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1.
Cell Death Dis ; 10(11): 804, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645547

RESUMO

Adipose-derived stem cells (ADSCs) have been shown to be beneficial in some pulmonary diseases, and the paracrine effect is the major mechanism underlying ADSC-based therapy. Autophagy plays a crucial role in maintaining stem cell homeostasis and survival. However, the role of autophagy in mediating ADSC paracrine effects has not been thoroughly elucidated. We examined whether ADSCs participate in lipopolysaccharide (LPS)-induced pulmonary microvascular endothelial cell (PMVEC) barrier damage in a paracrine manner and illuminated the role of autophagy in regulating ADSC paracrine effects. PMVECs and ADSCs with or without autophagy inhibition were cocultured without intercellular contact, and the microvascular barrier function was assessed after LPS treatment. ADSC paracrine function was evaluated by detecting essential growth factors for endothelial cells. For in vivo experiments, ADSCs with or without autophagy inhibition were transplanted into LPS-induced lung-injury mice, and lung injury was assessed. ADSCs significantly alleviated LPS-induced microvascular barrier injury. In addition, ADSC paracrine levels of VEGF, FGF, and EGF were induced by LPS treatment, especially in the coculture condition. Inhibiting autophagy weakened the paracrine function and the protective effects of ADSCs on microvascular barrier injury. Moreover, ADSC transplantation alleviated LPS-induced lung injury, and inhibiting autophagy markedly weakened the therapeutic effect of ADSCs on lung injury. Together, these findings show that ADSC paracrine effects play a vital protective role in LPS-induced pulmonary microvascular barrier injury. Autophagy is a positive mediating factor in the paracrine process. These results are helpful for illuminating the role and mechanism of ADSC paracrine effects and developing effective therapies in acute lung injury.

2.
Cancer Manag Res ; 11: 6887-6893, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413634

RESUMO

Purpose: Circular RNAs (circRNAs) are recently identified new noncoding RNAs and play an important role in tumorigenesis. Previous studies have indicated that hsa_circRNA_102958 is a potential diagnostic indicator in gastric cancer. However, its role in colorectal cancer (CRC) is poorly understood. Methods: qRT-PCR and ISH were used to test gene expression in tissues. Survival rate was analzyed by Kaplan-Meier curve. Luciferase reporter assay was used to determine the interaction between circRNA and miRNA or between miRNA and mRNA. Western blotting was used to test protein expression. CCK8 and colony formation assay was used to analyze proliferation. Transwell assay was used for migration and invasion determination. Results: In our research, we found that hsa_circRNA_102958 expression was significantly increased in CRC tissues, compared to adjacent normal controls. Increased hsa_circRNA_102958 levels in CRC patients indicated a poor prognosis. The effects of hsa_circRNA_102958 on CRC cell proliferation, migration and invasion were then determined by CCK8, colony formation and Transwell assays. We showed that hsa_circRNA_102958 silencing markedly suppressed CRC growth, migration and invasion. Furthermore, hsa_circRNA_102958 was identified as a sponge for miR-585. We demonstrated that hsa_circRNA_102958 promoted CDC25B expression through inhibiting miR-585 in CRC. Rescue assays illustrated that CDC25B overexpression reversed the suppressive effects of hsa_circRNA_102958 silencing on CRC. Conclusion: Taken together, our findings revealed the novel oncogenic roles of hsa_circRNA_102958 in CRC through miR-585/CDC25B axis.

3.
Cancer Med ; 8(7): 3544-3552, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31090199

RESUMO

Accumulating evidence supports the notion that epigenetic modifiers are abnormal in carcinogenesis and have a fundamental role in cancer progression. Among these aberrant epigenetic modifiers, the function of histone methyltransferase KMT2A in somatic tumors is not well known. By analyzing KMT2A expression in patient tissues, we demonstrated that KMT2A was overexpressed in colorectal cancer tissues in comparison with adjacent normal tissues and its expression was positively correlated with cancer stages. In KMT2A-knockdown HCT116 and DLD1 cells, cell invasion and migration were consequently suppressed. In addition, KMT2A depletion effectively suppressed cancer metastasis in vivo. Mechanistically, cathepsin Z (CTSZ) was demonstrated to be an important downstream gene of KMT2A. Further studies showed that p65 could recruit KMT2A on the promoter region of the downstream gene CTSZ and knockdown of p65 could reduce the KMT2A on the promoter of CTSZ. Finally, our present study revealed that KMT2A epigenetically promotes cancer progression by targeting CTSZ, which has specific functions in cancer invasion and metastasis.

4.
Biochem Biophys Res Commun ; 509(3): 734-738, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30616889

RESUMO

An increasing number of reports have indicated that long noncoding RNAs (lncRNAs) are involved in the pathogenesis of colorectal cancer (CRC). However, many lncRNAs remain unidentified in CRC, and their functions are yet to be elucidated. In this study, we investigated the function of lncRNA LOC101927746 in CRC progression. We found that LOC101927746 expression was significantly increased in CRC tissues according to the GEO dataset. Moreover, LOC101927746 expression was positively correlated with tumor stage and metastasis. Additionally, the high expression of LOC101927746 predicted poor prognosis in CRC patients. Functionally, we demonstrated that LOC101927746 silencing significantly suppressed the proliferation, migration, and invasion of CRC cells. In terms of its mechanism, LOC101927746 could serve as a competing endogenous RNA to inhibit miR-584-3p and activate its target gene SSRP1. The expression of miR-584-3p was inversely correlated with either LOC101927746 or SSRP1 in CRC tissues. The overexpression of SSRP1 or inhibition of miR-584-3p could reverse the effects of LOC101927746 knockdown in CRC cells. Taken together, our results suggest that the LOC101927746/miR-584-3p/SSRP1 axis modulates CRC progression.


Assuntos
Neoplasias Colorretais/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/genética , MicroRNAs/genética , Invasividade Neoplásica/genética , RNA Longo não Codificante/genética , Fatores de Elongação da Transcrição/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/patologia , Progressão da Doença , Humanos , Invasividade Neoplásica/patologia
5.
J Oncol ; 2018: 5072987, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30305811

RESUMO

Purpose: We aimed to identify new predictive biomarkers for cetuximab in first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC). Methods: The study included patients with KRAS wild-type unresectable liver-limited mCRC treated with chemotherapy with or without cetuximab. Next-generation sequencing was done for single nucleotide polymorphism according to custom panel. Potential predictive biomarkers were identified and integrated into a predictive model within a training cohort. The model was validated in a validation cohort. Results: Thirty-one of 247(12.6%) patients harbored RAS mutations. In training cohort (N=93), six potential predictive genes, namely, ATP6V1B1, CUL9, ERBB2, LY6G6D, PTCH1, and RBMXL3, were identified. According to predictive model, patients were divided into responsive group (n=66) or refractory group (n=27). In responsive group, efficacy outcomes were significantly improved by addition of cetuximab to chemotherapy. In refractory group, no benefit was observed. Interaction test was significant across all endpoints. In validation cohort (N=123), similar results were also observed. Conclusions: In the first-line treatment of mCRC, the predictive model integrating six new predictive mutations divided patients well, indicating a promising approach to further refine patient selection for cetuximab on the basis of RAS mutations.

6.
Cell Physiol Biochem ; 44(5): 1762-1774, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29216630

RESUMO

BACKGROUND/AIMS: Ischemia is one of the main causes of the high rate of absorption of transplanted autologous fat. Autophagy allows cells to survive by providing energy under starvation. Rapamycin has been found to play a role in promoting autophagy. In this study, we investigated whether rapamycin participates in the survival and adipogenesis of ischemia-challenged adipose-derived stem cells (ADSCs) by regulating autophagy. METHODS: Before the cells were exposed to oxygen-glucose deprivation (OGD), a simulated ischemic microenvironment, the level of autophagy was reduced or increased by lentiviral transfection with short hairpin RNA targeting microtubule-associated protein 1-light chain 3 gene (shRNA-LC3) or treatment with rapamycin, respectively. The level of autophagy was assessed by western blotting, transmission electron microscopythen the apoptosis ratio was determined through terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and flow cytometry. Adipogenesis was further evaluated by oil red O staining and the expressions level of some specific proteins for adipocytes. RESULTS: shRNA-LC3 and rapamycin treatment effectively decreased and improved the level of autophagy in cells with or without OGD challenge, respectively. In addition, autophagy inhibition increased the apoptosis rate and activated caspase-3 expression level in response to OGD, and these were markedly inhibited by rapamycin preconditioning. During adipogenesis, autophagy inhibition decreased not only oil droplet accumulation but also lipoprotein lipase (LPL) and peroxisome proliferator-activated receptor gamma (PPARγ) expression in cells with or without OGD challenge. However, autophagy promotion by rapamycin increased oil droplet accumulation and LPL and PPARγ expression. CONCLUSIONS: Rapamycin may promote the survival and adipogenesis of ischemia-challenged ADSCs by upregulating autophagy.


Assuntos
Adipogenia/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Sirolimo/farmacologia , Tecido Adiposo/citologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Hipóxia Celular , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Glucose/metabolismo , Humanos , Isquemia/metabolismo , Isquemia/patologia , Microscopia Eletrônica de Transmissão , Proteínas Associadas aos Microtúbulos/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/genética , PPAR gama/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/metabolismo , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Células-Tronco/ultraestrutura , Transfecção
7.
PLoS One ; 12(4): e0175284, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28394911

RESUMO

OBJECTIVE: To analyze the benefits and prognostic factors after surgical resection of pulmonary metastases from colorectal cancer (CRC). METHODS: From Jan. 2004 to Jan. 2015, continuous 88 cases diagnosed with pulmonary metastases from CRC, including 15 cases of synchronous metastases and 73 metachronous metastases, were analyzed in the retrospective study. RESULTS: All of these 88 cases underwent curative pulmonary resection including 8 cases of simultaneous surgery. The one-year, three-year and five-year survival of the 88 cases were 93.4%, 60.2% and 35.7%, respectively. 63 patients just have one metastasis, and 25 patients have more than one metastasis. Additionally, the one-year, three-year and five-year survival was 98.1%, 70.2% and 40.3% respectively in one metastasis group, while 80.1%, 37.9% and 22.5% respectively in more than one metastasis group (p = 0.003). DFS of 37 metachronous metastases were equal or greater than 18 months, and DFS of 36 metachronous metastases were less than 18 months. The one-year, three-year and five-year survival was 97.8%, 77.9% and 41.4% respectively in the DFS≥18 month group, while 88.2%, 44.6% and 28.1% respectively in the DFS<18 month group (p = 0.01). CONCLUSION: Surgical resection of pulmonary metastases from colorectal cancer can improve survival rate in selected patients. It seems that the number of metastases is an independence prognostic factor in surgical treatment. Furthermore, longer DFI implies longer survival for resectable CRC pulmonary metastases.


Assuntos
Neoplasias Colorretais/patologia , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
8.
Sci Rep ; 7: 44543, 2017 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-28291253

RESUMO

The molecular mechanisms underlying colorectal cancer (CRC) development remain elusive. In this study, we examined the miRNA and mRNA expressions in the adenoma-carcinoma sequence (ACS), a critical neoplastic progression in CRC development. We found that miR-137 was down-regulated in all adenoma and carcinoma tissues. Low miR-137 levels were correlated negatively with tumor progression and metastasis. Then we identified the inhibition effect of the miR-137 in CRC development, both in CRC cell lines and mouse models. MiR-137 was shown to control CRC cell proliferation, colony formation, migration and invasion and to control tumor growth and metastasis. We further confirmed the negative association between miR-137 and c-Met expression and thus validated this important oncogene as the target of miR-137 in CRC. In addition, we found a DNA methyl-CpG-binding protein, Mecp2, was up-regulated in ACS tissues via mRNA sequencing. Further experiment showed that miR-137 expression in CRC was subjected to epigenetic regulation mediated by Mecp2. We also confirmed c-Met expression can be up-regulated by silencing of miR-137 and suppressed by coexpression of Mecp2 and miR-137. These findings highlight the critical role of miR-137-c-Met nexus in CRC development and reveal Mecp2-regulated epigenetic silence causes the downregulation of miR-137 in colorectal adenoma and carcinoma.


Assuntos
Neoplasias Colorretais/genética , Proteína 2 de Ligação a Metil-CpG/genética , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-met/genética , Adenoma/genética , Adenoma/patologia , Animais , Carcinoma/genética , Carcinoma/patologia , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Epigênese Genética , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Humanos , Camundongos , MicroRNAs/antagonistas & inibidores , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Clin Chim Acta ; 473: 198-203, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27836106

RESUMO

BACKGROUND: Increased platelet has been identified as an independent and unfavorable prognostic indicator in various cancers including cervical cancer. In our study, the prognostic value of preoperative platelet count combining with FIGO (International Federation of Gynecology and Obstetrics) stage in patients with operable cervical cancer was investigated. METHODS: A large cohort study including 800 operable cervical cancer patients was conducted from May 2005 to December 2012. Cancer-related biomarkers such as platelet count, hematocrit, hemoglobin, RDW was evaluated together with FIGO staging system in stage IA1-IIA2 cervical cancer patients. The prediction validity of platelet together with FIGO stage was then evaluated by receiver operating characteristic (ROC) curve, and the areas under the curve (AUCs) were compared by Z test. RESULTS: Univariate cox proportional hazard analysis demonstrated that hematocrit, platelet count, hemoglobin, FIGO stage, tumor differentiation, PLN (pelvic lymph node metastasis), LVSI (vascular lymph node invasion) were associated with overall survival (OS) and disease free survival (DFS), instead of RDW (red cell distribution width), age and histological subtype. Multivariate analysis demonstrated that preoperative platelet and FIGO stage were independent predictors for OS and DFS in cervical cancer. Furthermore, significant improvements were found after the combination of platelet count and FIGO stage in predicting OS and DFS for cervical cancer patients (P=0.0128 and P=0.0385, respectively). CONCLUSIONS: Combination of platelet count and FIGO stage improved the prediction performance of FIGO staging and provide additional risk stratification for operable cervical cancer patients.


Assuntos
Período Pré-Operatório , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Contagem de Plaquetas , Prognóstico , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgia
10.
Mol Cell Biochem ; 425(1-2): 125-138, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27848074

RESUMO

Vascular endothelial cells are highly sensitive to oxidative stress, and this is one of the mechanisms by which widespread endothelial dysfunction is induced in most cardiovascular diseases and disorders. However, how these cells can survive in oxidative stress environments remains unclear. Salidroside, a traditional Chinese medicine, has been shown to confer vascular protective effects. We aimed to understand the role of autophagy and its regulatory mechanisms by treating human umbilical vein endothelial cells (HUVECs) with salidroside under oxidative stress. HUVECs were treated with salidroside and exposed to hydrogen peroxide (H2O2). The results indicated that salidroside exerted cytoprotective effects in an H2O2-induced HUVEC injury model and suppressed H2O2-induced apoptosis of HUVECs. Pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, increased oxidative stress-induced HUVEC apoptosis, while the autophagy activator rapamycin induced anti-apoptosis effects in HUVECs. Salidroside increased autophagy and decreased apoptosis of HUVECs in a dose-dependent manner under oxidative stress. Moreover, 3-MA attenuated salidroside-induced HUVEC autophagy and promoted apoptosis, whereas rapamycin had no additional effects compared with salidroside alone. Salidroside upregulated AMPK phosphorylation but downregulated mTOR phosphorylation under oxidative stress; however, administration of compound C, an AMPK inhibitor, abrogated AMPK phosphorylation and increased mTOR phosphorylation and apoptosis compared with salidroside alone. These results suggest that autophagy is a protective mechanism in HUVECs under oxidative stress and that salidroside might promote autophagy through activation of the AMPK pathway and downregulation of mTOR pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Glucosídeos/farmacologia , Células Endoteliais da Veia Umbilical Humana/enzimologia , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Humanos
11.
Tumour Biol ; 37(10): 14193-14203, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27553024

RESUMO

Paraoxonase (PON) enzymes possess antioxidant properties and protect against cardiovascular diseases. As a member of PON family, PON3 is primarily synthesized in the liver and poorly investigated. This study aimed to examine the expression of PON3 in human hepatocellular carcinoma (HCC) and investigate the clinical significance and biological function of PON3 in HCC patients. We first analyzed PON3 expression in 50 paired HCC samples (HCC tissues vs matched para-cancerous tissues) and 160 clinical HCC specimens by using immunohistochemistry (IHC). Our results showed that the expression of PON3 was downregulated in HCC and significantly associated with tumor-node-metastasis (TNM) stage, tumor size, and tumor number. Kaplan-Meier survival and Cox regression analyses showed that PON3 was an independent prognostic factor for overall survival (OS) and time to recurrence (TTR). Finally, we aimed to reveal the biological function of PON3 in HCC growth and metastasis, and our results showed that overexpression of PON3 potently inhibited growth and metastasis of HCC. Collectively, our study demonstrated that PON3 exhibited tumor-suppressive effects toward HCC and it might serve as a novel prognostic marker in HCC.


Assuntos
Arildialquilfosfatase/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/secundário , Neoplasias Hepáticas/patologia , Animais , Apoptose , Western Blotting , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/cirurgia , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirurgia , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Oncotarget ; 7(37): 58931-58938, 2016 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-27391344

RESUMO

Over-expression of long non-coding RNA (lncRNA)-CLMAT3 is significantly associated with colorectal liver metastasis and is an independent predictor of poor survival for colorectal cancer patients. However, as little is known regarding the role of this gene in the proliferation of colorectal cancer in vitro, we investigated the involvement of lncRNA-CLMAT3 in colorectal cancer cell proliferation. In this study, we demonstrate that lncRNA-CLMAT3 expression was significantly increased in colorectal cancer cells compared with a normal intestinal mucous cell line and that inhibition of lncRNA-CLMAT3 suppressed colorectal cancer cell proliferation in vitro. We also found that this reduced colorectal cancer cell proliferation due to lncRNA-CLMAT3 knockdown is associated with G0/G1 cell-cycle arrest induction and apoptosis enhancement. Furthermore, lncRNA-CLMAT3 knockdown enhanced Cdh1 expression and resulted in p27Kip accumulation via increased Skp2 protein ubiquitination. Taken together, our findings suggest that reducing lncRNA-CLMAT3 inhibits colorectal cancer cell proliferation by affecting cell cycle components.


Assuntos
Neoplasias Colorretais/genética , Mucosa Intestinal/metabolismo , RNA Longo não Codificante/genética , Antígenos CD , Apoptose , Caderinas/genética , Caderinas/metabolismo , Ciclo Celular , Proliferação de Células , Neoplasias Colorretais/terapia , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Mucosa Intestinal/patologia , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , Células Tumorais Cultivadas , Ubiquitinação
13.
FEBS Lett ; 590(5): 672-82, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26848942

RESUMO

The activation of hepatic stellate cells (HSCs) is a prominent event in liver fibrogenesis. However, how HSCs are activated in the hypoxic microenvironment remains unclear. Here, we found that hypoxia increased autophagy in rat HSCs. Moreover, hypoxia induced an elevation of the intracellular calcium concentration ([Ca(2+)]i), which was abolished by the cytosolic Ca(2+) chelator or the phospholipase C (PLC)-specific inhibitor. Furthermore, hypoxia-induced autophagy involved the calcium-dependent activation of the 5'-adenosine monophosphate-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) and protein kinase C-theta (PKCθ) pathways. In addition, hypoxia-mediated activation of HSCs depended on autophagy. Our results suggest that autophagy induction via the calcium-dependent AMPK-mTOR and PKCθ pathways might lead to the activation of HSCs during hypoxic stress.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia , Cálcio/metabolismo , Células Estreladas do Fígado/citologia , Estresse Oxidativo , Proteína Quinase C/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Hipóxia Celular , Citosol/metabolismo , Ratos , Transdução de Sinais
14.
Ann Surg ; 263(3): 434-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26465781

RESUMO

OBJECTIVES: The optimal time to initiate adjuvant chemotherapy after surgery in patients with colon cancer is not clear. We investigated the benefit of combined intraportal chemotherapy administered during radical surgery with adjuvant chemotherapy for treating stage II and III colon cancer. METHODS: Patients were randomly assigned to OCTREE arm (intraportal chemotherapy plus mFOLFOX6) or a standard adjuvant chemotherapy arm (mFOLFOX6). The primary study endpoint was disease-free survival. The secondary endpoints included metastasis-free survival, overall survival, and safety. RESULTS: The intent-to-treat population comprised 237 patients. With a median follow-up of 44 months, the hazard ratio (OCTREE vs mFOLFOX6) was 0.66 (95% confidence interval, 0.43-0.90), a 34% risk reduction in favor of OCTREE (P = 0.016). The 3-year disease-free survival rate was 85.2% for OCTREE and 75.6% for mFOLFOX6 alone (P = 0.030). The 3-year metastasis-free survival rates were 87.6% for OCTREE and 78.0% for mFOLFOX6 (P = 0.035). Patients had lower distant metastatic rate in the OCTREE arm (12.7% vs 22.7%; P = 0.044), when compared with the mFOLFOX6 arm. The 3-year overall survival was no significant difference between 2 arms (P = 0.178). Neutropenia occurred in 12.7% of the patients receiving OCTREE and in 2.5% of the patients receiving mFOLFOX6 (P = 0.003) within 2 weeks of surgery, and grade 3 or 4 toxicity event was no difference between 2 regimens. CONCLUSIONS: Combination of intraoperative intraportal chemotherapy with mFOLFOX6 reduced the occurrence of distant metastases and improved disease-free survival in patients with stage II and stage III colon cancer.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/análise , Quimioterapia Adjuvante , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Feminino , Floxuridina/administração & dosagem , Fluoruracila/administração & dosagem , Humanos , Infusões Intravenosas , Leucovorina/administração & dosagem , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Taxa de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do Tratamento
15.
Onco Targets Ther ; 8: 1493-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26124668

RESUMO

IL-27, a new member of the IL-12 family, has been found to have antitumor effects in colorectal cancer (CRC); therefore, polymorphisms of this protein may modulate CRC carcinogenesis. So, we studied the association of single nucleotide polymorphisms of the IL-27 gene with the risk of CRC occurrence using a case-control using 600 CRC patients and matched healthy controls. The IL-27 rs153109 polymorphism was analyzed with polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. Data indicate that GG, GA, and combined A-variant genotypes (GG + GA) conferred significantly greater risk of CRC (P=0.034, 0.002, and 0.001, respectively), and that G alleles were associated with higher susceptibility to CRC (P=0.001). However, no correlation was found between the IL-27 rs153109 polymorphism and particular clinical features. In conclusion, our data demonstrated a clear association of IL-27 rs153109 polymorphism and the risk of CRC development.

16.
Tumour Biol ; 36(11): 8747-54, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26050227

RESUMO

Long noncoding RNA (lncRNA) plays a crucial role in the regulation of various cellular processes and human diseases. However, little is known about the role of lncRNAs in colorectal liver metastasis (CLM). In the present study, we aimed to determine whether lncRNAs are differentially expressed in CLM tissue and to further assess their clinical value. lncRNA arrays were employed to screen for differentially expressed lncRNAs in colorectal cancer (CRC) tissues with synchronous, metachronous, or nonliver metastasis. Based on bioinformatics data, a quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assay was performed to identify target lncRNAs in an expanded set of CRC samples with various subtypes of liver metastasis. The relationships between the target lncRNAs and the clinical characteristics and patient prognosis were further analyzed. After determining the expression profile of lncRNAs (n = 1332) in CLM tissue, 40 differentially expressed lncRNAs that were potentially related to CLM were selected for further examination in an expanded set of clinical samples, and three novel target lncRNAs, termed lncRNA-CLMAT1-3, were verified. High lncRNA-CLMAT3 expression strongly correlated with liver metastasis (P = 0.03) and lymph node metastasis (P = 0.009). Moreover, patients displaying high lncRNA-CLMAT3 expression exhibited a shorter median overall survival duration than those displaying low lncRNA-CLMAT3 expression (30.7 vs. 35.2 months, P = 0.007). Multivariate analysis demonstrated that the lncRNA-CLMAT3 expression level is an independent prognostic factor (hazard ratio 2.05, P = 0.02) after adjusting for other known prognostic factors. lncRNA-CLMAT3 over-expression was significantly associated with CLM and was an independent predictor of poor survival for patients with CRC.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Hepáticas/genética , Prognóstico , RNA Longo não Codificante/biossíntese , Adolescente , Adulto , Idoso , Neoplasias Colorretais/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Metástase Linfática , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/genética
17.
Qual Life Res ; 24(11): 2663-70, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26003317

RESUMO

OBJECTIVE: Enhanced recovery after surgery (ERAS) integrates evidence-based interventions to reduce surgical stress and accelerate rehabilitation. Our study was to compare the short-term quality of life (QOL) in patients undergoing open colonic surgery using ERAS program or conventional management. METHODS: A prospective study of 57 patients using ERAS program and 60 patients using conventional management was conducted. The clinical characteristics of all patients were recorded. QOL was evaluated longitudinally using the questionnaires (EORTC QLQ-C30 and QLQ-CR29) pre- and postoperatively. Generalized estimating equation was used to do the analysis in order to determine the effective impact of correlative factors on the postoperative QOL, including age, sex, BMI, ASA grade, tumor location, tumor size, pTNM stage, recovery program and length of time after surgery. RESULTS: The morbidity in ERAS and control group was 17.5 versus 26.7 % (p = 0.235). The patients in ERAS group had much faster rehabilitation and less hospital stay. In the primary statistical analysis, the scores of global QOL (on POD3, POD6, POD10, POD14, POD21), physical functioning (on POD3, POD6, POD10, POD14, POD21), role functioning (on POD6, POD10, POD14, POD21), emotional functioning (on POD3, POD6, POD10, POD14, POD21), cognitive functioning (on POD3, POD6) and social functioning (on POD3, POD6, POD10, POD14, POD21, POD28) were higher in ERAS group than in control group, which suggested that the patients in ERAS group had a better life status. However, the scores of pain (on POD10, POD14, POD21), appetite loss (on POD3, POD6), constipation (on POD3, POD6, POD10), diarrhea (on POD3, POD10), financial difficulties (on POD10, POD14, POD21), perspective of future health (on POD6, POD10, POD14), gastrointestinal tract problems (on POD3, POD6, POD10) and defecation problems (on POD6, POD10, POD14) were lower in ERAS group than in control group, which revealed that the patients in ERAS group suffered less symptoms. In the further generalized estimating equation analysis, the result showed that recovery program and length of time after surgery had independently positive impact on the patient's postoperative QOL. CONCLUSION: Short-term QOL in patients undergoing colonic cancer using ERAS program was better than that using conventional management.


Assuntos
Neoplasias do Colo/cirurgia , Período Perioperatório/reabilitação , Gerenciamento Clínico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Inquéritos e Questionários
18.
Tumour Biol ; 36(8): 5839-48, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25716203

RESUMO

Emerging evidence indicates that O(6)-methylguanine-DNA methyltransferase (MGMT) is a candidate for tumor suppression in several types of human tumors including colorectal cancer (CRC). However, the correlation between MGMT hypermethylation and clinicopathological characteristics of CRC remains unclear. In this study, we conducted a systematic review and meta-analysis to quantitatively evaluate the effects of MGMT hypermethylation on the incidence of CRC and clinicopathological characteristics. A comprehensive literature search was done from Web of Science, the Cochrane Library Database, PubMed, EMBASE, CINAHL, and the Chinese Biomedical Database for related research publications written in English and Chinese. Methodological quality of the studies was also evaluated. Analyses of pooled data were performed with Review Manager 5.2. Odds ratio (OR) and hazard ratio (HR) were calculated and summarized, respectively. Final analysis from 28 eligible studies was performed. MGMT hypermethylation is found to be significantly higher in CRC than in normal colorectal mucosa, the pooled OR from 13 studies including 1085 CRC and 899 normal colorectal mucosa, OR = 6.04, 95 % confidence interval (CI) = 4.69-7.77, p < 0.00001. MGMT hypermethylation is also significantly higher in colorectal adenoma than in normal colorectal mucosa, but it is significantly less compared to that in CRC patients. Interestingly, MGMT hypermethylation is correlated with sex status and is significantly higher in female than in male. MGMT hypermethylation is also associated with high levels of microsatellite instability (MSI). The pooled HR for overall survival (OS) shows that MGMT hypermethylation is not associated with worse survival in CRC patients. The results of this meta-analysis suggest that MGMT hypermethylation is associated with an increased risk and high levels of MSI and may play an important role in CRC initiation. However, MGMT hypermethylation may play an important role in the early stage of CRC progression and development, as well as having limited value in prediction of prognosis in CRC patients. We also discussed that MGMT may serve as a potential drug target of CRC.


Assuntos
Neoplasias Colorretais/genética , Metilação de DNA/genética , O(6)-Metilguanina-DNA Metiltransferase/biossíntese , Prognóstico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Guanina/análogos & derivados , Guanina/metabolismo , Humanos , Mutação , Estadiamento de Neoplasias , O(6)-Metilguanina-DNA Metiltransferase/genética , Regiões Promotoras Genéticas
19.
Oncol Lett ; 9(3): 1039-1045, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25663854

RESUMO

Colorectal cancer (CRC) is one of the greatest threats to public health. Recent advances in whole-genome transcriptome analyses have enabled the identification of numerous members of a novel class of non-coding (nc)RNA, long ncRNA (lncRNA), which is broadly defined as RNA molecules that are >200 nt in length and lacking an open reading frame. In the present review, all lncRNAs associated with CRC are briefly summarized, with a particular focus on their potential roles as clinical biomarkers. CRC-associated lncRNAs involved in the underlying mechanisms of CRC progression are also initially included. This should benefit the development of novel markers and effective therapeutic targets for patients with CRC.

20.
Cancer Biol Ther ; 16(2): 244-52, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25602156

RESUMO

Colorectal cancer (CRC) is one of the most common cancers worldwide. The molecular mechanisms underlying CRC development involve a multistep process with the accumulation of both genetic and epigenetic changes. To deeply understand CRC tumorigenesis and progression, advances in identification of novel mechanisms and key factors are therefore in an urgent need. Here, we examined the correlation of factor inhibiting HIF-1α (FIH-1) expression with clinicopathological features of CRC. The finding that FIH-1 was not only significantly decreased in tumor tissue but also was significantly correlated with tumor invading depth, lymph node involvement, and metastasis suggested the role of FIH-1 as a tumor suppressor in CRC development. To further support the above hypothesis, we performed both in vitro and in vivo experiments to identify the role of FIH-1 in CRC development. FIH-1 was found to inhibit CRC cell proliferation, migration, invasion, and colony formation in vitro. FIH-1 was also shown to repress LOVO xenograft tumor growth in vivo. To decipher the mechanism, we examined the expression level of HIF-1α and its target genes. We found that FIH-1 was able to inhibit HIF1α mediated transcription of GLUT1 and VEGF in CRC cells. The above observation points to the possibility that loss or decreased expression of FIH-1 gene may lead to a constitutive activation of HIF1α and an alteration of HIF-1 targets such as GLUT-1 and VEGF. These findings highlight the critical role of FIH-1 in CRC and indicate FIH-1 functions as a tumor suppressor in human CRC by repressing HIF1α pathway.


Assuntos
Neoplasias Colorretais/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Progressão da Doença , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Xenoenxertos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Prognóstico , Proteínas Supressoras de Tumor/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
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