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1.
Int J Mol Sci ; 22(24)2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34948207

RESUMO

In minimal change nephrotic syndrome, podocyte vesicle transport is enhanced. Adenomatous polyposis coli (APC) anchors microtubules to cell membranes and plays an important role in vesicle transport. To clarify the role of APC in vesicle transport in podocytes, nephrotic syndrome was induced by puromycin amino nucleoside (PAN) injection in mice expressing APC1638T lacking the C-terminal of microtubule-binding site (APC1638T mouse); this was examined in renal tissue changes. The kidney size and glomerular area of APC1638T mice were reduced (p = 0.014); however, the number of podocytes was same between wild-type (WT) mice and APC1638T mice. The ultrastructure of podocyte foot process was normal by electron microscopy. When nephrotic syndrome was induced, the kidneys of WT+PAN mice became swollen with many hyaline casts, whereas these changes were inhibited in the kidneys of APC1638T+PAN mice. Electron microscopy showed foot process effacement in both groups; however, APC1638T+PAN mice had fewer vesicles in the basal area of podocytes than WT+PAN mice. Cytoplasmic dynein-1, a motor protein for vesicle transport, and α-tubulin were significantly reduced in APC1638T+PAN mice associated with suppressed urinary albumin excretion compared to WT+PAN mice. In conclusion, APC1638T mice showed reduced albuminuria associated with suppressed podocyte vesicle transport when minimal change nephrotic syndrome was induced.


Assuntos
Polipose Adenomatosa do Colo/patologia , Albuminúria/patologia , Síndrome Nefrótica/patologia , Podócitos/patologia , Transcitose/fisiologia , Polipose Adenomatosa do Colo/metabolismo , Albuminúria/metabolismo , Animais , Modelos Animais de Doenças , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndrome Nefrótica/induzido quimicamente , Síndrome Nefrótica/metabolismo , Podócitos/metabolismo , Puromicina/farmacologia , Puromicina Aminonucleosídeo/farmacologia
2.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575971

RESUMO

BACKGROUND: The tumor immune microenvironment exerts a pivotal influence in tumor initiation and progression. The aim of this study was to analyze the immune context of sporadic and familial adenomatous polyposis (FAP) lesions along the colorectal adenoma-carcinoma sequence (ACS). METHODS: We analyzed immune cell counts (CD3+, CD4+, CD8+, Foxp3+, and CD57+), tumor mutation burden (TMB), MHC-I expression and PD-L1 expression of 59 FAP and 74 sporadic colorectal lesions, encompassing adenomas with low-grade dysplasia (LGD) (30 FAP; 30 sporadic), adenomas with high-grade dysplasia (22 FAP; 30 sporadic), and invasive adenocarcinomas (7 FAP; 14 sporadic). RESULTS: The sporadic colorectal ACS was characterized by (1) a stepwise decrease in immune cell counts, (2) an increase in TMB and MHC-I expression, and (3) a lower PD-L1 expression. In FAP lesions, we observed the same patterns, except for an increase in TMB along the ACS. FAP LGD lesions harbored lower Foxp3+ T cell counts than sporadic LGD lesions. A decrease in PD-L1 expression occurred earlier in FAP lesions compared to sporadic ones. CONCLUSIONS: The colorectal ACS is characterized by a progressive loss of adaptive immune infiltrate and by the establishment of a progressively immune cold microenvironment. These changes do not appear to be related with the loss of immunogenicity of tumor cells, or to the onset of an immunosuppressive tumor microenvironment.


Assuntos
Adenocarcinoma/imunologia , Polipose Adenomatosa do Colo/imunologia , Antígeno B7-H1/genética , Neoplasias Colorretais/imunologia , Microambiente Tumoral/imunologia , Imunidade Adaptativa/imunologia , Adenocarcinoma/complicações , Adenocarcinoma/genética , Adenocarcinoma/patologia , Polipose Adenomatosa do Colo/complicações , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/imunologia , Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígenos CD57/imunologia , Linfócitos T CD8-Positivos/imunologia , Contagem de Células , Linhagem da Célula/imunologia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Fatores de Transcrição Forkhead/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade
3.
Cancer Sci ; 112(11): 4722-4735, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34431598

RESUMO

The Wnt/ß-catenin signaling pathway plays an important role in tissue homeostasis, and its malignant activation is closely related to the occurrence and development of many cancers, especially colorectal cancer with adenomatous polyposis coli (APC) and CTNNB1 mutations. By applying a TCF/lymphoid-enhancing factor (LEF) luciferase reporter system, the high-throughput screening of 18 840 small-molecule compounds was performed. A novel scaffold compound, C644-0303, was identified as a Wnt/ß-catenin signaling inhibitor and exhibited antitumor efficacy. It inhibited both constitutive and ligand activated Wnt signals and its downstream gene expression. Functional studies showed that C644-0303 causes cell cycle arrest, induces apoptosis, and inhibits cancer cell migration. Moreover, transcription factor array indicated that C644-0303 could suppress various tumor-promoting transcription factor activities in addition to Wnt/ß-catenin. Finally, C644-0303 suppressed tumor spheroidization in a 3-dimensional cell culture model and inhibited xenograft tumor growth in mice. In conclusion, we report a novel structural small molecular inhibitor targeting the Wnt/ß-catenin signaling pathway that has therapeutic potential for colorectal cancer treatment.


Assuntos
Polipose Adenomatosa do Colo/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Via de Sinalização Wnt/efeitos dos fármacos , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Descoberta de Drogas , Feminino , Células HCT116 , Células HT29 , Humanos , Luciferases , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia de Alvo Molecular/métodos , Esferoides Celulares/efeitos dos fármacos , Fatores de Transcrição TCF , Fatores de Transcrição/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genética
4.
Am J Surg Pathol ; 45(12): 1626-1632, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34232600

RESUMO

Familial adenomatous polyposis (FAP) is an inherited cancer predisposition syndrome associated with numerous gastrointestinal tract adenomatous polyps, as well as gastric fundic gland polyps and pyloric gland adenomas in the upper gastrointestinal tract. While colonic FAP-associated traditional serrated adenomas (TSAs) have been reported in a few studies, small bowel FAP-associated adenomas with TSA morphology have not been characterized. This study describes the clinicopathologic and molecular findings of this type of adenoma in the small bowel of patients with FAP. We reviewed small bowel adenomas in 45 consecutive FAP patients to identify adenomas with zones showing slit-like serrations, cells with eosinophilic cytoplasm, ectopic crypt formation, and vesicular nuclei. Sporadic small bowel adenomas from 51 consecutive patients were also reviewed for adenomas with the same features. Of the 177 polyps from 45 FAP patients and 60 polyps from 51 nonsyndromic patients, 18 TSAs from 9 FAP patients (20%) and 10 TSAs from the sporadic group (19.6%) were identified. FAP patients presented at a younger age than nonsyndromic patients (median: 43 vs. 66; P=0.0048). FAP-associated TSAs were asymptomatic and smaller than sporadic TSAs (median size: 0.6 vs. 2.5 cm; P=0.00006). Immunostaining for ß-catenin and testing for BRAF and KRAS mutations were performed in a subset of the cohort. Nuclear ß-catenin was seen in 1 FAP-associated TSA and 3 nonsyndromic TSAs. All TSAs (FAP-associated and nonsyndromic) showed wild-type BRAF, while KRAS mutations were identified only in the nonsyndromic setting. In summary, small bowel FAP-associated and sporadic TSAs share a similar morphology, and the BRAF-serrated pathway does not contribute to their pathogenesis.


Assuntos
Polipose Adenomatosa do Colo , Biomarcadores Tumorais/genética , Intestino Delgado/patologia , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Polipose Adenomatosa do Colo/química , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Feminino , Predisposição Genética para Doença , Humanos , Intestino Delgado/química , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Adulto Jovem , beta Catenina/análise
5.
Am J Surg Pathol ; 45(12): 1694-1702, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34138799

RESUMO

Nonampullary duodenal adenomas (NADAs) develop sporadically or in the setting of a hereditary syndrome such as familial adenomatous polyposis (FAP). Although they are thought to progress into duodenal adenocarcinomas via an adenoma to carcinoma sequence similar to colorectal cancer, limited data suggested that they may be biologically dissimilar to colorectal adenomas. The clinicopathologic features of 71 patients diagnosed with NADAs (37 FAP and 34 sporadic) were analyzed. From the 71 patients, 89 NADA biopsies (42 FAP and 47 sporadic) were evaluated by DNA flow cytometry. Eighty-two samples showed low-grade dysplasia, and 7 demonstrated high-grade dysplasia (HGD). Twenty-one low-grade adenomas of the ileal pouch (n=19) and jejunum (n=2) from 15 FAP patients who underwent total proctocolectomy were also analyzed by DNA flow cytometry. The FAP patients were more likely to be younger (mean: 28 y) and have multifocal disease (92%) than the sporadic patients (66 y and 24%, respectively) (P<0.001). Most NADAs presented as polypoid lesions (87%) in the duodenal bulb and/or second portion of the duodenum (94%). Sporadic NADAs (mean: 2.4 cm) were significantly larger than FAP-related NADAs (1.3 cm) (P=0.005). Three (4%) patients (2 sporadic and 1 FAP) had high-grade NADAs at the first endoscopy, while the remaining 68 (96%) patients had low-grade dysplasia. Two additional sporadic and 1 FAP patients developed HGD on follow-up. Although the overall detection rate of advanced neoplasia (either HGD or adenocarcinoma) was similar between the FAP (n=5; 14%) and sporadic groups (n=4; 12%) (P=1.000), 3 FAP patients (all with Spigelman stage III to IV) developed adenocarcinoma in the duodenum (n=2) or in the ileal pouch (n=1) within a mean follow-up time of 76 months, while no adenocarcinoma was found in the sporadic group. Of the 37 FAP patients, 29 (78%) had a history of total proctocolectomy, and 15 (52%) developed low-grade adenomas in the ileal pouch with (n=2) or without (n=13) jejunal involvement (vs. 0% in the sporadic patients, P<0.001). All 15 patients had ≥Spigelman stage II. Aneuploidy was detected in only 1 (1%) sporadic NADA with HGD, whereas the remaining 109 duodenal, ileal pouch, and jejunal adenomas showed normal DNA content. The overall 3-, 9-, and 15-year detection rates of adenocarcinoma (in the duodenum and ileal pouch) in all NADA patients were 1.4%, 7.2%, and 18.8%, respectively. Three-, 9-, and 15-year detection rates of adenocarcinoma in the FAP patients were 2.7%, 9.7%, and 22.6%, respectively, while these rates remained at 0% in the sporadic patients. In conclusion, FAP-related NADAs have distinct clinicopathologic features compared with their sporadic counterpart. However, the vast majority of both FAP-related and sporadic NADAs (99%) lack the DNA content abnormality that is characteristic of the typical adenoma-carcinoma sequence involved in other gastrointestinal carcinogenesis. Although adenocarcinoma is more likely to develop in FAP patients with a high adenoma burden, probably due to the higher likelihood that some advanced lesions are missed endoscopically, FAP-related and sporadic NADAs may have a comparable risk of developing advanced neoplasia on a per-adenoma basis.


Assuntos
Adenocarcinoma/genética , Polipose Adenomatosa do Colo/genética , Aneuploidia , DNA de Neoplasias/genética , Neoplasias Duodenais/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Polipose Adenomatosa do Colo/patologia , Polipose Adenomatosa do Colo/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Criança , Progressão da Doença , Neoplasias Duodenais/patologia , Neoplasias Duodenais/cirurgia , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Medição de Risco , Fatores de Risco , Adulto Jovem
6.
Clin Transl Gastroenterol ; 12(5): e00353, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33999013

RESUMO

INTRODUCTION: Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer (CRC) syndrome characterized by accelerated adenoma development due to inherited (or de novo) mutations in the APC regulator of WNT signaling pathway (APC) gene. The mechanism underlying this accelerated polyp development in subjects with FAP has not been defined. Given that LGR5+ stem cells drive crypt cell proliferation, we hypothesized that FAP crypts would demonstrate aberrant leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) staining patterns. METHODS: Biopsies were taken from 11 healthy subjects, 7 subjects with Lynch syndrome, 4 subjects with FAP, and 1 subject with MUTYH-associated polyposis syndrome during routine screening or surveillance colonoscopy. Crypt staining was evaluated by immunohistochemistry of paraffin-embedded tissue sections. Stem cell numbers were estimated by immunofluorescence staining of isolated crypts using antibodies against LGR5 and other proteins. RESULTS: Subjects with FAP exhibited a greater number of LGR5+ stem cells in their crypts than healthy subjects and subjects with Lynch syndrome and MUTYH-associated polyposis syndrome. Most crypts of subjects with FAP harbored LGR5+ cells located above the lower third of the crypts. DISCUSSION: These findings support a model in which inactivation of one copy of APC leads to increased numbers of LGR5+ stem cells, many of which are ectopic, in colon crypts of subjects with FAP. Overabundant and ectopic LGR5+ stem cells could lead to an expanded proliferative zone of dividing cells more likely to develop mutations that would contribute to the accelerated adenoma development observed in FAP.


Assuntos
Polipose Adenomatosa do Colo/patologia , Colo/patologia , Receptores Acoplados a Proteínas G/análise , Células-Tronco/patologia , Adulto , Idoso , Biópsia , Estudos de Casos e Controles , Proliferação de Células , Neoplasias Colorretais Hereditárias sem Polipose/patologia , DNA Glicosilases/análise , Feminino , Imunofluorescência , Humanos , Imuno-Histoquímica , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Adulto Jovem
7.
PLoS One ; 16(5): e0250072, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33945535

RESUMO

Circulating microRNAs (miRNAs) are considered promising biomarkers for diagnosis, prognosis, and treatment efficacy of diseases. However, usefulness of circulating miRNAs as biomarkers for hereditary gastrointestinal diseases have not been confirmed yet. We explored circulating miRNAs specific for patients with familial adenomatous polyposis (FAP) as a representative hereditary gastrointestinal disease. Next-generation sequencing (NGS) indicated that plasma miR-143-3p, miR-183-5p, and miR-885-5p were candidate biomarkers for five FAP patients compared to three healthy donors due to moderate copy number and significant difference. MiR-16-5p was considered as an internal control due to minimum difference in expression across FAP patients and healthy donors. Validation studies by real-time PCR showed that mean ratios of maximum expression and minimum expression were 2.2 for miR-143-3p/miR-16-5p, 3.4 for miR-143-3p/miR-103a-3p, 5.1 for miR-183-5p/miR-16-5p, and 4.9 for miR-885-5p/miR-16-5p by using the samples collected at different time points of eight FAP patients. MiR-143-3p/16-5p was further assessed using specimens from 16 FAP patients and 7 healthy donors. MiR-143-3p was upregulated in FAP patients compared to healthy donors (P = 0.04), but not significantly influenced by clinicopathological features. However, miR-143-3p expression in colonic tumors was rare for upregulation, although there was a significant difference by existence of desmoid tumors. MiR-143-3p transfection significantly inhibited colorectal cancer cell proliferation compared to control microRNA transfection. Our data suggested regulation of miR-143-3p expression differed by samples (plasma or colonic tumors) in most FAP patients. Upregulation of plasma miR-143-3p expression may be helpful for diagnosis of FAP, although suppressive effect on tumorigenesis seemed insufficient in FAP patients.


Assuntos
Polipose Adenomatosa do Colo/sangue , Biomarcadores Tumorais/sangue , MicroRNA Circulante/sangue , MicroRNAs/sangue , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Células CACO-2 , Proliferação de Células , MicroRNA Circulante/genética , MicroRNA Circulante/metabolismo , Feminino , Células HCT116 , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade
8.
Dis Colon Rectum ; 64(7): e391-e394, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33872285

RESUMO

INTRODUCTION: When patients with familial adenomatous polyposis have a severely affected rectum, it is usually assumed that endoscopic control is impossible or unwise. The standard approach is proctectomy with either an end ileostomy or an IPAA. Here we show that application of aggressive, multistage snare polypectomy to this situation can be effective and allow the patient to avoid surgery, at least in the short term. TECHNIQUE: Standard polypectomy using snare excision with coagulation is used, taking 2 or 3 sessions, and beginning with the largest polyps. The procedures are performed with the patient under general anesthesia. Endoscopic mucosal resection technique with fluid injection to lift polyps is not necessary. RESULTS: Complete control of the rectal polyps, sustained for at least 2 years, is possible without functional sequelas. CONCLUSIONS: Patients with familial adenomatous polyposis with severe rectal polyposis can be offered multistage rectal polypectomy and safely avoid proctectomy.


Assuntos
Polipose Adenomatosa do Colo/cirurgia , Pólipos/cirurgia , Protectomia/instrumentação , Proctocolectomia Restauradora/efeitos adversos , Reto/cirurgia , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/patologia , Adulto , Anastomose Cirúrgica/métodos , Neoplasias Colorretais/prevenção & controle , Humanos , Masculino , Pólipos/diagnóstico , Protectomia/classificação , Protectomia/métodos , Proctocolectomia Restauradora/métodos , Neoplasias Retais/patologia , Reto/patologia , Segurança , Resultado do Tratamento , Adulto Jovem
9.
Lancet Gastroenterol Hepatol ; 6(6): 474-481, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33812492

RESUMO

BACKGROUND: The only established treatment for preventing colorectal cancer in patients with familial adenomatous polyposis (FAP) is colectomy, which greatly reduces patient quality of life. Thus, an alternative method is warranted. In this trial, we aimed to clarify the individual and joint effects of low-dose aspirin and mesalazine on the recurrence of colorectal polyps in Japanese patients with FAP. METHODS: This was a randomised, double-blind, placebo-controlled, multicentre trial with a two-by-two factorial design done in 11 centres in Japan. Eligible patients were aged 16-70 years and had a history of more than 100 adenomatous polyps in the large intestine, without a history of colectomy. Before the study, patients underwent endoscopic removal of all colorectal polyps of at least 5·0 mm in diameter. Randomisation was done with a minimisation method with a random component to balance the groups with respect to the adjustment factors of sex, age (<30 years vs ≥30 years), or smoking status at the time of entry. Patients and researchers were masked to the treatment group. There were four groups: aspirin (100 mg per day) plus mesalazine (2 g per day), aspirin (100 mg per day) plus mesalazine placebo, aspirin placebo plus mesalazine (2 g per day), or aspirin placebo plus mesalazine placebo. Treatment was continued until 1 week before 8 month colonoscopy. The primary endpoint was the incidence of colorectal polyps of at least 5·0 mm at 8 months and was assessed in the intention-to-treat population. Safety was assessed in the ITT population. We also did a per-protocol analysis including only patients who took at least 70% of the allocated study drug. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000018736, and is complete. FINDINGS: Between Sept 25, 2015, and March 13, 2017, 104 patients were randomly assigned to receive either aspirin or aspirin placebo (n=52) or mesalazine or mesalazine placebo (n=52). Two patients withdrew from the aspirin plus mesalazine placebo group. 26 (50%) of 52 patients who received no aspirin had colorectal polyps of at least 5·0 mm at 8 months, as did 15 (30%) of the 50 patients who received any aspirin, 21 (42%) of the 50 patients who received no mesalazine, and 20 (38%) of the 52 patients who received any mesalazine. The adjusted odds ratio for polyp recurrence was 0·37 (95% CI 0·16-0·86) in the patients who received any aspirin and 0·87 (95% CI 0·38-2·00) in any who received mesalazine. The most common adverse events were grade 1-2 upper gastrointestinal symptoms in three (12%) of 26 patients who received aspirin plus mesalazine, one (4%) of 24 patients who received aspirin plus mesalazine placebo, and one (4%) of 26 patients who received mesalazine plus aspirin placebo. There was one grade 4 event in the mesalazine plus aspirin placebo group, but not related to the treatment. INTERPRETATION: Low-dose aspirin safely suppressed the recurrence of colorectal polyps larger than 5·0 mm in patients with FAP. These results suggest an effect of low-dose aspirin for FAP and could be an alternative method for preventing colorectal cancer in FAP. FUNDING: Japan Agency for Medical Research and Development.


Assuntos
Polipose Adenomatosa do Colo/tratamento farmacológico , Aspirina/uso terapêutico , Quimioprevenção/métodos , Neoplasias Colorretais/prevenção & controle , Mesalamina/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Estudos de Casos e Controles , Colectomia/métodos , Colectomia/estatística & dados numéricos , Colonoscopia/métodos , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/cirurgia , Método Duplo-Cego , Quimioterapia Combinada/métodos , Humanos , Incidência , Japão/epidemiologia , Mesalamina/administração & dosagem , Mesalamina/efeitos adversos , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/prevenção & controle , Avaliação de Resultados em Cuidados de Saúde , Efeito Placebo , Qualidade de Vida
10.
PLoS One ; 16(4): e0249238, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33901189

RESUMO

The crypt-villus axis represents the essential unit of the small intestine, which integrity and functions are fundamental to assure tissue and whole-body homeostasis. Disruption of pathways regulating the fine balance between proliferation and differentiation results in diseases development. Nowadays, it is well established that microRNAs (miRNAs) play a crucial role in the homeostasis maintenance and perturbation of their levels may promote tumor development. Here, by using microarray technology, we analysed the miRNAs differentially expressed between the crypt and the villus in mice ileum. The emerged miRNAs were further validated by Real Time qPCR in mouse model (ApcMin/+), human cell lines and human tissue samples (FAP) of colorectal cancer (CRC). Our results indicated that miRNAs more expressed in the villi compartment are negatively regulated in tumor specimens, thus suggesting a close association between these microRNAs and the differentiation process. Particularly, from our analysis let-7e appeared to be a promising target for possible future therapies and a valuable marker for tumor staging, being upregulated in differentiated cells and downregulated in early-stage colonic adenoma samples.


Assuntos
Adenoma/patologia , Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Neoplasias Colorretais/patologia , MicroRNAs/metabolismo , Adenoma/genética , Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Regulação para Baixo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo
11.
Sci Rep ; 11(1): 9143, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33911117

RESUMO

Mandibular cortical and trabecular bone abnormalities in patients with familial adenomatous polyposis (FAP) were evaluated using dental panoramic radiographs (DPR) radiomorphometric indices and fractal dimension (FD). Sixty DPRs from 15 FAP patients and 45 healthy controls were evaluated. FAP group was composed of 33.3% females and 66.6% males, agemean = 37.2 years (SD 15.79). The non-FAP group was paired by gender and sex. The parameters analyzed were: FD of the trabecular bone in four regions of interest (ROI), mandibular cortical index (MCI) and width (MCW). FD values were lower for the FAP group. Statistically significance differences were shown by ROI 2 and 3 anteriorly to the mental foramen bilaterally, p = 0.001, and p = 0.006. The ROI 1 and 4, at the mandibular angle trabeculae, indicated statistical significances on the right side (p = 0.036) and no differences on the left side (p = 0.091). There was no significant difference in MCI and MCW when the groups were compared, MCW (L) p = 0.247, and MCW (R) p = 0.070. Fractal values of FAP patients' mandibular trabecular bone were lower than healthy controls. The radiomorphometric indices MCI and MCW were not useful for analyzing the cortical bone pattern. Therefore, FD is a promising tool for detection of abnormal bone structure in DPRs and for supporting the appropriate referral of FAP patients.


Assuntos
Polipose Adenomatosa do Colo/patologia , Osso Esponjoso/fisiologia , Osso Cortical/fisiologia , Adulto , Estudos de Casos e Controles , Feminino , Fractais , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia Panorâmica
12.
Am J Pathol ; 191(5): 930-946, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33545120

RESUMO

Hepatocellular carcinoma (HCC) and hepatoblastoma are the major types of primary liver cancer in adulthood and childhood, respectively. Wnt/ß-catenin signaling deregulation is one of the most frequent genetic events in hepatocarcinogenesis. APC regulator of WNT signaling pathway (APC) encodes an inhibitor of the Wnt cascade and acts as a tumor suppressor. Germline defects of the APC gene lead to familial adenomatous polyposis, and its somatic mutations occur in multiple tumor types. However, the contribution of APC in hepatocarcinogenesis remains unclear. Therefore, APC mutations and expression patterns were examined in human HCC and hepatoblastoma samples. Whether loss of Apc alone or in cooperation with other oncogenes triggers liver tumor development in vivo was also investigated. sgApc alone could not drive liver tumor formation, but synergized with activated oncogenes (YapS127A, TazS89A, and c-Met) to induce hepatocarcinogenesis. Mechanistically, Apc deletion induced the activation of ß-catenin and its downstream targets in mouse liver tumors. Furthermore, Ctnnb1 ablation or TCF4-mediated transcription blockade completely prevented liver tumor formation, indicating the requirement of a functional ß-catenin pathway for loss of Apc-driven hepatocarcinogenesis. This study shows that a subset of HCC patients with loss-of-function APC mutations might benefit from therapeutic strategies targeting the Wnt/ß-catenin pathway.


Assuntos
Proteína da Polipose Adenomatosa do Colo/metabolismo , Polipose Adenomatosa do Colo/genética , Carcinoma Hepatocelular/genética , Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Via de Sinalização Wnt/genética , Polipose Adenomatosa do Colo/patologia , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Carcinogênese , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Hepatoblastoma/patologia , Humanos , Fígado/patologia , Neoplasias Hepáticas/patologia , Mutação com Perda de Função , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oncogenes
13.
Eur J Med Chem ; 212: 113149, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33445154

RESUMO

Colorectal cancer (CRC) is one of the major causes of carcinogenic mortality in numbers only after lung and breast cancers. The mutations in adenomatous polyposis coli (APC) gene leads to formation of colorectal polyps in the colonic region and which develop as a malignant tumour upon coalition with patient related risk factors. The protein-protein interaction (PPI) of APC with Asef (A Rac specific guanine nucleotide exchange factor) overwhelms the patient's conditions by rapidly spreading in the entire colorectal region. Most mutations in APC gene occur in mutated cluster region (MCR), where it specifically binds with the cytosolic ß-catenin to regulate the Wnt signalling pathway required for CRC cell adhesion, invasion, progression, differentiation and stemness in initial cell cycle phages. The current broad spectrum perspective is attempted to elaborate the sources of identification, development of selective APC inhibitors by targeting emopamil-binding protein (EBP) & dehydrocholesterol reductase-7 & 24 (DHCR-7 & 24); APC-Asef, ß-catenin/APC, Wnt/ß-catenin, ß-catenin/TCF4 PPI inhibitors with other vital Wnt signal cellular proteins and APC/Pol-ß interface of colorectal cancer. In this context, this perspective would serve as a platform for design of new medicinal agents by targeting cellular essential components which could accelerate anti-colorectal potential candidates.


Assuntos
Polipose Adenomatosa do Colo/tratamento farmacológico , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Polipose Adenomatosa do Colo/metabolismo , Polipose Adenomatosa do Colo/patologia , Antineoplásicos/química , Química Farmacêutica , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Estrutura Molecular , Via de Sinalização Wnt/efeitos dos fármacos
14.
Carcinogenesis ; 42(1): 70-79, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32445578

RESUMO

Many hereditary disorders in dogs have equivalents in humans and thus attract attention as natural animal models. Breed predisposition to certain diseases often provides promising clues to explore novel hereditary disorders in dogs. Recently, cases of gastrointestinal (GI) polyps in Jack Russell Terriers (JRTs) have increased in Japan. In 21 affected JRTs, polyps were found in either or both the stomach and colorectum, with a predilection for the gastric antrum and rectum. Multiple polyps were found in 13 of 21 examined dogs, including 5 dogs with both gastric and colorectal polyps. Some dogs were found to have GI polyps at an early age, with the youngest case being 2.3 years old. Histopathologically, 43 of 46 GI polyps (93.5%) were diagnosed as adenomas or adenocarcinomas. Immunohistochemical analysis revealed cytoplasmic and nuclear accumulation of ß-catenin in the tumor cells. As in the case of human patients with familial adenomatous polyposis, all examined JRTs with GI polyps (n = 21) harbored the identical heterozygous germline APC mutations, represented by a 2-bp substitution (c.[462A>T; 463A>T]). The latter substitution was a non-sense mutation (p.K155X) resulting in a truncated APC protein, thus suggesting a strong association with this cancer-prone disorder. Somatic mutation and loss of the wild-type APC allele were detected in the GI tumors of JRTs, suggesting that biallelic APC inactivation was involved in tumor development. This study demonstrated that despite differences in the disease conditions between human and dog diseases, germline APC mutation confers a predisposition to GI neoplastic polyps in both dogs and humans.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/veterinária , Doenças do Cão/genética , Cães/genética , Predisposição Genética para Doença , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Animais , Feminino , Mutação em Linhagem Germinativa , Masculino
15.
Dig Dis ; 39(1): 25-32, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32450557

RESUMO

INTRODUCTION: There are gaps in the literature regarding outcome of multiple polyps and dilemmas in the management issues in polyposis syndromes in children. OBJECTIVE: We aimed to study the clinical behaviour of gastrointestinal (GI) polyps with emphasis on therapeutic outcomes of polyposis syndrome. METHODS: Proven cases of GI polyp(s) on endoscopy were classified as single polyp, multiple polyps, and polyposis syndrome. Complex presentation was defined as 1 or more of the following: severe anaemia, anasarca, intussusception, rectal mucosal prolapse, and diarrhoea. A clinico-endoscopic criterion was applied in polyposis syndrome patients for the decision of surgery versus endoscopic therapy with surveillance. RESULTS: Of total 240 patients, there were no significant differences between single (52.5%, n = 126) versus multiple polyps (27.5%, n = 66) with respect to age, symptoms, histology, and recurrence. Polyposis syndrome (20%, n = 48) presented with complex symptoms (50%), higher family history, significantly lower haemoglobin, total protein, and albumin as compared to single and multiple polyps (p < 0.01). Nineteen polyposis patients with favourable clinico-endoscopic criteria were endoscopically eradicated for polyps in 3 (1-4) sessions with sustenance of laboratory parameters at 1 year and 30% symptomatic recurrence at follow-up of 23.5 (7-40) months. There were no major endoscopic complications. Nineteen patients required proctocolectomy with improvement in laboratory parameters 6 months post-surgery. CONCLUSIONS: Multiple polyps behave similar to single polyps in children. A clinico-endoscopic criterion may guide for optimal management of polyposis syndrome. Colectomy may be effectively deferred in a large proportion of polyposis syndrome patients if maintained on an endoscopic protocol.


Assuntos
Polipose Adenomatosa do Colo/cirurgia , Endoscopia , Pólipos/cirurgia , Polipose Adenomatosa do Colo/patologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pólipos/patologia , Resultado do Tratamento
16.
Carcinogenesis ; 42(1): 148-158, 2021 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32710739

RESUMO

Artesunate (ART) is a clinically approved antimalarial drug and was revealed as a candidate of colorectal cancer chemopreventive agents in our drug screening system. Here, we aimed to understand the suppressive effects of ART on intestinal tumorigenesis. In vitro, ART reduced T-cell factor/lymphoid enhancer factor (TCF/LEF) promoter transcriptional activity. In vivo, ART inhibited intestinal polyp development. We found that ART reduces TCF1/TCF7 nuclear translocation by binding the Ras-related nuclear protein (RAN), suggesting that ART inhibits TCF/LEF transcriptional factor nuclear translocation by binding to RAN, thereby inhibiting Wnt signaling. Our results provide a novel mechanism through which artesunate inhibits intestinal tumorigenesis.


Assuntos
Polipose Adenomatosa do Colo/prevenção & controle , Artesunato/farmacologia , Carcinogênese/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Artesunato/uso terapêutico , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Técnicas de Silenciamento de Genes , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Transgênicos , Mutação , Regiões Promotoras Genéticas , Fator 1 de Transcrição de Linfócitos T/genética , Fator 1 de Transcrição de Linfócitos T/metabolismo , Ativação Transcricional/efeitos dos fármacos , Via de Sinalização Wnt/genética , Proteína ran de Ligação ao GTP/antagonistas & inibidores , Proteína ran de Ligação ao GTP/genética , Proteína ran de Ligação ao GTP/metabolismo
18.
Cell Death Dis ; 11(12): 1045, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33303756

RESUMO

Eukaryotic Translation Initiation Factor 5A (EIF5A) is a translation factor regulated by hypusination, a unique posttranslational modification catalyzed by deoxyhypusine synthetase (DHPS) and deoxyhypusine hydroxylase (DOHH) starting from the polyamine spermidine. Emerging data are showing that hypusinated EIF5A regulates key cellular processes such as autophagy, senescence, polyamine homeostasis, energy metabolism, and plays a role in cancer. However, the effects of EIF5A inhibition in preclinical cancer models, the mechanism of action, and specific translational targets are still poorly understood. We show here that hypusinated EIF5A promotes growth of colorectal cancer (CRC) cells by directly regulating MYC biosynthesis at specific pausing motifs. Inhibition of EIF5A hypusination with the DHPS inhibitor GC7 or through lentiviral-mediated knockdown of DHPS or EIF5A reduces the growth of various CRC cells. Multiplex gene expression analysis reveals that inhibition of hypusination impairs the expression of transcripts regulated by MYC, suggesting the involvement of this oncogene in the observed effect. Indeed, we demonstrate that EIF5A regulates MYC elongation without affecting its mRNA content or protein stability, by alleviating ribosome stalling at five distinct pausing motifs in MYC CDS. Of note, we show that blockade of the hypusination axis elicits a remarkable growth inhibitory effect in preclinical models of CRC and significantly reduces the size of polyps in APCMin/+ mice, a model of human familial adenomatous polyposis (FAP). Together, these data illustrate an unprecedented mechanism, whereby the tumor-promoting properties of hypusinated EIF5A are linked to its ability to regulate MYC elongation and provide a rationale for the use of DHPS/EIF5A inhibitors in CRC therapy.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Lisina/análogos & derivados , Fatores de Iniciação de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas de Ligação a RNA/metabolismo , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias Colorretais/genética , Regulação para Baixo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Lisina/metabolismo , Camundongos Nus , Fases de Leitura Aberta/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/antagonistas & inibidores , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Fatores de Iniciação de Peptídeos/química , Peptídeos/metabolismo , Poliaminas/metabolismo , Biossíntese de Proteínas , Proteínas de Ligação a RNA/química
19.
Exp Physiol ; 105(12): 2154-2167, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33150708

RESUMO

NEW FINDINGS: What is the central question of this study? What is the localization and distribution pattern of adenomatous polyposis coli (APC) in intestinal epithelial cells? Does this distribution change in different regions of the colon or in the condition of inflammation? What is the main finding and its importance? Colonic epithelia from mice and humans contain a subset of goblet cells displaying high APC levels. The number of APChigh goblet cells increases in inflamed tissue, which also displays increased GRP78, indicating potential stress from mucin production. In cultured human colon cells, expression of interleukin 1 pathway components (inducers of MUC2 expression) is reduced upon APC depletion raising the potential for APC participation in an inflammatory response. ABSTRACT: Adenomatous polyposis coli (APC) serves as a gatekeeper of intestinal homeostasis by promoting cellular differentiation and maintaining crypt architecture. Although appreciated as a critical colon tumour suppressor, roles for APC in disease states such as inflammation have yet to be fully delineated. This study aimed to characterize the localization of APC protein in gastrointestinal tissues from human patients with active inflammatory bowel disease and mice with dextran sodium sulfate (DSS)-induced colitis. Fluorescence immunohistochemistry revealed a subset of goblet cells with elevated Apc staining intensity in the small intestines and proximal/medial colons of mice. Upon induction of colitis with DSS, these 'APChigh ' goblet cells remained in the proximal and medial colon, but now were also observed in the distal colon. This phenotype was recapitulated in humans, with APChigh goblet cells observed only in the descending colons of patients with active ulcerative colitis. In cultured human colon cells derived from normal tissue, APC depletion reduced expression of mRNAs encoding the interleukin 1 (IL1) signalling pathway components IL1ß and interleukin-1 receptor (IL1R), known regulators of Muc2 expression. Treating cancer cells lacking wild-type APC with IL1ß, or induction of full-length APC in these cells led to increases in IL1R and MUC2 expression. Combining IL1ß treatment with APC induction led to an increase of MUC2 expression greater than expected for additive affects, suggesting that APC sensitizes cells to IL1 signalling. These findings suggest that APC has novel roles in maintaining proper goblet cell function, thus providing further evidence for APC as an important factor in intestinal tissue homeostasis and disease.


Assuntos
Polipose Adenomatosa do Colo/patologia , Colo/patologia , Células Caliciformes/patologia , Inflamação/patologia , Polipose Adenomatosa do Colo/metabolismo , Animais , Células Cultivadas , Colo/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Células Caliciformes/metabolismo , Humanos , Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mucina-2/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Transdução de Sinais/fisiologia
20.
Int J Mol Sci ; 21(22)2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33228212

RESUMO

To discover novel high-penetrant risk loci for hereditary colorectal cancer (hCRC) and polyposis syndromes many whole-exome and whole-genome sequencing (WES/WGS) studies have been performed. Remarkably, these studies resulted in only a few novel high-penetrant risk genes. Given this observation, the possibility and strategy to identify high-penetrant risk genes for hCRC and polyposis needs reconsideration. Therefore, we reviewed the study design of WES/WGS-based hCRC and polyposis gene discovery studies (n = 37) and provide recommendations to optimize discovery and validation strategies. The group of genetically unresolved patients is phenotypically heterogeneous, and likely composed of distinct molecular subtypes. This knowledge advocates for the screening of a homogeneous, stringently preselected discovery cohort and obtaining multi-level evidence for variant pathogenicity. This evidence can be collected by characterizing the molecular landscape of tumors from individuals with the same affected gene or by functional validation in cell-based models. Together, the combined approach of a phenotype-driven, tumor-based candidate gene search might elucidate the potential contribution of novel genetic predispositions in genetically unresolved hCRC and polyposis.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Loci Gênicos , PTEN Fosfo-Hidrolase/genética , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/metabolismo , Polipose Adenomatosa do Colo/patologia , Proteína da Polipose Adenomatosa do Colo/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Exoma , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Proteína 1 Homóloga a MutL/genética , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Penetrância , Fenótipo , Sequenciamento Completo do Exoma
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