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1.
Nutrients ; 13(6)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199311

RESUMO

Despite multimodal treatment strategies, clinical outcomes of advanced stage colorectal cancer (CRC) patients remain poor. Neoadjuvant/adjuvant chemotherapy efficacy is limited due to chemoresistance, toxicity, and negative side effects. Since both melatonin and glycine have anti-cancer activities without relevant side effects, this study was designed to investigate their combined effects in experimental CRC liver metastases. CRC metastasis with CC531 cells were induced in male Wistar rats. Melatonin and glycine alone or their combination were supplemented for 14 days (n = 100). Blood parameters, a micro-computed tomography scan (tumor volume over time), and immunohistochemistry for Ki67 and CD31 expression in tumor tissue were compared between groups. Melatonin and glycine alone significantly reduced the tumor volume by 63.2% (p = 0.002) and 43% (p = 0.044) over time, respectively, while tumor volume increased by 8.7% in the controls. Moreover, treatment with melatonin and glycine alone reduced the tumor proliferation index. Most interestingly, the combination therapy did not have any influence on the above-mentioned tumor parameters. The leukocyte count was significantly increased with melatonin at the end of the experiment (p = 0.012) which was due to a high lymphocytes count. Tumor microvascular density was significantly reduced in all treatment groups. The results of this study suggest an inhibitory function for melatonin and glycine alone in the case of CRC liver metastasis growth by acting as natural antiangiogenic molecules, followed by angiogenesis-dependent cancer proliferation and immunomodulation.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Neoplasias Colorretais/patologia , Glicina/administração & dosagem , Neoplasias Hepáticas/dietoterapia , Neoplasias Hepáticas/secundário , Melatonina/administração & dosagem , Animais , Linhagem Celular Tumoral , Dieta , Contagem de Leucócitos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Masculino , Microvasos , Transplante de Neoplasias , Ratos , Ratos Wistar , Carga Tumoral
2.
Pathol Oncol Res ; 27: 612969, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34257580

RESUMO

The epidemic of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in the world pose a global health emergency. Cancer has been identified as a risk factor for the novel Coronavirus disease 2019 (COVID-19). The ACE2 and TMPRSS2 have been implicated in SARS-CoV-2 infection for mediating viral entry into the host cell. However, a systematic analysis of aberrant expression of ACE2 and TMPRSS2 was not yet reported in multiple human cancers. Here, we analyzed gene expression of ACE2 and TMPRSS2 across 31 types of tumors. Notably, overexpression of ACE2 and TMPRSS2 have been observed in colorectal cancer including colon adenocarcinoma (COAD), and rectum adenocarcinoma (READ). In addition, the colorectal tumors with upregulated gene expressing presented with decreased DNA methylation levels. DNA methylation might be one of the reasons for abnormal expression of ACE2 and TMPRSS2. Conclusively, colorectal cancer was the only cancer with the upregulated expression of ACE2 and TMPRSS2. More care of colorectal cancer patients is needed in multiple cancers affected by the COVID-19 outbreak.


Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Neoplasias Colorretais , Serina Endopeptidases , Enzima de Conversão de Angiotensina 2/análise , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Metilação de DNA/genética , Bases de Dados Genéticas , Humanos , SARS-CoV-2 , Serina Endopeptidases/análise , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Transcriptoma/genética
3.
Int J Mol Sci ; 22(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200314

RESUMO

The influence of PVT1 and MALAT1 variants on colorectal cancer (CRC) susceptibility and their impact on PVT1/miRNA-186/epithelial-mesenchymal transition (EMT) and MALAT1/miRNA-101/EMT axes in CRC are unknown. We investigated the influence of PVT1 rs13255292 and MALAT1 rs3200401 on the risk of CRC and adenomatous polyps (AP), their impact on the long noncoding RNAs PVT1 and MALAT1 expression and their target miRNA-186, miRNA-101/E-cadherin pathways, along with their potential as early CRC biomarkers. Overall, 280 individuals were recruited: 140 patients with CRC, 40 patients with AP, and 100 healthy volunteers. Genotyping and serum expression profiles were assessed using qPCR. The EMT biomarker, E-cadherin, was measured by ELISA. rs3200401 was associated with increased CRC risk, whereas rs13255292 was protective. Serum PVT1 and MALAT1 were upregulated in CRC and AP patients versus healthy controls, whereas, miRNA-186, miRNA-101 and E-cadherin were downregulated in CRC versus non-CRC groups. MALAT1 showed superior diagnostic potential for CRC and predicted CRC risk among non-CRC groups in the multivariate logistic analysis. PVT1, MALAT1, miRNA-186 and miRNA-101 levels were correlated with E-cadherin, tumor stage, lymph node and distant metastasis. E-cadherin was lost in metastatic vs. non-metastatic CRC. rs3200401CC genotype carriers showed higher E-cadherin levels than CC + CT carriers. rs3200401 was correlated with lymph node status. For the first time, rs13255292 and rs3200401 are potential genetic CRC predisposition markers, with rs3200401 possibly impacting the EMT process. Serum PVT1, MALAT1, miRNA-186 and miRNA-101 are novel non-invasive diagnostic biomarkers that could improve the clinical outcome of CRC.


Assuntos
Adenocarcinoma/secundário , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal , MicroRNAs/genética , RNA Longo não Codificante/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Genótipo , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Transcriptoma , Células Tumorais Cultivadas , Adulto Jovem
4.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200790

RESUMO

Exosomes released from tumor cells are instrumental in shaping the local tumor microenvironment to allow cancer progression. Recently, it has been shown that tumor exosomes carry large fragments of dsDNA, which may reflect the mutational status of parental cells. Although it has been described that a stressful microenvironment can influence exosomal cargo, the effects on DNA packing and its transfer into recipient cells have yet to be investigated. Here, we report that exosomes derived from SW480 (human colorectal adenocarcinoma cell line) cells can carry dsDNA fragments containing the entire coding sequence of both TP53 and KRAS genes, harboring the SW480-related TP53 c.818G > A and KRAS c.35G > T typical mutations. We also report the following: that cell stimulation with lipopolysaccharides (LPS) promotes the selective packaging of the TP53 gene, but not the KRAS gene; that exosomes secreted by SW480 cells efficiently transfer the mutated sequences into normal CCD841-CoN colon epithelial and THLE-2 hepatic cells; that this mechanism is more efficient when the cells had been previously incubated with pro-inflammatory cytokines; that the TP53 gene appears actively transcribed in both recipient cells; and that mutated mRNA levels are not influenced by cytokine treatment. Our data strongly suggest that pro-inflammatory stimulation promotes the horizontal transfer of an oncogene by exosomes, although this remains a rare event. Further studies are needed to assess the impact of the oncogenic transfer by exosomes in malignant transformation and its role in tumor progression.


Assuntos
Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/patologia , Exossomos/genética , Mediadores da Inflamação/imunologia , Mutação , Microambiente Tumoral/imunologia , Proteína Supressora de Tumor p53/genética , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/genética , Humanos , Células Tumorais Cultivadas
5.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200820

RESUMO

Colorectal carcinoma (CRC) is one of the most frequently diagnosed carcinomas and one of the leading causes of cancer-related death worldwide. Metabolic reprogramming, a hallmark of cancer, is closely related to the initiation and progression of carcinomas, including CRC. Accumulating evidence shows that activation of oncogenic pathways and loss of tumor suppressor genes regulate the metabolic reprogramming that is mainly involved in glycolysis, glutaminolysis, one-carbon metabolism and lipid metabolism. The abnormal metabolic program provides tumor cells with abundant energy, nutrients and redox requirements to support their malignant growth and metastasis, which is accompanied by impaired metabolic flexibility in the tumor microenvironment (TME) and dysbiosis of the gut microbiota. The metabolic crosstalk between the tumor cells, the components of the TME and the intestinal microbiota further facilitates CRC cell proliferation, invasion and metastasis and leads to therapy resistance. Hence, to target the dysregulated tumor metabolism, the TME and the gut microbiota, novel preventive and therapeutic applications are required. In this review, the dysregulation of metabolic programs, molecular pathways, the TME and the intestinal microbiota in CRC is addressed. Possible therapeutic strategies, including metabolic inhibition and immune therapy in CRC, as well as modulation of the aberrant intestinal microbiota, are discussed.


Assuntos
Reprogramação Celular , Neoplasias Colorretais/patologia , Microbioma Gastrointestinal/imunologia , Imunoterapia/métodos , Microambiente Tumoral/imunologia , Animais , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/terapia , Humanos
6.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202548

RESUMO

Colorectal cancer (CRC) is one of the most common cancer in the world. The first line chemotherapeutic agent, 5-fluorouracil (5-FU), plays a predominant role in the clinical treatment of CRC. However, with the wide use of 5-FU, more and more CRC patients have been obtaining drug resistance to 5-FU, which leads to a large amount of treatment failures. One of the effective strategies to overcome this obstacle is to find bioactive natural products from traditional medicine. In our previous work, Sanguisorba officinalis L. was found to exert a strong anti-proliferative activity against 5-FU-senstive/resistant CRC cells. Therefore, several compounds were isolated from this herb and screened for their anti-CRC effects to find promising compounds. Among them, a triterpenoid compound named 3ß-[(α-l-arabinopyranosyl) oxy]-urs-12,18(19)-dien-28-oic acid ß-d-glucopyranosyl ester (AGE), showed strong activity against both 5-FU-senstive and resistant CRC cells. In order to further study the mechanism of AGE on CRC cells, flow cytometer analysis, mitochondrial membrane potential (MMP) measurement, Western blotting, and RT-PCR assays were performed. Results demonstrated that AGE induced cell death by apoptosis pathway and autophagy, and inhibited cell proliferation via cell cycle arrest in G0-G1 phase mediated by Wnt signaling pathway. Therefore, AGE may be a potential bioactive compound for CRC treatment in clinic.


Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluoruracila/farmacologia , Compostos Fitoquímicos , Sanguisorba/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia
7.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202896

RESUMO

The human epidermal growth factor receptor 2 (HER2) is a well-established oncogenic driver and a successful therapeutic target in several malignancies, such as breast and gastric cancers. HER2 alterations, including amplification and somatic mutations, have also been detected in a small but not negligible subset of patients affected by advanced colorectal cancer (aCRC). However, to date, there are no available oncotargets in this malignancy beyond RAS and BRAF that are available. Here we present an overview on the present predictive and prognostic role of HER2 expression in aCRC, as well as on its consequent potential therapeutic implications from preclinical investigations towards ongoing trials testing anti-HER2 agents in aCRC. While HER2's role as a molecular predictive biomarker for anti-EGFR therapies in CRC is recognized, HER2 prognostic value remains controversial. Moreover, thanks to the impressive and growing body of clinical evidence, HER2 is strongly emerging as a new potential actionable oncotarget in aCRC. In conclusion, in the foreseeable future, HER2-targeted therapeutic strategies may integrate the algorithm of aCRC treatment towards an increasingly tailored therapeutic approach to this disease.


Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais/etiologia , Proteínas Proto-Oncogênicas B-raf/genética , Receptor ErbB-2/genética , Proteínas ras/genética , Animais , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Gerenciamento Clínico , Suscetibilidade a Doenças , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Prognóstico , Proteínas Proto-Oncogênicas B-raf/metabolismo , Receptor ErbB-2/metabolismo , Transdução de Sinais , Proteínas ras/metabolismo
8.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34208855

RESUMO

Patients with advanced colorectal cancer (CRC) with distant metastases have a poor prognosis. We evaluated the clinicopathological relevance of GRP94 expression in these cases. The immunohistochemical expression of GRP94 was studied in 189 CRC patients with synchronous (SM; n = 123) and metachronous metastases (MM; n = 66), using tissue microarray; the association between GRP94 expression, outcome, and tumor-infiltrating lymphocytes (TILs) was also evaluated. GRP94 was expressed in 64.6% (122/189) patients with CRC; GRP94 positivity was found in 67.5% and 59.1% patients with SM and MM, respectively. In the SM group, high GRP94 expression was more common in patients with a higher density of CD4+ TILs (p = 0.002), unlike in the MM group. Survival analysis showed that patients with GRP94 positivity had significantly favorable survival (p = 0.030); after multivariate analysis, GRP94 only served as an independent prognostic factor (p = 0.034; hazard ratio, 0.581; 95% confidence interval, 0.351-0.961) in the SM group. GRP94 expression was detected in 49.4% of metastatic sites and showed significant heterogeneity between primary and metastatic lesions (p = 0.012). GRP94 is widely expressed in CRC with distant metastases; its expression was associated with favorable prognosis in the SM group, unlike in the MM group.


Assuntos
Neoplasias Colorretais/patologia , Glicoproteínas de Membrana/metabolismo , Neoplasias Primárias Múltiplas/patologia , Segunda Neoplasia Primária/patologia , Regulação para Cima , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/metabolismo , Segunda Neoplasia Primária/metabolismo , Prognóstico , Análise de Sobrevida , Análise Serial de Tecidos
9.
Aging (Albany NY) ; 13(13): 17349-17369, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226299

RESUMO

miR-144-3p is aberrantly expressed in several types of human cancer and functions as a tumor suppressor by inhibiting metastasis. However, the clinical significance and biological function of miR-144-3p in colorectal adenocarcinoma (CRA) have yet to be elucidated. Here we reported that miR-144-3p expression level was significantly down-regulated in CRA tissues compared with matched noncancerous colorectal mucosae tissues. Low miR-144-3p expression was correlated with adverse clinicopathologic characteristics and poor prognosis of CRA patients. Cox regression analysis showed that low miR-144-3p expression was an independent risk factor for DFS and OS in CRA. In vitro and in vivo assays showed that miR-144-3p significantly inhibited proliferation, migration and invasion of CRA cells. In particular, miR-144-3p could suppress EMT process of CRA cells by regulating the cytoskeleton and EMT markers. Bioinformatics analysis indicated that EMT associated transcription factors ZEB1 and ZEB2 were potential targets of miR-144-3p, and miR-144-3p inhibited ZEB1 and ZEB2 expression and was negatively correlated with their expression in CRA. Finally, we confirmed that ZEB1 and ZEB2 down-regulation collaboratively mediated the inhibitory effect of miR-144-3p on proliferation, invasion and EMT of CRA cells. In conclusion, our study provided evidence that miR-144-3p could inhibit CRA cell proliferation, invasion and EMT by targeting ZEB1/2.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/genética , MicroRNAs/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Mucosa Intestinal/química , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico
10.
Anticancer Res ; 41(8): 3905-3915, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281853

RESUMO

BACKGROUND/AIM: Primary tumor location and RAS and BRAF V600E mutations are predictors of the efficacy of epidermal growth factor receptor (EGFR) inhibitors. However, there are limited reports on their effects on the outcomes of third-line chemotherapy with EGFR inhibitors in metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: We retrospectively collected the clinical data of KRAS exon 2 wild type (WT) mCRC patients treated with EGFR inhibitor monotherapy or EGFR inhibitor plus irinotecan as third-line chemotherapy. The association between primary tumor location, RAS (KRAS exon 3, 4 or NRAS), BRAF V600E, and PIK3CA mutational status, and treatment outcome was evaluated. RESULTS: A total of 72 patients were included in this study. In multivariate analysis, RAS (p=0.004) and BRAF mutations (p=0.00008) were independent factors for shorter PFS. Poor performance status (p=0.01) and BRAF mutation (p=0.00002) were independent factors for shorter OS, whereas primary tumor location and PIK3CA mutation did not influence survival. CONCLUSION: Additional analysis of RAS and BRAF mutations could contribute to the selection of patients who are likely to benefit from third-line EGFR inhibitors, regardless of primary tumor location.


Assuntos
Antineoplásicos/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias Colorretais , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Resultado do Tratamento
11.
Anticancer Res ; 41(7): 3261-3270, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230120

RESUMO

BACKGROUND/AIM: Chronic inflammation generates large quantities of reactive oxygen and nitrogen species that damage DNA. DNA repair is important for cellular viability and genome integrity. MATERIALS AND METHODS: Expression levels of the DNA repair proteins OGG1, XPA, MLH1, PARP1, and XRCC6, which function in base excision repair, nucleotide excision repair, mismatch repair, single-strand break repair and double-strand break repair, respectively, were assessed using immunohistochemistry in ulcerative colitis and sporadic colorectal cancer biopsies. Levels of oxidative/ nitrosative stress biomarkers were also assessed. RESULTS: Ulcerative colitis and colorectal cancer lesions expressed significantly higher levels of all DNA repair proteins and oxidative/ nitrosative stress biomarkers compared to normal colonic mucosa. Ulcerative colitis had the highest XPA and XRCC6 expression. CONCLUSION: Oxidative/nitrosative stress is prevalent in the colon of both diseases. Nucleotide excision repair and non-homologous end-joining double-strand break repair may be compromised in colorectal cancer, but not in ulcerative colitis.


Assuntos
Colite Ulcerativa/genética , Neoplasias Colorretais/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , DNA/genética , Estresse Nitrosativo/genética , Estresse Oxidativo/genética , Biomarcadores Tumorais/genética , Colite Ulcerativa/patologia , Colo/patologia , Neoplasias Colorretais/patologia , Dano ao DNA/genética , Humanos , Mucosa Intestinal/patologia , Oxirredução
12.
Anticancer Res ; 41(7): 3429-3438, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230138

RESUMO

BACKGROUND/AIM: This study aimed to develop a new pathological finding, namely, invasion front grade and verify its clinical usefulness. MATERIALS AND METHODS: We re-examined haematoxylin-eosin-stained specimens in 162 stage II-III colorectal cancer patients who underwent radical resection. We assessed the desmoplastic reaction, Klintrup grade, and poorly differentiated cluster. These three findings were combined to form the invasion front grade (good prognosis group; Grade A, poor prognosis group; Grade B), and its reproducibility and prognostic stratification ability were statistically analysed. RESULTS: Invasion front grade was Grade A in 116 cases and Grade B in 46 cases, and its kappa coefficient was 0.81 for interobserver and 0.74 for intraobserver variability. The 3-year recurrence-free survival rates of Grade A and Grade B were 90.4% and 55.9%. Multivariate analysis showed that invasion front grade was an independent prognostic factor. CONCLUSION: Invasion front grade is useful as a prognostic stratification factor for stage II-III colorectal cancer.


Assuntos
Neoplasias Colorretais/patologia , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Estadiamento de Neoplasias/métodos , Variações Dependentes do Observador , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Taxa de Sobrevida
13.
Anticancer Res ; 41(7): 3459-3470, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230141

RESUMO

BACKGROUND/AIM: Studies have reported that the expression of c-Met and PrPC improves tumor progression. However, not much is known about their relationship. We hypothesized that c-Met and PrPC interact with each other, and enhance cancer stem cell (CSC) characteristics. MATERIALS AND METHODS: Magnetic activated cell sorting was used to examine the interaction between c-Met and PrPC The effects of the interaction on downstream signals, stem cell marker expression, and sphere formation of colorectal cancer (CRC) cells were investigated. RESULTS: We demonstrated the increased expression and binding levels of c-Met and PrPC in CRC cells compared to normal colon epithelial cells. We revealed that the c-Met and PrPC interaction induced the ERK activation and Oct4 upregulation. The inhibition of c-Met by crizotinib reduced ERK activation and Oct4 expression and suppressed CSC properties. CONCLUSION: c-Met and PrPC interact with each other, and targeting c-Met using crizotinib could be a powerful strategy for CRC therapy.


Assuntos
Neoplasias Colorretais/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas PrPC/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Crizotinibe/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
14.
Anticancer Res ; 41(7): 3615-3624, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230158

RESUMO

BACKGROUND/AIM: The aim of this study was to investigate the efficacy and safety of adjuvant chemotherapy in elderly patients with stage III colorectal cancer in a real-world setting. PATIENTS AND METHODS: A total of 165 patients of ≥70 years of age with stage III colorectal cancer who underwent a curative operation between 2008 and 2020 were enrolled in this study. RESULTS: Among septuagenarians, the relapse-free and overall survival rates in the single-agent therapy group and the combination therapy group were significantly better than those in the group treated by surgery alone. However, no significant differences were observed in the relapse-free and overall survival rates of the single-agent therapy group and the combination therapy group. Among octogenarians in whom all regimens were single-agent therapy, adjuvant chemotherapy tended to improve the relapse-free and overall survival rates but not the time to recurrence or cancer-specific survival. CONCLUSION: Single-agent adjuvant chemotherapy may be a useful treatment option for septuagenarians with stage III colorectal cancer. However, the efficacy of adjuvant chemotherapy in octogenarians was not shown in this study.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante/métodos , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias/métodos , Taxa de Sobrevida
15.
Anticancer Res ; 41(7): 3657-3665, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230164

RESUMO

BACKGROUND/AIM: We attempted to stratify prognosis using the modified Journal of Hepato-Biliary-Pancreatic Sciences (mJHBPS) nomogram upon identification of colorectal liver metastasis (CRLM) and to investigate which strategy is better, surgery first (SF) or chemotherapy first (CF), in each risk group. PATIENTS AND METHODS: A total of 137 patients with CRLM who underwent resection of the primary tumor were included. Patients with brain, bone, or perihilar lymph node metastases were excluded. Patients were scored using the mJHBPS nomogram upon identification of CRLM. Prognosis was investigated using event-free survival (EFS) and overall survival (OS). RESULTS: The nomogram allowed stratification of patients using EFS and OS: low-risk (0-6 score, n=38), medium-risk (7-11 score, n=42), and high-risk (12≥ score, n=57). In the low-risk group, the EFS and OS of the CF group were significantly poorer than those of the SF group (p=0.019 and p=0.014, respectively). CF was an independent prognostic factor for both EFS and OS. CONCLUSION: The mJHBPS nomogram can stratify CRLM patients with sufficient differences in EFS and OS. SF was recommended for patients in the low-risk group.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Fígado/patologia , Idoso , Feminino , Humanos , Metástase Linfática/patologia , Masculino , Nomogramas , Pâncreas/patologia , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos
16.
Anticancer Res ; 41(8): 3801-3808, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281839

RESUMO

BACKGROUND/AIM: Colorectal adenocarcinoma has a poor prognosis due to its propensity for metastasis. It has been experimentally demonstrated that the microRNA (miRNA) let-7a can effectively inhibit tumor proliferation and metastasis by regulating the transforming growth factor (TGF)-ß signaling pathway; however, limited research has been conducted in the area of on colorectal cancer. Herein, we aimed to clarify the role and regulation of let-7a in a colorectal adenocarcinoma cell line (LS-174T). MATERIALS AND METHODS: LS-174T cells were transfected to express let-7a. Let-7a miRNA expression was detected by quantitative real-time polymerase chain reaction (RT-qPCR). Cell growth was assessed by methyl thiazolyl tetrazolium (MTT) assay; invasion and migration were examined by Matrigel invasion and wound healing assays. The expression levels of matrix metalloproteinase (MMP)-2, phosphorylated Drosophila mothers against decapentaplegic 2 (p-SMAD2), and TGF-ß1 were analyzed by western blotting. The mRNA expression levels of TGFB1 were also analyzed by RT-qPCR. RESULTS: Overexpression of let-7a resulted in significant inhibition of LS-174T cell proliferation in vitro. The invasion and migration abilities of the cells overexpressing let-7a were decreased, compared to the control group and miR-negative control group. Transfection of LS-174T cells with let-7a resulted in down-regulation of MMP-2, as well as of TGF-ß1 and p-SMAD2 protein expression. Moreover, TGF-ß1 mRNA levels were reduced following let-7a overexpression. CONCLUSION: Let-7a inhibited the growth and metastasis of colonic mucinous adenocarcinoma cells, at least partially, by regulating the TGF-ß/Smad signaling pathway.


Assuntos
Adenocarcinoma/patologia , Neoplasias Colorretais/patologia , MicroRNAs/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Transdução de Sinais/genética , Proteínas Smad/genética , Fator de Crescimento Transformador beta1/genética
17.
Anticancer Res ; 41(8): 4061-4070, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281875

RESUMO

BACKGROUND/AIM: Among compounds from natural products selectively suppressing the growth of cancer spheroids, which have mutant (mt) KRAS, NP910 was selected and its derivatives explored. MATERIALS AND METHODS: The area of HKe3 spheroids expressing wild type (wt) KRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS) were measured in three-dimensional floating (3DF) cultures treated with 18 NP910 derivatives. The 50% cell growth inhibition (GI50) was determined by long-term 3DF (LT3DF) culture and nude mice assay. RESULTS: We selected NP882 (named STAR3) as the most effective inhibitor of growth of HKe3-mtKRAS spheroids with the least toxicity among NP910 derivatives. GI50s of STAR3 in LT3DF and nude mice assay were 6 µM and 30.75 mg/kg, respectively. However, growth suppression by STAR3 was observed in 50% of cell lines independent of KRAS mutation, suggesting that the target of STAR3 was not directly associated with KRAS mutation and KRAS-related signals. CONCLUSION: STAR3 is a low-toxicity compound that inhibits growth of certain tumour cells.


Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Esferoides Celulares/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Produtos Biológicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Feminino , Humanos , Camundongos Nus , Mutação , Esferoides Celulares/patologia , Células Tumorais Cultivadas
18.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201191

RESUMO

The role of oxidative stress (OS) in cancer is a matter of great interest due to the implication of reactive oxygen species (ROS) and their oxidation products in the initiation of tumorigenesis, its progression, and metastatic dissemination. Great efforts have been made to identify the mechanisms of ROS-induced carcinogenesis; however, the validation of OS byproducts as potential tumor markers (TMs) remains to be established. This interventional study included a total of 80 colorectal cancer (CRC) patients and 60 controls. By measuring reduced glutathione (GSH), its oxidized form (GSSG), and the glutathione redox state in terms of the GSSG/GSH ratio in the serum of CRC patients, we identified significant changes as compared to healthy subjects. These findings are compatible with the effectiveness of glutathione as a TM. The thiol redox state showed a significant increase towards oxidation in the CRC group and correlated significantly with both the tumor state and the clinical evolution. The sensitivity and specificity of serum glutathione levels are far above those of the classical TMs CEA and CA19.9. We conclude that the GSSG/GSH ratio is a simple assay which could be validated as a novel clinical TM for the diagnosis and monitoring of CRC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/patologia , Glutationa/química , Glutationa/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução
19.
Int J Mol Sci ; 22(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299137

RESUMO

The KRAS mutation is one of the leading driver mutations in colorectal cancer (CRC), and it is usually associated with poor prognosis and drug resistance. Therapies targeting the epidermal growth factor receptor (EFGR) are widely used for end-stage CRC. However, patients with KRAS mutant genes cannot benefit from this therapy because of Ras signaling activation by KRAS mutant genes. Our previous study revealed the anti-proliferative effect of 4-acetyl-antroquinonol B (4-AAQB) on CRC cells, but whether the drug is effective in KRAS-mutant CRC remains unknown. We screened CRC cell lines harboring the KRAS mutation, namely G12A, G12C, G12V and G13D, with one wild type cell line as the control; SW1463 and Caco-2 cell lines were used for further experiments. Sulforhodamine B assays, together with the clonogenicity and invasion assay, revealed that KRAS-mutant SW1463 cells were resistant to cetuximab; however, 4-AAQB treatment effectively resensitized CRC cells to cetuximab through the reduction of colony formation, invasion, and tumorsphere generation and of oncogenic KRAS signaling cascade of CRC cells. Thus, inducing cells with 4-AAQB before cetuximab therapy could resensitize KRAS-mutant, but not wild-type, cells to cetuximab. Therefore, we hypothesized that 4-AAQB can inhibit KRAS. In silico analysis of the publicly available GEO (GSE66548) dataset of KRAS-mutated versus KRAS wild-type CRC patients confirmed that miR-193a-3p was significantly downregulated in the former compared with the latter patient population. Overexpression of miR-193a-3p considerably reduced the oncogenicity of both CRC cells. Furthermore, KRAS is a key target of miR-193a-3p. In vivo treatment with the combination of 4-AAQB and cetuximab significantly reduced the tumor burden of a xenograft mice model through the reduction of the expression of oncogenic markers (EGFR) and p-MEK, p-ERK, and c-RAF/p-c-RAF signaling, with the simultaneous induction of miR-193a-3p expression in the plasma. In summary, our findings provide strong evidence regarding the therapeutic effect of 4-AAQB on KRAS-mutant CRC cells. Furthermore, 4-AAQB effectively inhibits Ras singling in CRC cells, through which KRAS-mutant CRC can be resensitized to cetuximab.


Assuntos
Biomarcadores Tumorais/metabolismo , Cetuximab/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Ubiquinona/análogos & derivados , Animais , Antineoplásicos Imunológicos/farmacologia , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Prognóstico , Células Tumorais Cultivadas , Ubiquinona/química , Ubiquinona/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Quinases raf/genética , Quinases raf/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
20.
World J Gastroenterol ; 27(25): 3901-3912, 2021 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-34321853

RESUMO

BACKGROUND: The proportion of young patients with colorectal cancer (CRC), especially in their 40s, is increasing worldwide. AIM: To confirm the clinical characteristics of such patients, we planned a study comparing them to patients in their 30s and 50s. METHODS: Patients undergoing primary resection for CRC, patients in their 30s, 40s and 50s were included in the study. Patient and tumor characteristics, and perioperative and oncologic outcomes were compared. RESULTS: Most clinical characteristics of 451 (10.5%) patients in their 40s were more similar to those of patients in their 30s than those in their 50s. On pathology data, there were more metastatic lesions (30s vs 40s vs 50s; 17.5% vs 21.1% vs 14.9%, P = 0.012) in patients in their 40s. There was a trend toward less frequent K-ras mutations among patients in their 40s (48.5% vs 33.3% vs 44.5%, P = 0.064). The proportion of patients receiving postoperative chemotherapy was also significantly greater among patients in their 40s (58.3% vs 63.9% vs 56.3%, P = 0.032). Five-year overall survival (OS) and disease-free survival (DFS) did not differ between the three groups (5-year OS, 92.2% vs 89.8% vs 92.2%, P = 0.804; 5-year total DFS, 98.6% vs 95.7% vs 96.1%, P = 0.754; 5-year local DFS, 98.6% vs 94.3% vs 94.9%, P = 0.579; 5-year systemic DFS, 86.4% vs 87.9 % vs 86.4%, P = 0.908). CONCLUSION: Patients with CRC in their 40s showed significantly more numerous metastatic lesions. The oncologic outcome of stage 1-3 patients in their 40s was not inferior compared to that of those in their 30s and 50s.


Assuntos
Neoplasias Colorretais , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Humanos , Estadiamento de Neoplasias , República da Coreia/epidemiologia , Estudos Retrospectivos
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