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1.
Zhonghua Wei Chang Wai Ke Za Zhi ; 23(1): 56-64, 2020 Jan 25.
Artigo em Chinês | MEDLINE | ID: mdl-31958932

RESUMO

Objective: To explore the application of endoscopic tattooing with carbon nanoparticles in the treatment of advanced colorectal cancer (ACRC). Methods: A randomized controlled study was used. Inclusion criteria: (1) age more than 18 years old, and colorectal cancer was found for the first time and confirmed by colonoscopy and biopsy; (2) advanced colorectal cancer (preoperative TNM stage of T3/N1 or above, local unresectable lesion, M1 stage and simultaneously resectable metastatic lesion), and patients agreed to receive neoadjuvant therapy; (3) advanced colorectal cancer (TNM stage of T3/N1 or above) with simultaneous unresectable metastatic lesion, and patients refused operation and consented to chemoradiotherapy. Patients with previous abdominal surgery history, radiotherapy and chemotherapy history, urgent need for surgery or endoscopic stent placement and those with severe allergic constitution were excluded. Based on the above criteria, 120 patients diagnosed with ACRC in No.900 Hospital of the Joint Logistics Team from January 2016 to December 2017 were prospectively enrolled and randomly divided into tattoo group and non-tattoo group by random number table method. Tattoo group were tattooed within 1-7 days before chemoradiotherapy. The labeling location of the lesions: (1) if the colonoscopy could pass smoothly, 4 points were injected into the intestinal wall of the both opposite sides 1 cm cephalad and caudad of the tumor; (2) if the colorectal cavity was severely narrow and the colonoscopy could not pass, only 4 points were injected in 4 quadrants at 1 cm caudad of the tumor. Each injection point was injected with 0.1 ml carbon nanoparticles, and the size of the tumor was measured according to the range of carbon nanoparticles staining. The efficacy was evaluated after 8 weeks of chemoradiotherapy. Patients who were defined to be suitable for operation underwent operation 6 weeks after chemoradiotherapy. The following parameters were compared between two groups: lesion identification time, operation time, blood loss, distance from lesion to distal margin, the rate of first positive margin and the rate of anal sphincter preservation (rectal cancer). Among patients who had been evaluated as having no indication for surgery, those who were effective in chemoradiotherapy continued to receive chemotherapy in the original regimen; if the treatment failed, the chemotherapy regimen was replaced, and the efficacy was finally evaluated after six months [referring to the revised RECIST guidelines (version 1.1)]. Results: Three patients withdrew from this study, and 117 patients were enrolled in this study finally, including 59 cases in tattoo group and 58 cases in the non-tattoo group. There were no significant differences in baseline data between two groups (all P>0.05). All the patients had slight adverse reactions of radiotherapy and chemotherapy before operation, and could tolerate after symptomatic management without interruption of treatment. All the patients in the tattoo group had no discomfort such as fever, abdominal pain, abdominal distention, hematochezia, etc. and the intestinal mucosa could be seen clearly with black staining after being tattooed. A total of 77 patients were evaluated with surgical indications, including 39 cases in the tattoo group (tattoo-operable) and 38 cases in the non-tattoo group (non-tattoo-operatable). There were no significant differences in baseline data between the two groups (all P>0.05). Forty patients without operation indications continued chemoradiotherapy, including 20 cases in tattoo group (tattoo-inoperable) and 20 cases in non-tattoo group (non-tattoo-inoperable), whose differences in baseline data between the two groups were not significant as well (all P>0.05). No obvious edema, necrosis or abscess were found in the tattooed segments and the black spots could be seen quickly and clearly on the serosa of rectum in tattoo-operable patients. As compared to non-tattoo group, tattoo group had significantly shorter lesion identification time [(3.4±1.4) minutes vs. (11.8±3.4) minutes, t=-14.07,P<0.001], shorter operation time [(155.7±44.5) minutes vs. (177.2±30.2) minutes, t=-2.48,P=0.015], less blood loss [(101.3±36.7) ml vs.(120.2±38.2) ml, t=-2.22,P=0.029], shorter distance from lesion to distal margin [(3.7±1.0) cm vs. (4.6±1.7) cm, t=-2.20, P=0.034], while tattoo group had slightly higher rate of anal sphincter preservation [66.7%(16/24) vs. 45.5%(10/22), χ(2)=2.10,P=0.234] and lower rate of first positive resection margin [0 vs. 4.5%(1/22), χ(2)=0.62,P=0.480], but their differences were not significant. There were no significant differences in the degree of tumor differentiation and TNM stage between two groups. Patients without operative indication were evaluated for efficacy of chemoradiotherapy again after half a year. One case of complete response (CR), 8 of partial response (PR), 10 of stable disease (SD) and 1 of progressive disease (PD) were found and the improvement rate was 45.0% (9/20) in tattoo-inoperable patients. No case of CR, 6 of PR, 11 of SD and 3 of PD were found and the improvement rate was 30.0% (6/20) in non-tattoo-inoperable patients. There was no significant difference in the improvement rate between the two groups (P=0.514). Conclusions: Endoscopic tattooing with carbon nanoparticles injection is safe and reliable for colorectal tumor positioning. It can assist rapid detection of lesions during surgery after neoadjuvant treatment, perform accurate resection, significantly shorten the operation time and reduce surgical trauma; can assist colonoscopy accurately to measure the size of the lesions before and after chemoradiotherapy, and increase the means of assessing the efficacy to guide the follow-up treatment plan. This technique is worth clinical promotion and application.


Assuntos
Carbono/administração & dosagem , Neoplasias do Colo/terapia , Nanopartículas/administração & dosagem , Neoplasias Retais/terapia , Tatuagem/métodos , Adolescente , Quimiorradioterapia Adjuvante , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Colonoscopia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/terapia , Terapia Combinada , Humanos , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
2.
Anticancer Res ; 40(1): 201-211, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31892568

RESUMO

BACKGROUND/AIM: This retrospective study focused on the correlation between molecular markers and prognostic outcomes of colon cancer patients depending on sidedness. MATERIALS AND METHODS: A total of 117 stage I-III colon cancer patients who underwent colectomy were enrolled. Novel methylation markers (KIF1A, PAX5 and VGF) were selected for epigenetic evaluation and p53 and ERCC1 protein expression was examined for the investigation of genetic alterations. RESULTS: High frequency of methylation was observed in 68.2% of right-sided and 39.7% of left-sided colon cancer cases (p=0.004). Abnormal p53 was identified in 52.3% of right-sided and 75.3% of left-sided cases (p=0.015). In right-sided cases, highly methylated genes demonstrated significantly favorable disease-free survival (p=0.049). Regarding left-sided cases, advanced T stage (p=0.028) and abnormal p53 (p=0.028) were revealed to be significant predictive factors of the disease-free survival outcome. CONCLUSION: Molecular alterations, as significant prognostic factors, might differ depending on the sidedness of colon cancers.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Idoso , Metilação de DNA/genética , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Análise Multivariada , Proteínas de Neoplasias/metabolismo , Curva ROC , Análise de Sobrevida
3.
J Surg Oncol ; 121(3): 538-546, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31853986

RESUMO

BACKGROUND: While the prognostic implications of positive circumferential resection margins (CRM) have been established for rectal cancer, its significance in colon cancer has not been well defined. The aim of the current study was to determine national rates for positive CRM in locally advanced colon cancer, associated factors, and survival impact. METHODS: The National Cancer Database was queried to identify patients with stage II-III adenocarcinoma of the colon (2004-2015). RESULTS: Positive CRM was identified in 9% of stage II and 12% of stage III patients. Factors associated with negative CRM included surgery in a high-volume facility, adequate lymph-node harvest, and negative distal/proximal margins. No difference in CRM rates was observed between surgical approaches, although having a positive CRM was significantly associated with higher conversion rates. Positive CRM was associated with significantly lower overall survival on both univariate and multivariable analysis. CONCLUSIONS: Positive CRM rates exceeded 10% nationally and have an adverse impact on survival. While several tumor characteristics were identified as independent risk factors, oncologic resections and surgery at high-volume centers were associated with lower rates of positive CRM. These findings emphasize the need for process improvement initiatives targeting modifiable factors, including adoption of appropriate oncologic techniques, standardized pathology reporting, and potential neoadjuvant strategies.


Assuntos
Neoplasias do Colo/mortalidade , Neoplasias do Colo/cirurgia , Margens de Excisão , Idoso , Neoplasias do Colo/patologia , Bases de Dados Factuais , Feminino , Humanos , Modelos Logísticos , Masculino , Estadiamento de Neoplasias , Fatores de Risco , Análise de Sobrevida , Estados Unidos/epidemiologia
4.
Life Sci ; 242: 117185, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31862453

RESUMO

Colorectal cancer (CRC) is a multifactorial syndrome that drives to uncontrollable cell division, genetic alterations, and functional alteration. In the present work, we evaluated the immunomodulatory properties of P-mapa, a compound extracted from Aspergillus oryzae fungus, versus Fluorouracil (5-FU) treatment in chemically induced CRC. CRC was induced by DMH in F344 rats. Animals of treated groups receive weekly 15 mg/Kg of 5-FU or 5 mg/Kg of P-mapa, over 10 weeks. Tissues were stained for aberrant crypt foci (ACF) counting and histopathology evaluation, immunostained for TLR4 pathways and quantified for TNFα Cytokine assay. DMH was efficient to induce hyperplastic lesions and ACF. Both treatments reduced significantly ACF formation and tumor aggressiveness. Immunohistochemistry for TLR4 signaling reveals that both treatments had no effect over the TLR4-NFκB signaling pathway. On the other hand, both succeed in increase interferon signaling, with activation of the TRIF-IRF3 pathway and consequently inducing IFNγ synthesis. The present results show the immunomodulatory properties of P-mapa in chemically induced CRC model. P-mapa induced a significant increase in Type-I IFNs synthesis and subsequently immune cell recruitment, resulting in an increase of IFNγ concentration in colorectal mucosa and its inhibitory effects over tumoral growth. In this scenario, P-mapa showed an interesting antitumoral effect by inhibiting tumor growth.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Focos de Criptas Aberrantes/patologia , Animais , Biopolímeros/uso terapêutico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Ensaio de Imunoadsorção Enzimática , Fluoruracila/uso terapêutico , Masculino , Ratos , Ratos Endogâmicos F344 , Fator de Necrose Tumoral alfa/metabolismo
5.
Biosci Biotechnol Biochem ; 84(1): 111-117, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31512553

RESUMO

Slow skeletal muscle troponin T (TNNT1) has been reported to be correlated with several cancers, but there are no evidences proving that TNNT1 is required in colon adenocarcinoma (COAD). TNNT1 expression in COAD tissues and its prognostic significance were acquired from TCGA database. The proliferative, migratory, and invasive abilities of COAD cells were detected by CCK-8 and transwell assays, respectively. Correlations between TNNT1 and epithelial-mesenchymal transition (EMT)-related markers were determined using western blotting and Pearson's analysis. Our results stated that TNNT1 expression was high-regulated in COAD tissues, which was related with unfavorable prognosis of COAD patients. Functional analyses suggested that TNNT1 promoted the cellular behaviors. Moreover, aberrant expression of TNNT1 affected the expression level of EMT-related proteins. And TNNT1 was negatively linked with E-cadherin. In conclusion, our findings indicated that TNNT1 may promote the progression of COAD, mediating EMT process, and thus shed a novel light on COAD therapeutic treatments.


Assuntos
Adenocarcinoma/patologia , Movimento Celular , Proliferação de Células , Neoplasias do Colo/patologia , Transição Epitelial-Mesenquimal , Troponina T/genética , Troponina T/metabolismo , Antígenos CD/metabolismo , Caderinas/metabolismo , Bases de Dados Genéticas , Expressão Gênica , Técnicas de Silenciamento de Genes , Células HCT116 , Humanos , Invasividade Neoplásica , Prognóstico , Transfecção
6.
Biol Res ; 52(1): 60, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847887

RESUMO

BACKGROUND: Recent studies have confirmed that RASAL1 has an antitumor effect in many cancers, but its functional role and the molecular mechanism underlying in colon cancer has not been investigated. RESULTS: We collected human colon cancer tissues and adjacent non-tumor tissues, human colon cancer cell lines LoVo, CaCo2, SW1116, SW480 and HCT-116, and normal colonic mucosa cell line NCM460. RT-qPCR was used to detect the RASAL1 level in the clinical tissues and cell lines. In LoVo and HCT-116, RASAL1 was artificially overexpressed. Cell viability and proliferation were measured using CCK-8 assays, and cell cycle was detected via PI staining and flow cytometry analysis. RASAL1 significantly inhibited the cell proliferation via inducing cell cycle arrest, suppressed cell cycle associated protein expression, and decreased the lipid content and inhibited the SCD1 expression. Moreover, SCD1 overexpression induced and downregulation repressed cell proliferation by causing cell cycle arrest. Additionally, luciferase reporter assays were performed to confirm the direct binding between SREBP1c, LXRα and SCD1 promoter, we also demonstrated that RASAL1 inhibit SCD1 3'-UTR activity. RASAL1 inhibited tumor growth in xenograft nude mice models and shows inhibitory effect of SCD1 expression in vivo. CONCLUSION: Taken together, we concluded that RASAL1 inhibited colon cancer cell proliferation via modulating SCD1 activity through LXRα/SREBP1c pathway.


Assuntos
Proliferação de Células/fisiologia , Neoplasias do Colo/patologia , Proteínas Ativadoras de GTPase/metabolismo , Receptores X do Fígado/metabolismo , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Linhagem Celular Tumoral , Regulação para Baixo , Proteínas Ativadoras de GTPase/genética , Humanos , Receptores X do Fígado/genética , Camundongos , Estearoil-CoA Dessaturase/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
7.
Zhonghua Wei Chang Wai Ke Za Zhi ; 22(12): 1105-1109, 2019 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-31874523

RESUMO

Colon cancer is one of the most common malignancies of the alimentary tract, and one main metastatic route is lymph node metastasis. Thorough dissections of regional lymph nodes is one of the core surgical treatment of right colon cancer. D3 lymphadenectomy and complete mesocolic excision (CME) are generally accepted surgical methods for right colon cancer, which can improve the standardization of surgery, improve the quality of tumor resection, and provide more lymph nodes dissectal. Colon cancer of hepatic flexure is likely to have metastasis of the infrapyloric lymph nodes (No.206), which are not regional lymph nodes. Lymph node dissection of No.206 group belongs to extended right hemicolectomy, which involves many vascular variations and complicated peripheral anatomical structure. The theory of fascial surgery provides surgeons with anatomic basis and a clear understanding of the anatomical structure of the infrapyloric region, which is an important theoretical basis for the thorough dissection of lymph nodes in No.206 group, and can completely remove the mass, regional lymph nodes and adipose connective tissue, so as to achieve the goal of non-bleeding surgery. Lymph nodes in No.206 group were dissected, not just the visible lymph nodes, but the entire lymph nodes and lymphatic vessels in the region, including adipose tissue. Extended right hemicolectomy requires higher surgical techniques. The survival benefits of extended right hemicolectomy are not supported by high-level evidence. It is still controversial whether the infrapyloric lymph node dissection should become routine for colon cancer of hepatic flexure. In this article, the metastasis and dissection of infrapyloric lymph node in colon cancer of hepatic flexure is elucidated.


Assuntos
Colo Ascendente/patologia , Neoplasias do Colo/patologia , Excisão de Linfonodo/métodos , Linfonodos/patologia , Mesocolo/patologia , Colectomia , Colo Ascendente/cirurgia , Neoplasias do Colo/cirurgia , Humanos , Linfonodos/cirurgia , Metástase Linfática , Mesocolo/cirurgia
8.
Zhonghua Wei Chang Wai Ke Za Zhi ; 22(12): 1152-1158, 2019 Dec 25.
Artigo em Chinês | MEDLINE | ID: mdl-31874531

RESUMO

Objective: To investigate the effect of tumor deposits (TD) on the prognosis of patients with stage III colon cancer, and to explore whether TD number included into regional lymph node count can predict the prognosis more accurately. Methods: A retrospective cohort study was carried out. Case inclusion criteria: (1) primary colon cancer; (2) undergoing colon cancer radical operation; (3) definite pathological diagnosis; (4) colon cancer stage III according to AJCC 8th edition; (5) complete follow-up data; (6) without preoperative neoadjuvant treatment. Clinicopathological data of 296 patients undergoing colon cancer radical operation from January 2005 to December 2008 in the Cancer Hospital of Chinese Academy of Medical Sciences were retrospectively collected. The effect of TD and its amount on the prognosis was evaluated. Colon cancer TNM staging method based on the 8th edition of AJCC was compared with the modified TNM staging (mTNM) adjusted by the number of TD. The differences of the disease-free survival (DFS) and overall survival (OS) between groups were also examined. The Kaplan-Meier curve was used to analyze the survival, and prognostic factors were analyzed by Cox univariate and multivariate analyses. Results: Among 296 patients with stage III colon cancer, 78 patients had TD. The median number of TD was 2 (1-10). Tumor T stage, N stage, vascular tumor thrombus and preoperative carcinoembryonic antigen (CEA) were associated with TD in patients with colon cancer (all P<0.05). The right hemicolon appears likely to have TD than left hemicolon, but the difference was not statistically significant (P=0.059). The median follow-up of the whole group was 71 (6-102) months. During the follow-up period, 129 patients (43.6%) had recurrence or metastasis, and 111 patients died (37.5%). The 5-year DFS in TD group was 44.9%, which was lower than that in the non-TD group (60.6%), with statistically significant difference (P=0.003). The 5-year OS in TD group was 50.0%, which was also lower than 67.0% in the non-TD group, and the difference was statistically significant (P=0.002). According to TD number, patients were divided into 3 groups: 1 TD (25 cases), 2-3 TD (32 cases), ≥4 TD (21 cases). The 5-year DFS in these 3 groups was 68%, 56.3%, and 0, respectively (P<0.001), and 5-year OS was 76%, 59.4%, and 4.8% respectively (P<0.001). Univariate analysis showed that TD presence (95% CI: 1.234-2.694, P=0.003) and TD number (95% CI: 3.531-14.138, P<0.001) were associated with the prognosis of patients with stage III colon cancer. At the same time, age, tumor N stage, tumor location, chemotherapy, and preoperative CEA elevation were also associated with the prognosis of stage III colon cancer patients (all P<0.05). Multivariate analysis revealed that TD presence (HR=1.957, 95%CI: 1.269-3.017, P=0.002) and TD number (HR=8.020, 95% CI: 3.414-18.842, P<0.001) were still independent risk factors for the prognosis of patients with stage III colon cancer.According to the TD number counted as metastatic lymph nodes, in 78 patients with TD, 24 patients were upstaged in N stage, and 16 patients upstaged from TNM stage IIIB to stage IIIC. For 16 stage IIIB cases with staging modification, 30 unadjusted stage IIIB cases with TD, and 148 stage IIIB cases without TD, the 5-year OS was 37.5%, 73.3% and 76.4%, respectively with significant difference (P<0.001). However, for 16 patients adjusted as stage IIIC (mTNM), 32 patients with unchanged stage IIIC with TD (TNM, AJCC 8th edition), and 63 stage IIIC cases without TD, the 5-year OS was 37.5%, 36.4%, and 41.3%, respectively without significant difference (P=0.707). Conclusions: TD presence and TD number are independent risk factors for prognosis of stage III colon cancerpatients. TNM staging evaluation with lymph node number including TD number can predict the prognosis of patients more accurately.


Assuntos
Neoplasias do Colo/patologia , Estadiamento de Neoplasias/métodos , Neoplasias do Colo/cirurgia , Humanos , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida
9.
Life Sci ; 239: 117035, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31697952

RESUMO

AIMS: The purpose of this study was to investigate the role of long non-coding RNA taurine-upregulated gene 1 (TUG1) in colon cancer (Cc) and related molecular mechanisms. MATERIALS AND METHODS: RT-qPCR, Western blot and immunohistochemistry were used to detect the expression of related proteins. BrdU and Transwell assays were used to detect cell proliferation and invasion, respectively. Immunofluorescence was used to detect the expression of Vimentin. KEY FINDINGS: TUG1 expression was up-regulated in CaCO-2, SW620 and HT-29 cells, while miR-26a-5p was down-regulated. Bioinformatics analysis showed that miR-26a-5p was the target of TUG1, and the targeting relationship was further confirmed by dual-luciferase report analysis. Besides, matrix metalloproteinases-14 (MMP-14) was a target of mir-26a-5p. Knockdown of TUG1 by shRNA (sh-TUG1) inhibited MMP-14 expression. Functional analysis showed that sh-TUG1 significantly inhibited Cc cell proliferation, invasion and epithelial-mesenchymal transformation (EMT). Notably, miR-26a-5p inhibitor reversed the promotion of Cc caused by sh-TUG1. Mechanically, the overexpression of TUG1 significantly up-regulated the levels of MMP-14, VEGF, p-p38 mitogen-activated protein kinase (p-p38 MAPK) and p-HSP27 (heat shock protein 27), and promoted the proliferation, invasion and EMT of Cc cells. However, MAPK pathway inhibitor SB203580 has shown the opposite effect. Additionally, animal studies have shown that sh-TUG1 inhibited tumor growth and motility in vivo in the same way. SIGNIFICANCE: This study demonstrated that TUG1 accelerates the development of colon cancer by regulating miR-26a-5p/MMP14/p38 MAPK/Hsp27 axis in vitro and in vivo. Therefore, TUG1 provides a new direction for the treatment of Cc.


Assuntos
Carcinogênese/genética , Neoplasias do Colo/genética , Proteínas de Choque Térmico/biossíntese , Sistema de Sinalização das MAP Quinases/genética , Metaloproteinase 14 da Matriz/biossíntese , MicroRNAs/biossíntese , Chaperonas Moleculares/biossíntese , RNA Longo não Codificante/genética , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Biologia Computacional , Transição Epitelial-Mesenquimal/genética , Proteínas de Choque Térmico/genética , Humanos , Masculino , Metaloproteinase 14 da Matriz/genética , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Chaperonas Moleculares/genética , Regulação para Cima
10.
Cell Physiol Biochem ; 53(5): 820-831, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31701729

RESUMO

BACKGROUND/AIMS: MLK4 (KIAA1804) is the second most frequently mutated kinase in microsatellite stable (MSS) colorectal carcinomas (CRC). This molecule is known to regulate different physiological cellular processes, including cell cycle, senescence and apoptosis, and mechanistic evidence has been provided that MLK4 plays a role in carcinogenesis. However, whether this kinase exerts a tumor suppressive role or an oncogenic function is still an object of debate. This study aims to elucidate the role of MLK4 in the pathogenesis of CRC by investigating human tumor specimens. METHODS: This study assessed MLK4 expression levels by immunohistochemistry in surgical tumor samples from 204 early-stage CRC patients and their correlation with various clinical-pathological features and patients' outcomes. In addition, MLK4 mRNA transcription was analysed in an independent cohort of 786 colon cancer samples. RESULTS: Loss of MLK4 staining was associated with poor overall (OS) and progression free survival (PFS) in CRC patients during a univariate analysis (OS:101 vs 164 months, p=0.0002; PFS:85 vs 125 months, p=0.0001), as well as in multivariate analysis (OS:HR=1.70; p=0.001; PFS:HR=1,61; p=0.001). This was confirmed by analysis of MLK4 mRNA in the second independent cohort. A subgroup analysis according to KRAS mutation status showed that MLK4 staining was associated with better OS and PFS in KRAS mutated cases (HR=2.77; p=0.0001 and HR=2.31; p=0.0003, respectively) and microsatellite stable tumors (HR=1.87; p=0.002 and HR=1.06; p=0.006) but not in KRAS wildtype and microsatellite unstable tumors. CONCLUSION: By providing the first report from clinical specimens on the prognostic significance of MLK4, we define an oncogenic loss-of-function of this kinase and suggest a possible role in the interaction with KRAS signaling in determining an aggressive phenotype of CRC. These findings warrant the further investigation of MLK4 in wider cohorts and various clinical settings.


Assuntos
Neoplasias Colorretais/patologia , MAP Quinase Quinase Quinases/metabolismo , Instabilidade de Microssatélites , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Idoso , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , MAP Quinase Quinase Quinases/genética , Masculino , Mutação , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas p21(ras)/genética
11.
Anticancer Res ; 39(11): 6049-6055, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704831

RESUMO

BACKGROUND/AIM: For patients undergoing cancer surgery, the risk for cancer progression is enhanced during the perioperative period. To what extent the type of anesthetic can affect the metastatic process and finally the outcome of patients with cancer is under debate. For this reason, the aim of this study was to investigate the effects of the volatile anesthetics sevoflurane and desflurane on colon cancer cells in vitro. MATERIALS AND METHODS: SW480 colon carcinoma cells were exposed for 3 or 6 h to sevoflurane (1 or 2.5 vol%) or desflurane (6 or 12 vol%). Cell cycle distribution was analyzed by flow cytometry after a 24-72 h recovery and apoptosis was detected by annexin V staining after a 0-48 h recovery. Viability was tested by measuring ATP content after 0 and 24 h recovery. RESULTS: Treatment with sevoflurane or desflurane caused no or only slight changes in cell-cycle distribution and apoptosis rate. Desflurane at 12vol% significantly reduced cell viability by 17±25% and 11±22% after 3 and 6 h incubation and 24 h recovery, respectively, while 2.5 vol% sevoflurane slightly increased viability. CONCLUSION: At clinically relevant concentrations, sevoflurane and desflurane had only slight effects on SW480 colon cancer cells in vitro.


Assuntos
Anestésicos Inalatórios/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/patologia , Desflurano/farmacologia , Sevoflurano/farmacologia , Neoplasias do Colo/tratamento farmacológico , Humanos , Técnicas In Vitro , Células Tumorais Cultivadas
12.
Anticancer Res ; 39(11): 6067-6071, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704834

RESUMO

BACKGROUND/AIM: Thrombin plays significant roles in various types of cancer. However, the expression levels of prothrombin, the thrombin precursor, in cancer remain unclear. Variants of the 3'end of the prothrombin gene lead to increased prothrombin expression. This study aimed to analyze prothrombin 3'end gene variants in colon tumor and adjacent normal tissue samples. MATERIALS AND METHODS: The study group consisted of 93 patients suffering from colon adenocarcinoma. The 3'end of the prothrombin gene was analyzed by DNA sequencing. RESULTS: Three variants, all previously associated with increased prothrombin expression were detected. Frequency of the FII 19911G allele was 46.77% and 47.85% in tumor and normal tissue, respectively. For the FII 20210A allele, the detected frequencies were 2.15% and 1.61%, respectively. The frequency of the FII c.1824T allele was 0.54% in both tissues. Four patients showed different genotypes in tumor and normal tissue. CONCLUSION: Prothrombin 3' end gene variants may play a role in colorectal cancer.


Assuntos
Regiões 3' não Traduzidas/genética , Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Neoplasias do Colo/genética , Regulação Neoplásica da Expressão Gênica , Variação Genética , Protrombina/genética , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Neoplasias do Colo/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
13.
Anticancer Res ; 39(11): 6115-6123, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704839

RESUMO

BACKGROUND/AIM: Colon cancer is the second most common deadliest malignancy in the world and better understanding of its underlying mechanisms is needed to improve clinical management. Natural plant extracts are gaining attention in the development of new therapeutic strategies against various cancer types. Shikonin is a naturally extracted naphthoquinone pigment with effects against cancer, including colon cancer. MATERIALS AND METHODS: In this study, we conducted a series of in vitro experiments to show the effects of Shikonin on colon cancer cell apoptosis. A colon cancer cell line with overexpression of peroxiredoxin V (PrxV) was constructed and the relationship of PrxV expression with Shikonin-induced cell apoptosis was investigated. RESULTS: Shikonin induced colon cancer cell apoptosis via regulation of mammalian target of rapamycin signaling. Shikonin-induced cell apoptosis was abrogated by overexpression of PrxV. CONCLUSION: According to the results obtained in this study, targeting PrxV may provide new insight for the successful management of colon cancer by inducing cell apoptosis.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Naftoquinonas/farmacologia , Peroxirredoxinas/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Humanos , Células Tumorais Cultivadas
14.
Anticancer Res ; 39(11): 6291-6297, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704859

RESUMO

BACKGROUND/AIM: Cyclins D1 and E play different roles in the cell cycle. Cyclin E promotes chromosome instability, whereas cyclin D1 regulates apoptosis of cells. This study evaluated the prognostic significance of G1 cyclins, p21 and pRb in tumor proliferation. PATIENTS AND METHODS: A total of 102 patients with colon cancer were operated on and staged according to TNM. Follow-up was 2 to 68 months (mean 38.3±16.7 months). Expression of cyclin E and D1 were evaluated using immunohistochemistry. RESULTS: Levels of cyclin E expression were correlated with cyclin D1 expression (p=0.038), p21 expression (p=0.047), and pRb expression (p=0.004). The 5-year survival rate along with prognosis of patients with advanced stage (III, IV) colon cancer and cyclin D1 positive tumors, were significantly worse (p=0.009). Statistically significant association was observed between tumor proliferative capacity Ki-67, cyclin D1 (p=0.009), pRb (p=0.031) and p21 (p=0.050). CONCLUSION: Cyclin D1 is highly expressed in advanced stage colon cancer patients, implying a potential prognostic value.


Assuntos
Neoplasias do Colo/metabolismo , Ciclina D1/metabolismo , Ciclina E/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fase G1 , Proteínas de Neoplasias/metabolismo , Proteínas Oncogênicas/metabolismo , Proteína do Retinoblastoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/química , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Ciclina D1/análise , Ciclina E/análise , Inibidor de Quinase Dependente de Ciclina p21/análise , Feminino , Seguimentos , Humanos , Antígeno Ki-67/análise , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas/análise , Prognóstico , Proteína do Retinoblastoma/análise , Taxa de Sobrevida
15.
Anticancer Res ; 39(11): 6379-6387, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704871

RESUMO

BACKGROUND/AIM: In the present retrospective study, we assessed the molecular profile and clinicopathological correlations of Greek colorectal carcinoma (CRC) patients. PATIENTS AND METHODS: Data from 157 CRC patients were collected. High Resolution Melting Analysis and Pyrosequencing/Sanger sequencing were applied to identify KRAS, BRAF, NRAS mutations and microsatellite instability (MSI) status. Immunohistochemistry was performed to characterize the associated Mismatch Repair Protein loss. Statistical calculations were performed using the statistical package SPSS v21.0. RESULTS: KRAS mutations were detected in 39.3% of cases, BRAF in 10.9% and NRAS in 4.9%. MSI status was recognized in 11.5% of CRC patients and was associated with right colon tumors. MSI phenotype was inversely correlated with stage, N status and KRAS mutations and positively correlated with BRAF mutations. CONCLUSION: MSI positive CRCs in the Greek population are more often right-sided, free of metastasis, KRAS wild type and BRAF mutated. Providing more detailed clinicopathological and molecular data for specific populations will enable better clinical management and individualized therapy in the future.


Assuntos
Neoplasias do Colo/genética , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Instabilidade de Microssatélites , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/patologia , Feminino , Grécia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores Sexuais , Neoplasias do Colo Sigmoide/genética , Neoplasias do Colo Sigmoide/patologia
16.
Medicine (Baltimore) ; 98(44): e17462, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689749

RESUMO

RATIONALE: Oxaliplatin is a key part of the standard treatment for colorectal cancer which is formally contraindicated in patients with severe renal dysfunction. Here, we investigated a safe and efficient dosing schedule of oxaliplatin in folinic acid, fluorouracil, and oxaliplatin (FOLFOX) regimen by monitoring total and free platinum concentrations in plasma. PATIENT CONCERNS: A 47-year-old female with chronic hemodialysis was diagnosed with left-sided colon cancer and underwent colectomy. One year later, she was presented with omentum metastasis and needed further treatment. DIAGNOSES: The computed tomography (CT) scanning revealed multiple omental nodules. Positron emission tomography-CT (PET-CT) showed increased uptake of the nodules. INTERVENTIONS: The patient was treated with FOLFOX therapy every 3 weeks. The oxaliplatin began with 50 mg/m and gradually increased 85 mg/m as in the standard regimen. A 4-hour dialysis was started 1 hour after the end of oxaliplatin infusion. OUTCOMES: The free platinum concentration time curve showed a biomodel pattern. The Cmax of the 1st peak we observed in our patients at the standard dose is comparable to patients with normal renal function. This patient was treated with FOLFOX for 12 courses. No apparent adverse effect was observed during the treatment. LESSONS: The FOLFOX can be safely administered in hemodialysis patients on a long-term basis. Dose reduction of oxaliplatin is not necessarily needed if hemodialysis is performed soon after the infusion. Further studies are needed to distinguish between active and inactive oxaliplatin products during the 2nd peak of the free platinum concentration curve in this population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Glomerulonefrite/terapia , Oxaliplatina/uso terapêutico , Diálise Renal/métodos , Doença Crônica , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina/administração & dosagem
17.
Khirurgiia (Mosk) ; (11): 88-92, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31714536

RESUMO

Colorectal cancer (CRC) is one of the leading forms of cancer. In 2017, over 72,000 of Russian citizens have been diagnosed with CRC. Cancer stage IV was diagnosed in 18 149 of them. Peritoneal carcinomatosis (PC) is one of the forms of metastatic dissemination throughout the peritoneum. There no any unified and standardized approaches to the treatment or prevention of PC associated with CRC. Therefore, it is advisable to identify PC predictors in patients with colon cancer and prevention measures.


Assuntos
Neoplasias do Colo/patologia , Neoplasias Peritoneais/prevenção & controle , Neoplasias Peritoneais/secundário , Neoplasias Colorretais/patologia , Humanos
18.
J Biochem Mol Toxicol ; 33(12): e22403, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31714660

RESUMO

Zingerone (ZO), an active phenolic agent derived from Zingiber officinale (Ginger), has many pharmacological properties such as antioxidant, antiangiogenic, and antitumor. However, its potential value in cancer and the mechanism by which ZO wields its therapeutic effects remain obscure. Therefore, in this current study, we explored the effects of ZO on suppressing cell proliferation and enhancing apoptosis in colon cancer cells (HCT116). Our results indicated that ZO significantly enhances the production of reactive oxygen species, lipid peroxidation (thiobarbituric acid reactive substance [TBARS]), and loss of cell viability; and reduces mitochondrial membrane potential and antioxidant levels (SOD, CAT, and GSH) in ZO-treated HCT116 cells in a dose-dependent (2.5, 5, and 10 µM) manner. Furthermore, ZO induces oxidative stress-mediated apoptosis as evidenced by apoptotic morphological changes predicted by AO/EtBr, Hoechst staining and further confirmed by comet assay. Moreover, immunoblotting techniques showed that ZO treatment effectively enhances Bax, caspase-9, and caspase-3 expressions and decreases the expression of Bcl-2 in colon cancer cells. Together, our results evidenced that the antitumor effects of ZO reduce cell proliferation and stimulate apoptosis through modulating pro- and antiapoptotic molecular events in HCT116 colon cancer cells. Therefore, based on our findings, ZO may be used as a therapeutic agent for the treatment of colon cancer.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/patologia , Gengibre/química , Guaiacol/análogos & derivados , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Guaiacol/farmacologia , Células HCT116 , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo
19.
J Surg Oncol ; 120(8): 1427-1435, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31729037

RESUMO

BACKGROUND AND OBJECTIVES: Mucinous adenocarcinoma is a distinct subtype of colorectal cancer (CRC) with a worse prognosis when compared with non-mucinous adenocarcinoma. The aim of this study was to compare somatic mutations and copy number alteration (CNA) between mucinous and non-mucinous CRC. METHODS: Data from The Cancer Genome Atlas-colon adenocarcinoma and rectum adenocarcinoma projects were utilized. Mucinous and non-mucinous CRC were compared with regard to microsatellite status, overall mutation rate, the most frequently mutated genes, mutations in genes coding for mismatch repair (MMR) proteins and genes coding for mucin glycoproteins. CNA analysis and pathway analysis was undertaken. RESULTS: Mucinous CRC was more likely to be microsatellite instability-high (MSI-H) and hypermutated. When corrected for microsatellite status the single-nucleotide variation and insertion-deletion rate was similar between the two cohorts. Mucinous adenocarcinoma was more likely to have mutations in genes coding for MMR proteins and mucin glycoproteins. Pathway analysis revealed further differences between the two histological subtypes in the cell cycle, RTK-RAS, transforming growth factor-ß, and TP53 pathways. CONCLUSIONS: Mucinous CRC has some distinct genomic aberrations when compared with non-mucinous adenocarcinoma, many of which are driven by the increased frequency of MSI-H tumors. These genomic aberrations may play an important part in the difference seen in response to treatment and prognosis in mucinous adenocarcinoma.


Assuntos
Adenocarcinoma Mucinoso/genética , Adenocarcinoma/genética , Neoplasias do Colo/genética , Genômica , Neoplasias Retais/genética , Adenocarcinoma/patologia , Adenocarcinoma Mucinoso/patologia , Estudos de Coortes , Neoplasias do Colo/patologia , Variações do Número de Cópias de DNA , Proteínas de Ligação a DNA/genética , Conjuntos de Dados como Assunto , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação INDEL , Instabilidade de Microssatélites , Mucinas/genética , Mutação , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Retais/patologia , Proteína Smad4/genética , Fator de Crescimento Transformador beta/genética , Proteína Supressora de Tumor p53/genética
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