the gastrointestinal refluxate. In this review, we discuss the involvement of NFkB and Nrf2 in esoph...

Biomarkers of dietary intake are prominent tools in nutritional research. Alkylresorcinol metabolites, 3,5-dihydroxybenzoic acid (3,5-DHBA) and 3-(3,5-dihydroxyphenyl)propanoic acid (3,5-DHPPA), have been proposed as exposure biomarkers of whole-grain (WG) wheat and rye intake. However, the profile of alkylresorcinol metabolites is not fully unders...

This paper presents commentaries on animal models used for Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) research; acid- and bile-induced chromosomal instability and clonal selection during the progression of BE to EAC; how the components of gastric refluxate, especially acid and bile salts, promote carcinogenesis in metaplastic BE;...

This paper presents commentaries on reflux-induced injury of human esophageal epithelium; inflammation in human reflux esophagitis; motor consequences of reflux-induced inflammation in esophageal epithelium; the microscopic morphology of esophageal squamous epithelium; intraluminal impedance in the evaluation of the esophageal mucosa; endoscopic ti...

Barrett's esophagus (BE), the premalignant lesion of esophageal adenocarcinoma, is believed to develop as a result of chronic gastroesophageal reflux disease (GERD). Approximately 10 % of subjects with GERD progress to BE. Genetic, epigenetic and other risk factors may contribute to this inter-individual variability. Caudal type homeobox 1 (Cdx1) a...

Objective: As a major cellular defence mechanism, the Nrf2/Keap1 pathway regulates expression of genes involved in detoxification and stress response. Here we hypothesise that Nrf2 is involved in oesophageal barrier function and plays a protective role against gastro-oesophageal reflux disease (GERD). Design: Human oesophageal biopsy samples, mo...

Background and aims: Cdx2 has been suggested to play an important role in Barrett's esophagus (BE), or intestinal metaplasia (IM) in the esophagus. However, it is still unclear whether ectopic overexpression of Cdx2 may lead to IM in the esophagus in vivo. The aim of the present study was to investigate whether transgenic overexpression of Cdx1b, t...

Shogaols, a series of major constituents in dried ginger (Zingiber officinale), show high anti-cancer potencies. Previously, we reported that a major metabolite resulting from the mercapturic acid pathway, 5-cysteinyl-[6]-shogaol (M2), showed comparable growth inhibitory effects towards cancer cells to [6]-shogaol (6S). Here we probe the mechanism...

The barrier function of esophageal epithelium is a major defense against gastroesophageal reflux disease. Previous studies have shown that reflux damage is reflected in a decrease in transepithelial electrical resistance associated with tight junction alterations in the esophageal epithelium. In order to develop novel therapies, it is critical to u...

Purpose Many studies have demonstrated that curcumin has potent chemopreventive efficacy against many types of cancer. But its mechanism of actions is still not fully understood, and especially curcumin specific protein targets in oral cell has never been systematically studied. Therefore the aim of this study is to identify potential protein targe...

Purpose The purpose of this study was to evaluate the tumor inhibitory effects due to the topical application of water extracts from ZSP, a Chinese herbal drug, on 7,12-dimethlbenz(a) anthracene (DMBA) induced oral tumors in hamsters. The study also investigated the anti-cancer mechanisms of the ZSP water extraction on oral carcinogenesis. Materia...

G protein-coupled receptor kinases (GRKs) phosphorylate the activated form of G protein-coupled receptors leading to receptor desensitization and downregulation. We have recently shown that the chemokine receptor, CXCR2, couples to GRK6 to regulate cellular responses including chemotaxis, angiogenesis, and wound healing. In this study, we investiga...

Sox2 regulates the self-renewal of multiple types of stem cells. Recent studies suggest it also plays oncogenic roles in the formation of squamous carcinoma in several organs, including the esophagus where Sox2 is predominantly expressed in the basal progenitor cells of the stratified epithelium. Here, we use mouse genetic models to reveal a mechan...

Scope: Shogaols, a series of major constituents in dried ginger with the most abundant being [6]-, [8]-, and [10]-shogaols, show much higher anticancer potencies than gingerols. Previously, we reported the mercapturic acid pathway as a major metabolic route for [6]-shogaol in mice. However, it is still unclear how the side chain length affects the...

Objectives: Radiofrequency ablation (RFA) of Barrett's esophagus (BE) is safe and effective in eradicating dysplasia and intestinal metaplasia, and may reduce rates of esophageal adenocarcinoma (EAC). We assessed rates of and risk factors for disease recurrence after successful treatment of BE with RFA. Methods: We performed a retrospective coho...

Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis and can be targeted for cancer prevention. To develop potent topical agents for oral cancer chemoprevention, 5 known 5-Lox inhibitors from dietary and synthetic sources (Zileuton, ABT-761, lico...

Background & aims: The goal of radiofrequency ablation (RFA) for patients with Barrett's esophagus (BE) is to eliminate dysplasia and metaplasia. The efficacy and safety of RFA for patients with BE and neoplasia are characterized incompletely. Methods: We performed a retrospective study of 244 patients treated with RFA for BE with dysplasia or i...

6-Gingerol, a major pungent component of ginger (Zingiber officinale Roscoe, Zingiberaceae), has been reported to have anti-tumor activities. However, the metabolic fate of 6-gingerol and the contribution of its metabolites to the observed activities are still unclear. In the present study, we investigated the biotransformation of 6-gingerol in dif...

Previous human intervention trial demonstrated that vitamin E (Ve) and selenium (Se) supplementation decreased esophageal cancer deaths among younger participants, but may have no effect or produce an opposite effect among older ones. In our study, we intended to mimic this human nutritional trial to determine the chemopreventive effects of Ve/Se s...

Features of eosinophilic esophagitis (EoE) and gastroesophageal reflux disease (GERD) overlap. We aimed to determine whether staining for tissue biomarkers would differentiate EoE from GERD, suggesting utility for diagnosis of EoE. In this case-control study, EoE patients defined by consensus guidelines were compared to GERD patients with eosinophi...

EMR is commonly performed before radiofrequency ablation (RFA) for nodular dysplastic Barrett's esophagus (BE). To determine the efficacy and safety of EMR before RFA for nodular BE with advanced neoplasia (high-grade dysplasia [HGD] or intramucosal carcinoma [IMC]). Retrospective study. University of North Carolina Hospitals, from 2006 to 2011. 16...

Oral cancer is a common malignancy occurring in developing countries, and remains problematic due to lack of effective strategies of prevention and treatment. Our previous studies have shown that aberrant arachidonic acid metabolism, especially the 5-lipoxygenase (5-Lox) pathway, is involved in oral carcinogenesis, and can be targeted for cancer pr...

[This corrects the article on p. e36504 in vol. 7.].

Morphological changes during human and mouse esophageal development have been well characterized. However, changes at the molecular level in the course of esophageal morphogenesis remain unclear. This study aims to globally profile critical genes and signaling pathways during the development of mouse esophagus. By using microarray analysis this stu...

Hierarchical clustering analysis and PCA analysis of gene expression array data of wild-type mouse definitive endoderm (E8.25) and esophagi (E11.5): (A) clustering analysis; (B) PCA analysis. (TIF)

Hierarchical clustering analysis and PCA analysis of gene expression array data of P7 mouse esophagi (wild-type, Nrf2−/−, Keap1−/−, Nrf2−/−Keap1−/−): (A) clustering analysis; (B) PCA analysis. (TIF)

Real-time PCR analysis of mRNA expression in wild-type and Keap1−/− mouse esophagi: relative mRNA levels of Pax9, Sbsn, Calm4, Ppard, Pten and Akt2 in the whole esophagi of wild type and Keap1−/− mice at P7. (TIF)

Differential gene expression in the specification phase during wild-type mouse esophageal development: (1) Raw gene expression array data after data pre-processing (E8.25 endoderm and E11.5 esophagus); (2) SAM analysis of differentially expressed genes (E8.25 endoderm vs E11.5 esophagus); (3) GSA analysis of differentially expressed gene sets (E8.2...

Differential gene expression in the metaplasia phase during wild-type mouse esophageal development: (1) Raw gene expression array data after data pre-processing (E11.5, E15.5, P0 and P7); (2) SAM analysis of differentially expressed genes (E11.5 vs E15.5 vs P0 vs P7); (3) GSA analysis of differentially expressed gene sets (E11.5 vs E15.5 vs P0 vs P...

Dynamic expression of eighteen gene expression patterns and nine knowledge-based gene sets in the metaplasia phase. (XLSX)

Differential gene expression at P7 between wild-type mice, Nrf2−/− mice, Keap1−/− mice, and Nrf2−/−Keap1−/− mice: (1) Raw gene expression array data after data pre-processing (wild-type P7, Nrf2−/− P7, Keap1−/− P7, Nrf2−/−Keap1−/− P7); (2) SAM analysis of differentially expressed genes (wild-type P7 vs Nrf2−/− P7 vs Keap1−/− P7 vs Nrf2−/−Keap1−/− P...

Hierarchical clustering analysis and PCA analysis of gene expression array data of wild-type mouse esophagi (E11.5, E15.5, P0, P7): (A) clustering analysis; (B) PCA analysis. (TIF)

Hierarchical clustering analysis and PCA analysis of gene expression array data of mouse esophagi (wild-type adult, Nrf2−/− adult): (A) clustering analysis; (B) PCA analysis. (TIF)

Knowledge-based gene sets and references. (XLS)

Differential gene expression in the maturation phase during the development of wild-type mouse esophageal epithelium: (1) Raw gene expression array data after data pre-processing (P7 and adult esophagus); (2) SAM analysis of differentially expressed genes (P7 vs adult esophagus); (3) GSA analysis of differentially expressed gene sets (P7 vs adult e...

Real-time PCR analysis of mRNA expression in wild-type mouse esophagi: relative mRNA levels of Pax9 and its target genes (Sbsn, Calm4) in mouse esophageal epithelium of E15.5, P0, P7 and adult mice. (TIF)