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1.
EMBO Rep ; 22(2): e48351, 2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33403789

RESUMO

Esophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer worldwide. The most commonly mutated gene in ESCC is TP53. Using a combinatorial genetic and carcinogenic approach, we generate a novel mouse model of ESCC expressing either mutant or null p53 and show that mutant p53 exhibits enhanced tumorigenic properties and displays a distinct genomic profile. Through RNA-seq analysis, we identify several endocytic recycling genes, including Rab Coupling Protein (Rab11-FIP1), which are significantly downregulated in mutant p53 tumor cells. In 3-dimensional (3D) organoid models, genetic knockdown of Rab11-FIP1 results in increased organoid size. Loss of Rab11-FIP1 increases tumor cell invasion in part through mutant p53 but also in an independent manner. Furthermore, loss of Rab11-FIP1 in human ESCC cell lines decreases E-cadherin expression and increases mesenchymal lineage-specific markers, suggesting induction of epithelial-mesenchymal transition (EMT). Rab11-FIP1 regulates EMT through direct inhibition of Zeb1, a key EMT transcriptional factor. Our novel findings reveal that Rab11-FIP1 regulates organoid formation, tumor cell invasion, and EMT.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Transição Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica
2.
Am J Gastroenterol ; 117(8): 1324-1328, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35926495

RESUMO

INTRODUCTION: Acetaminophen (APAP) toxicity is the main cause of acute liver failure in the United States. A prior series (1992-1995) identified 71 hospitalized adults with APAP toxicity through the International Statistical Classification of Disease and Related Health Problems, 9th revision (ICD-9) code at Parkland Hospital, Dallas, TX. METHODS: We used a laboratory database search of serum APAP levels from 2011 to 2015 to identify patients with APAP toxicity in the same hospital. RESULTS: We identified 140 patients hospitalized for APAP toxicity from 27,143 APAP levels obtained; 35 required Intensive Care Unit (ICU) admission, and there were no deaths. APAP toxicity/100,000 admissions was similar between eras. DISCUSSION: APAP toxicity continues unabated after 20 years but with improved overall outcomes.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Overdose de Drogas , Falência Hepática Aguda , Acetaminofen , Adulto , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Bases de Dados Factuais , Overdose de Drogas/epidemiologia , Hospitais de Condado , Humanos , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/epidemiologia , Estados Unidos/epidemiologia
3.
Carcinogenesis ; 36(5): 598-606, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25795715

RESUMO

Esophageal cells overexpressing epidermal growth factor receptor (EGFR) and TP53 mutation can invade into the extracellular matrix when grown in 3D-organotypic cultures (OTC) and mimic early invasion in esophageal squamous cell carcinoma (ESCC). We have performed laser capture microdissection with RNA microarray analysis on the invasive and non-invasive tumor cells of p53(R175H)-overexpressing OTC samples to determine candidate genes facilitating tumor invasion. WNT10A was found to be >4-fold upregulated in the invasive front. Since WNT10A is also prominently upregulated during placode promotion in hair follicle development, a process that requires epithelial cells to thicken and elongate, in order to allow downward growth, we hypothesized that WNT10A may be important in mediating a similar mechanism of tumor cell invasion in ESCC. We have found that WNT10A expression is significantly upregulated in human ESCC, when compared with normal adjacent tissue. Furthermore, high WNT10A expression levels correlate with poor survival. Interestingly, we observe that WNT10A is expressed early in embryogenesis, but is reduced dramatically postnatally. We demonstrate that overexpression of WNT10a promotes migration and invasion, and proliferation of transformed esophageal cells. Lastly, we show that WNT10A overexpression induces a greater CD44(High)/CD24(Low) population, which are putative markers of cancer stem cells, and increases self-renewal capability. Taken together, we propose that WNT10A acts as an oncofetal factor that is highly expressed and may promote proper development of the esophagus. During tumorigenesis, it is aberrantly overexpressed in order to promote ESCC migration and invasion, and may be linked to self-renewal of a subset of ESCC cells.


Assuntos
Carcinoma de Células Escamosas/patologia , Diferenciação Celular , Transformação Celular Neoplásica/patologia , Neoplasias Esofágicas/patologia , Esôfago/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Wnt/metabolismo , Animais , Apoptose , Western Blotting , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Citometria de Fluxo , Imunofluorescência , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Proteínas Wnt/genética
4.
Health Equity ; 5(1): 345-352, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34084986

RESUMO

Purpose: Influenza/pneumonia is the eighth leading cause of death in the United States. The 2020-2021 influenza season is predicted to be further impacted by COVID-19 infections. Historical data reflect disproportionate morbidity and mortality rates in the Hispanic population for influenza and COVID-19. Influenza vaccination rates remain low in the Hispanic community. We aim to improve vaccination through a community-led event, partnering with the Cristo Rey School Dallas, located in a zip code with a higher age-adjusted influenza/pneumonia mortality rate. A survey was administered to adults attending the Influenza vaccine event to understand attitudes and perceptions about influenza, vaccination, and effective messaging strategies for the campaign. Methods: Messaging was cocreated with student health ambassadors to promote immunization and delivered through trusted sources. The health department administered vaccines to individuals >age 3 at no cost. Adults were asked to complete a 19-question survey postvaccination offered in both English and Spanish. Results: Two hundred and forty-one of 394 (61.2%) participants completed the survey. Ninety-eight percent identified as Hispanic/Latino, and the majority of surveys were administered in Spanish. Among Spanish language participants, the church bulletins (57.3%) and Spanish language radio (30.5%) were reported to be most effective modes of messaging versus word of mouth (32.9%) and social media (26.3%) for English-speaking participants. Sixteen percent of participants surveyed had never received an influenza vaccine before this event. Conclusion: Cocreated messaging delivered by trusted sources in the Hispanic community led to a successful Influenza vaccine drive with the Dallas County health department.

5.
Curr Colorectal Cancer Rep ; 13(4): 341-351, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29129972

RESUMO

Colorectal cancer (CRC) is the fourth most common cancer in both men and women in the United States, resulting in over 55,000 deaths annually. Environmental and genetic factors influence the development of CRC, and inflammation is a critical hallmark of cancer that may arise from a variety of factors. PURPOSE OF REVIEW: While patients with inflammatory bowel disease (IBD) have a higher risk of developing CRC, sporadic CRCs may engender or be potentiated by inflammation as well. In this review, we focus on recent advances in basic and translational research utilizing murine models to understand the contribution of inflammatory signaling pathways to CRC. RECENT FINDINGS: We discuss advances in the utility of three-dimensional enteroid/colonoid/tumoroid cultures to understand immune-epithelial interactions in CRC, as well as the potential for utilizing patient-derived tumoroids for personalized therapies. SUMMARY: This review underscores the importance of understanding the complex molecular mechanisms underlying inflammation in sporadic CRC and highlights up-and-coming or new avenues for CRC biomarkers or therapies.

6.
J Clin Invest ; 127(6): 2378-2391, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28481227

RESUMO

The esophageal lumen is lined by a stratified squamous epithelium comprised of proliferative basal cells that differentiate while migrating toward the luminal surface and eventually desquamate. Rapid epithelial renewal occurs, but the specific cell of origin that supports this high proliferative demand remains unknown. Herein, we have described a long-lived progenitor cell population in the mouse esophageal epithelium that is characterized by expression of keratin 15 (Krt15). Genetic in vivo lineage tracing revealed that the Krt15 promoter marks a long-lived basal cell population able to self-renew, proliferate, and generate differentiated cells, consistent with a progenitor/stem cell population. Transcriptional profiling demonstrated that Krt15+ basal cells are molecularly distinct from Krt15- basal cells. Depletion of Krt15-derived cells resulted in decreased proliferation, thereby leading to atrophy of the esophageal epithelium. Further, Krt15+ cells were radioresistant and contributed to esophageal epithelial regeneration following radiation-induced injury. These results establish the presence of a long-lived and indispensable Krt15+ progenitor cell population that provides additional perspective on esophageal epithelial biology and the widely prevalent diseases that afflict this epithelium.


Assuntos
Esôfago/citologia , Queratina-15/metabolismo , Células-Tronco/fisiologia , Animais , Diferenciação Celular , Movimento Celular , Proliferação de Células , Sobrevivência Celular/efeitos da radiação , Esôfago/fisiologia , Esôfago/efeitos da radiação , Homeostase , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucosa/citologia , Regiões Promotoras Genéticas , Lesões Experimentais por Radiação/fisiopatologia , Regeneração , Células-Tronco/efeitos da radiação , Ativação Transcricional
7.
Nat Commun ; 8(1): 1758, 2017 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-29170450

RESUMO

Notch1 transactivates Notch3 to drive terminal differentiation in stratified squamous epithelia. Notch1 and other Notch receptor paralogs cooperate to act as a tumor suppressor in squamous cell carcinomas (SCCs). However, Notch1 can be stochastically activated to promote carcinogenesis in murine models of SCC. Activated form of Notch1 promotes xenograft tumor growth when expressed ectopically. Here, we demonstrate that Notch1 activation and epithelial-mesenchymal transition (EMT) are coupled to promote SCC tumor initiation in concert with transforming growth factor (TGF)-ß present in the tumor microenvironment. We find that TGFß activates the transcription factor ZEB1 to repress Notch3, thereby limiting terminal differentiation. Concurrently, TGFß drives Notch1-mediated EMT to generate tumor initiating cells characterized by high CD44 expression. Moreover, Notch1 is activated in a small subset of SCC cells at the invasive tumor front and predicts for poor prognosis of esophageal SCC, shedding light upon the tumor promoting oncogenic aspect of Notch1 in SCC.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Transição Epitelial-Mesenquimal , Carcinoma de Células Escamosas do Esôfago/metabolismo , Receptor Notch1/metabolismo , Receptor Notch3/metabolismo , Animais , Carcinogênese , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/fisiopatologia , Linhagem Celular Tumoral , Carcinoma de Células Escamosas do Esôfago/genética , Carcinoma de Células Escamosas do Esôfago/fisiopatologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Receptores de Hialuronatos/genética , Receptores de Hialuronatos/metabolismo , Camundongos , Camundongos Nus , Camundongos Transgênicos , Receptor Notch1/genética , Receptor Notch3/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo
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