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1.
Cancer Biomark ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34487019

RESUMO

BACKGROUND: The Notch signaling regulates numerous cell growth, differentiation, and death. However, the expression pattern of its ligand Delta-like 4 (DLL4) in tumors is still uncertain. OBJECTIVE: In the present study, we examined DLL4 expression in colorectal cancer as well as assessed its role as a prognostic indicator in the present study. METHODS: DLL4 expression was examined by immunohistochemistry in 265 surgically resected specimens of colorectal cancer and adjacent normal tissues. The relationship between DLL4 expression and clinicopathological characteristics was analyzed. The association of DLL4 expression with the patients' overall survival rate was assessed by Kaplan-Meier and Cox proportional-hazards regression. RESULTS: Increased DLL4 level was detected in colorectal cancer compared with that of normal tissues. Elevated DLL4 level in colorectal cancer was associated with increased body mass index of patients. Moreover, increased DLL4 level was also found to be correlated with tumor invasion, metastases and unfavorable clinical outcom of patients. CONCLUSIONS: DLL4 level is increased in colorectal cancer, especially in patients with increased body mass index, indicating potential involvement of obesity-related tumorigenesis and development. It might also serve as a novel molecular marker to predicate outcome of patients.

2.
Life Sci ; 282: 119817, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34273374

RESUMO

R-spondins 2 (RSPO2) protein is a member of RSPO family which plays an essential role in stem cell survival, development and tumorigenicity. There has several evidence suggested that RSPO2 involved in breast, gastric, liver and colorectal cancer. However, the specific function and mechanism of RSPO2 in nasopharyngeal carcinoma (NPC) remain unknown. In the present study, we first observed that RSPO2 expression was elevated in NPC cell lines SUNE-6-10B, SUNE-5-8F, and CNE-1 compared with the normal laryngeal epithelia cell line NP69. Knockdown of RSPO2 significantly inhibits SUNE-6-10B and CNE-1 cell survival and proliferation by using CCK-8 assay and Edu assay, respectively. Further studies verified that RSPO2 silence suppressed migration and invasion of SUNE-6-10B and CNE-1 cells. Further studies suggested that RSPO2 silence suppressed epithelial-to-mesenchymal transition (EMT) related protein E-cadherin expression and promoted Vimentin and N-cadherin expression both in SUNE-6-10B and CNE-1 cells. Molecular mechanism explorations showed that RSPO2 deletion increased ZNRF3 expression and inhibited Gli1 expression. Additionally, knockdown ZNRF3 expression or overexpression Gli1 both reversed the effects of RSPO2 silence on NPC growth and metastasis. Finally, RSPO2 depletion was impaired NPC tumor growth in vivo animal experiments. In conclusion, the present study confirmed that RSPO2 silence inhibits the tumorigenesis of NPC via ZNRF3/Hedgehog-Gli1 signal pathway.


Assuntos
Carcinogênese/metabolismo , Inativação Gênica , Proteínas Hedgehog/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Transdução de Sinais , Ubiquitina-Proteína Ligases/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismo , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Proteínas Hedgehog/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Ubiquitina-Proteína Ligases/genética , Proteína GLI1 em Dedos de Zinco/genética
3.
Lancet Oncol ; 22(8): 1081-1092, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34252374

RESUMO

BACKGROUND: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. METHODS: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. FINDINGS: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. INTERPRETATION: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. FUNDING: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Junção Esofagogástrica/patologia , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/cirurgia , Adulto , Idoso , Capecitabina/administração & dosagem , Quimioterapia Adjuvante/métodos , Combinação de Medicamentos , Neoplasias Esofágicas/cirurgia , Feminino , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Ácido Oxônico/administração & dosagem , Neoplasias Gástricas/cirurgia , Tegafur/administração & dosagem
4.
World J Surg Oncol ; 19(1): 200, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34229721

RESUMO

BACKGROUND: The prognosis of patients with colorectal cancer and peritoneal metastasis (CRC-PM) after incomplete cytoreductive surgery (CRS) or palliative surgery is poor. Novel and effective therapies are urgently needed. This study aimed to assess the effects of palliative postoperative hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with CRC-PM. METHODS: This retrospective study included patients with CRC-PM at the First Affiliated Hospital of Xi'an Jiaotong University in 05/2014-05/2019. Observation indicators included overall survival (OS), ascites-free survival, peritoneal cancer index (PCI), and completeness of cytoreduction (CC). Kaplan-Meier survival curves and multivariable Cox regression models were used to determine the factors associated with OS and ascites-free survival. The ascites-specific quality of life (QoL) was measured using the Functional Assessment of Chronic Illness Therapy-Ascites Index (FACIT-AI). RESULTS: Eighty-two patients were included, including 37 and 45 in the HIPEC and non-HIPEC groups, respectively. Mean OS was 10.3±3.7 (95% CI 9.5-11.2) months. Multivariable Cox proportional hazard regression suggested that PCI (HR=6.086, 95% CI 3.187-11.620, P < 0.0001) was independently associated with OS. The degree of ascites (HR=2.059, 95% CI 1.412-3.005, P < 0.0001), PCI (HR=6.504, 95% CI 2.844-14.875, P < 0.0001), and HIPEC (HR=0.328, 95% CI 0.191-0.562, P < 0.0001) were independently associated with ascites-free survival. In patients with survival >6 months, postoperative ascites-specific QoL was significantly improved after HIPEC compared with the non-HIPEC group (P < 0.001). Oxaliplatin-based HIPEC significantly increased the rates of neutropenia and peripheral neurotoxicity (both P < 0.05). CONCLUSION: These data indicate that postoperative oxaliplatin-based HIPEC might help increase ascites-free survival in CRC-PM patients after incomplete CRS or palliative surgery, with improved QoL after 6 months of follow-up.


Assuntos
Neoplasias Colorretais , Hipertermia Induzida , Neoplasias Peritoneais , Neoplasias Colorretais/terapia , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Humanos , Oxaliplatina , Cuidados Paliativos , Neoplasias Peritoneais/terapia , Prognóstico , Qualidade de Vida , Estudos Retrospectivos , Taxa de Sobrevida
5.
Urol Int ; : 1-8, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34265766

RESUMO

PURPOSE: The aim of this study was to investigate the role of BIRC5 for early diagnosis and prognosis in clear-cell renal cell carcinoma (ccRCC) by studying the expression of BIRC5 and the correlation between BIRC5 expression and clinicopathological parameters and prognosis in ccRCC. METHODS: The BIRC5 expression in ccRCC tissues and normal kidney tissues was measured using the Cancer Genome Atlas database and the Human Protein Atlas database. The correlation between BIRC5 expression and clinicopathological parameters and prognosis in ccRCC was analyzed using UALCAN, the Kaplan-Meier plotter, GEPIA, and SurvExpress. Thirteen-paired ccRCC plasma samples were used to verify the BIRC5 early diagnosis value of ccRCC. RESULTS: The BIRC5 expression is significantly higher in ccRCC than in normal kidney tissues, and is correlated with the clinical stage and pathological grade of ccRCC (p < 0.05). The result of analyzing the relationship between BIRC5 expression and outcomes in ccRCC indicates that a high BIRC5 expression is an independent prognostic factor affecting the overall survival and disease-free survival of ccRCC (p < 0.05). Compared with normal kidney tissues, the immunohistochemical test shows that BIRC5 is significantly upregulated in ccRCC tissues. mRNA expression levels of BIRC5 were significantly higher in the ccRCC plasma than normal (p < 0.05). CONCLUSIONS: The high expression of BIRC5 is an important indicator for the prognosis of ccRCC, which makes BIRC5 an effective biomarker for predicting the prognosis of patients in ccRCC. BIRC5 may be a great potential biomarker for early diagnosis of ccRCC.

6.
Oncologist ; 26(10): e1693-e1703, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34105207

RESUMO

BACKGROUND: Treatment options for refractory metastatic colorectal cancer (mCRC) were limited. Anlotinib is a novel multitarget tyrosine kinase inhibitor. ALTER0703 study was conducted to assess efficacy and safety of anlotinib for patients with refractory mCRC. MATERIALS AND METHODS: This was a multicenter, double-blinded, placebo-controlled, randomized phase III trial involving 33 hospitals in China. Patients had taken at least two lines of therapies were 2:1 randomized to receive oral anlotinib (12 mg/day; days 1-14; 21 days per cycle) or placebo, plus best supportive care. Randomization was stratified by previous VEGF-targeting treatments and time from diagnosis to metastases. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and safety. RESULTS: A total of 419 patients (anlotinib: 282; placebo: 137) were treated from December 2014 to August 2016. The median PFS was improved in anlotinib group (4.1 months; 95% confidence interval [CI], 3.4-4.5) over placebo group (1.5 months; 95% CI, 1.4-1.5), with a hazard ratio (HR) of 0.34 (95% CI, 0.27-0.43; p < .0001). However, median OS was similar between two groups (8.6 months; 95% CI, 7.8-9.7 vs. 7.2 months; 95% CI, 6.2-8.8; HR, 1.02; p = .870). Improvements of ORR and DCR were observed in anlotinib over placebo. The most common grade ≥ 3 anlotinib related adverse events were hypertension (20.92%), increased γ-GT (7.09%), and hand-foot skin reaction (6.38%). CONCLUSION: Anlotinib was tolerated in Chinese patients with refractory mCRC. Although OS did not reach significant difference, anlotinib still provided clinical benefits by substantially prolonged PFS in these patients. IMPLICATIONS FOR PRACTICE: In this randomized clinical trial that included 419 patients with refractory metastatic colorectal cancer, substantial prolonged in progression-free survival was noted in patients who received anlotinib compared with those given placebo. Improvements on objective response rate and disease control rate was also observed in anlotinib group. However, overall survival was similar between the two groups. In a word, in third-line or above treatment of Chinese patients with refractory metastatic colorectal cancer, anlotinib provided clinical benefit by significantly prolonged progression-free survival.

7.
Oncol Rep ; 46(2)2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34132367

RESUMO

Methyltransferase­like 3 (METTL3) is an RNA methyltransferase that mediates modification of N6­methyladenosine (m6A), which serves as an oncogene in various types of cancer. The role of m6A modification in the onset and progression of cancer has attracted growing attention. However, the functional and regulatory mechanisms of METTL3 in non­small cell lung cancer (NSCLC) progression are still poorly understood. In the present study, METTL3 expression in NSCLC tissue was analyzed using the Gene Expression Profiling Interactive Analysis database. Western blotting and reverse transcription­quantitative PCR were performed to evaluate the expression of METTL3 in NSCLC tissue and cell lines. Here, knockdown and overexpression of METTL3 notably decreased NSCLC cell viability, apoptosis and migration in vitro and, as well as tumorigenicity in vivo. Expression of METTL3 was upregulated in NSCLC tissue. METTL3 overexpression promoted cell viability and migration in NSCLC, while knockdown of METTL3 yielded the opposite result in vivo and in vitro. METTL3 increased Bcl­2 translation via m6A modification, which increased viability and enhanced migration of NSCLC cells. METTL3 served as an oncogene in NSCLC via METTL3­mediated Bcl­2 mRNA m6A modification, which indicated that targeting METTL3 may be an effective therapeutic strategy for clinical management of NSCLC.

8.
Life Sci ; 277: 119505, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33872662

RESUMO

PURPOSE: We aimed to investigate the patterns and prognostic roles of tumor mutation burden and immune microenvironment in pancreatic cancer. METHODS: The somatic mutation data, transcriptome profiles and clinical information were downloaded from the Cancer Genome Atlas database. Gene expression difference, Gene ontology, KEGG, gene set enrichment analyses and "CIBERSORT" algorithm were performed to screen differentially expressed genes, enriched functions or pathways and immune infiltrates differences between high and low TMB groups. Single sample gene set enrichment and unsupervised consensus clustering analyses were used for immunity grouping. Immune cell infiltration and expressions of HLA and checkpoint genes were investigated. Finally, a nomogram model integrating TMB and immune infiltration was established. RESULTS: A total of 608 differentially expressed genes were identified between high and low TMB groups, KEGG base excision repair and DNA replication pathways were enriched in high TMB group. Infiltration levels of M0 macrophages were higher and dendritic resting cells were lower in high TMB group. The risk model based on TMB-related immune genes, FAM19A2 and SLC22A17 was established and high risk scores indicated poorer prognosis. The expressions of HLA genes and immune checkpoint genes were higher in high immunity group. The nomogram showed remarkable ability for individualized survival estimation with good AUC values (0.794 and 0.800, respectively) for 3- and 5-year survival rates prediction. CONCLUSIONS: The characteristics of tumor mutation burden and immune infiltration in pancreatic cancer provide new insights into the tumor microenvironment, immunotherapies and a novel prognostic nomogram model for pancreatic cancer patients.


Assuntos
Biomarcadores Tumorais/genética , Biologia Computacional/métodos , Neoplasias Pancreáticas/genética , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Nomogramas , Prognóstico , Transcriptoma/genética , Microambiente Tumoral/genética
9.
Onco Targets Ther ; 13: 12181-12193, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33268996

RESUMO

Background: Cisplatin resistance results in the failure of platinum-based chemotherapy and relapse of gastric cancer. We aimed to investigate the potential regulating role of SNHG6/miR-325-3p/GITR in reversing cisplatin resistance. Patients and Methods: A total of 137 gastric cancer patients were recruited. qRT-PCR and ELISA were used to test the expression of target genes. CCK-8 and caspase 3/7 kit were used to test the cell viability and apoptosis rate. Dual luciferase reporter gene and RNA-pull down assay were used to investigate the potential interaction between target genes. Results: SNHG6 and GITR were up regulated in gastric cancer; however, miR-325-3p was down-regulated. Besides, SNHG6, miR-325-3p and GITR expression were associated with gastric cancer prognosis. Then, we found that GITR and SNHG6 promoted proliferation and inhibited apoptosis of MKN45 and MKN45 cisplatin resistance cell line; however, miR-325-3p inhibited proliferation and promoted apoptosis of these cell lines. Furthermore, SNHG6 might bind to miR-325-3p to regulate its expression, and miR-325-3p directly interacted with the 3`UTR of GITR. Conclusion: SNHG6 binds to miR-325-3p, which directly interacted with GITR to regulate cisplatin resistance of gastric cancer.

10.
Aging (Albany NY) ; 12(24): 25828-25844, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33234735

RESUMO

BACKGROUND: Esophageal adenocarcinoma (EAC) is a growing problem with a rapidly rising incidence and carries a poor prognosis. We aimed to develop a glycolysis-related gene signature to predict the prognostic outcome of patients with EAC. RESULTS: Five genes (CLDN9, GFPT1, HMMR, RARS and STMN1) were correlated with prognosis of EAC patients. Patients were classified into high-risk and low-risk groups calculated by Cox regression analysis, based on the five gene signature risk score. The five-gene signature was an independent biomarker for prognosis and patients with low risk scores showed better prognosis. Nomogram incorporating the gene signature and clinical prognostic factors was effective in predicting the overall survival. CONCLUSION: An innovative identified glycolysis-related gene signature and an effective nomogram reliably predicted the prognosis of EAC patients. METHODS: The Cancer Genome Atlas database was investigated for the gene expression profile of EAC patients. Glycolytic gene sets difference between EAC and normal tissues were identified via Gene set enrichment analysis (GSEA). Univariate and multivariate Cox analysis were utilized to construct a prognostic gene signature. The signature was evaluated by receiver operating characteristic curves and Kaplan-Meier curves. A prognosis model integrating clinical parameters with the gene signature was established with nomogram.


Assuntos
Adenocarcinoma/genética , Neoplasias Esofágicas/genética , Transcriptoma , Adenocarcinoma/metabolismo , Idoso , Arginina-tRNA Ligase/genética , Claudinas/genética , Bases de Dados Genéticas , Neoplasias Esofágicas/metabolismo , Proteínas da Matriz Extracelular/genética , Feminino , Glutamina-Frutose-6-Fosfato Transaminase (Isomerizante)/genética , Glicólise/genética , Humanos , Receptores de Hialuronatos/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estatmina/genética
11.
Cancer Biol Ther ; 21(12): 1179-1190, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33218268

RESUMO

Breast cancer is the most common malignant tumor in women. Its incidence is associated with obesity and metabolic syndrome (MetS), which are highly prevalent world widely and have been identified as poorer prognosis factors in breast cancer including triple-negative breast cancer (TNBC), which has poorer response to chemotherapy, radiotherapy, and endocrine therapy. Programmed death ligand 1 (PD-L1) is one of the immune checkpoints ligands that facilitates tumor escape and progress. Obesity/MetS could cause systemic inflammation and immune disorders, however, whether and how obesity/MetS affect PD-L1 expression in breast cancer had not been clarified. In the present study, we examined the PD-L1 expression profile in breast cancer either in online database or cell lines. We found higher PD-L1 mRNA level but not DNA copy number in breast cancer than normal breast tissue, and higher PD-L1 expression in TNBC than other subtypes. Moreover, we found a positive relationship between PD-L1 expression in TNBC and metabolic complications in patients. Next, obesity/MetS related M1 macrophage was found to promote the expression of PD-L1 in breast cancer cells cocultured with polarized macrophages derived from either monocyte-like cell line THP-1 or Wistar rat models. IL6/JAK/STAT pathway was further identified to be involved in the process. In addition, we discovered that the PD-L1 expression promoted by obesity/MetS could be restored by telmisartan, one of the angiotensin II receptor blockers (ARBs) and could affect macrophage polarization, through its selective peroxisome proliferator-activated receptor-gamma (PPARG) activation and NFKB p65 inhibition and therefore downregulates IL6 secretion from M1 macrophage.

12.
Int J Biol Markers ; 35(3): 83-89, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32921226

RESUMO

BACKGROUND: MiR-183-5p plays an important role in the pathophysiology of many tumors, while the role of MiR-183-5p in liver cancer is unclear. METHODS: In this study, quantitative reverse transcription-polymerase chain reaction and Western blotting were used to detect the expression of miR-183-5p in liver cancer cell lines, liver cancer tissues, and normal tissues adjacent to the cancer, and to explore the mechanism of miR-183-5p regulating liver cancer progression. The in vitro effects of miR-183-5p were evaluated by CCK-8, colony formation test, and wound healing test. Various databases were used to predict the target mRNA of miR-183-5p and verified by luciferase report analysis. In addition, the effects of miR-183-5p and its target gene on the survival of patients with liver cancer were also analyzed. RESULTS: miR-183-5p was highly expressed in hepatocellular carcinoma cells and tissues, and was related to some clinicopathological features. MiR-183-5p can promote the proliferation and migration of liver cancer cells. Using the bioinformatics database, we proved that miR-183-5p is related to the survival of liver cancer patients. Insulin receptor substrate 1 (IRS1) is a target of miR-183-5p, and luciferase analysis confirmed that miR-183-5p combines with the 3'-untranslated region (3'-UTR) of IRS1. CONCLUSION: The miR-183-5p/IRS1 axis may be a new target for liver cancer research.

13.
Oncol Rep ; 44(5): 1971-1984, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32901882

RESUMO

The KIAA0101 protein (also referred to as NS5ATP9 or Paf15) is overexpressed in esophageal squamous cell carcinoma (ESCC) and is associated with disease progression and poor patient survival, but how KIAA0101 expression is regulated remains unknown. The relationship between tumor miR­216a­5p expression and prognosis in patients with ESCC was revealed by survival analyses. Quantitative reverse­transcriptase PCR and western blot analysis were used to evaluate miR­216a­5p and KIAA0101 expression in human ESCC tissues and cell lines. The targeting of KIAA0101 by miR­216a­5p was verified by dual­luciferase reporter assays. The EC9706 and TE1 cell lines were transfected with miR­216a­5p mimics and inhibitor, or KIAA0101­specific shRNA and KIAA0101­expressing plasmids, in order to evaluate the effect of manipulating miR­216a­5p and KIAA0101 expression on ESCC cell proliferation, cell cycle progression, migration, and invasion. miR­216a­5p was lowly expressed and inversely correlated with KIAA0101 protein expression in ESCC tissues and cell lines. Lower miR­216a­5p expression was associated with worse prognosis in patients with ESCC. miR­216a­5p negatively regulated KIAA0101 expression by directly targeting the 3'­untranslated region of the KIAA0101 mRNA. Overexpression of miR­216a­5p suppressed the proliferation, migration, and invasion of the ESCC cell lines, whereas inhibition of miR­216a­5p had the opposite effects. Meanwhile, KIAA0101 promoted ESCC migration and invasion, and its overexpression abolished the antitumor effects of miR­216a­5p mimics. As a tumor suppressor, miR­216a­5p targets KIAA0101 to inhibit the proliferation, migration, and invasion of ESCC. Therefore, the miR­216a­5p/KIAA0101 axis may be a potential target for ESCC treatment.

14.
Dig Dis Sci ; 65(10): 2949-2958, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31858324

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is a serious threat to human lives and is usually diagnosed at the late stages. Recently, there has been a rapid advancement in the treatment options for HCC, but novel therapeutic targets are still needed, especially for precision medicine. AIMS: We aimed to investigate the involvement of non-coding RNA RP11-81H3.2 in HCC. METHODS: The expression of RP11-81H3.2 was examined in the blood samples of HCC patients, and in the human HCC cell lines, including HepG2, Smmc-7721, and Huh7. Cell proliferation was determined using the CCK-8 and EdU assay, and cell invasion and migration were determined using the transwell/wound healing assay. The effects of RP11-81H3.2 knockdown on in vivo tumor growth were evaluated utilizing the nude mice HepG2 tumor xenograft model. RESULTS: Here, we have identified a long non-coding RNA, RP11-81H3.2, which is enriched in HCC and can promote its proliferation, migration, and invasion both in vitro and in vivo. In addition, our results showed that RP11-81H3.2 binds to and regulate miR-490-3p expression in the HCC cells. Moreover, we found that RP11-81H3.2 regulates the expression of TNKS2 via miR-490-3p. Further, we found that RP11-81H3.2 and miR-490-3p form a regulatory loop; the release of RP11-81H3.2 leads to the suppression of miR-490-3p expression, thus, further enhancing the expression of RP11-81H3.2. CONCLUSIONS: Our data have provided a novel target for the diagnosis and treatment of HCC, and sheds light on the lncRNA-miRNA regulatory nexus that can control the HCC related pathogenesis.


Assuntos
Carcinoma Hepatocelular/enzimologia , Neoplasias Hepáticas/enzimologia , MicroRNAs/metabolismo , Oncogenes , RNA Longo não Codificante/metabolismo , Tanquirases/biossíntese , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica , RNA Longo não Codificante/genética , Transdução de Sinais , Tanquirases/genética , Carga Tumoral
15.
Sci Rep ; 9(1): 19915, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882986

RESUMO

In contrast to what is known about the complicated roles of Notch signalling in human malignancies, the direct target genes of Notch signalling are still unclear. Recently, long noncoding RNAs (lncRNAs) have been found to play various roles in the post-transcriptional regulation of gene expression. In the present study, we investigated the potential role of the Notch-induced lncRNA LUNAR1 in colorectal cancer (CRC). We recruited 196 cases of clinical CRC specimens and investigated LUNAR1 levels in these specimens. The associations of LUNAR1 with tumour aggressiveness and clinical outcomes were evaluated. Moreover, the impact of LUNAR1 on the malignant behaviour of tumour cells was tested in cell lines. Significantly increased expression of LUNAR1 in clinical CRC specimens was detected compared with that in matching normal tissues. LUNAR1 expression in CRC was found to be associated with the tumour aggressiveness, disease-free survival and overall survival of patients. The downregulation of LUNAR1 in SW620 cells inhibited cell proliferation, migration, invasion and tumour growth while inducing apoptosis. Moreover, the inhibition of LUNAR1 can significantly suppress IGF1 signalling in CRC. These results indicated that LUNAR1 was increased in CRC and might promote tumour progression. Thus, LUNAR1 may constitute a promising prognostic marker for the clinical management of CRC.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , RNA Longo não Codificante/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Neoplasias Colorretais/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Longo não Codificante/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
16.
Int J Biol Markers ; 34(4): 364-372, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31668113

RESUMO

PURPOSE: miR-491 functions as a tumor suppressor in several types of cancer. However, its function and mechanism in gastric cancer proliferation and metastasis have not been well defined. The aim of this study was to explore the role and regulatory mechanism of miR-491 in cell proliferation and migration in gastric cancer. METHODS: Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) was used to detect the expression pattern of miR-491 in gastric cancer tissues. miR-491 overexpression vector, miR-491 inhibitor, and siHMGA2 were used; and MTT, wound healing, and transwell assays were employed to examine proliferation and migration for BGC-823 cells. A dual-luciferase reporter gene was used to measure the target relationship between miR-491 and HMGA2. RESULTS: Most gastric cancer patients exhibit decreased miR-491 expression. miR-491 overexpression inhibited cell proliferation and migration, whereas miR-491 inhibitor treatment produced the opposite effect. Mechanistically, HMGA2 was identified as a direct target of miR-491. Moreover, HMGA2 knockdown inhibited cell proliferation and migration, which was similar to the effect of miR-491 overexpression. HMGA2 was decreased after transfection of the miR-491 vector and increased after transfection of the miR-491 inhibitor. CONCLUSION: Our results suggest that miR-491 suppressed cell proliferation and cell motility in gastric cancer by targeting HMGA2. Silencing HMGA2 produced a similar effect to miR-491 overexpression on cell proliferation and migration. miR-491/HMGA2 signaling may be a potential therapeutic target for gastric cancer patients with decreased miR-491 expression.


Assuntos
Proteína HMGA2/metabolismo , MicroRNAs/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Regulação para Baixo , Feminino , Proteína HMGA2/genética , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Transfecção
17.
BMC Cancer ; 19(1): 803, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412872

RESUMO

BACKGROUND: The risk of lymph node positivity in early-stage colon cancer is a parameter that impacts therapeutic recommendations. However, little is known about the effect of age on lymph node positivity in colon cancer with mucosal invasion. In this study, we aimed to quantify the effect of younger age on lymph node positivity in colon cancer with mucosal invasion. METHODS: All patients were identified between 2004 and 2014 in the Surveillance, Epidemiology, and End Results database. Patients were stage T1-T2, did not undergo preoperative radiotherapy, had at least one lymph node examined, and underwent a standard colon cancer operation. Demographics and pathological data were compared between different age ranges. A nomogram model was built to estimate the probability of nodal involvement according to different characteristics. Decision curve analysis was performed by calculating the net benefits for a range of threshold probabilities. RESULTS: This study identified 41,490 patients who met the eligibility criteria for our study. 1.4% (n = 620) of patients were under 40 years old; 5.9% (n = 2571) were between 40 and 49 years old. Within each T stage, positive lymph node rates decreased with increasing age. In univariate analyses, the positive lymph node rates for patients 20 to 39 years of age were significantly higher than in patients in the reference group for stages T1 and T2. After dividing the colon into the left and right parts, these trends remained. The lymph node metastatic rate was higher in the right colon than in the left colon in terms of different age ranges. The nomogram prediction system represents a novel model with which to estimate lymph node metastasis in early T stage colon adenocarcinomas based on four risk factors with a C-index of 0.657 (95% CI: 0.658-0666). CONCLUSIONS: Our study demonstrates that the risk of lymph node metastasis was higher in young (< 40 years) patients with early-stage colon adenocarcinomas. Therefore, more aggressive screening and therapeutic strategies should be considered for young patients with colon adenocarcinoma.


Assuntos
Adenocarcinoma/patologia , Neoplasias do Colo/patologia , Linfonodos/patologia , Adenocarcinoma/cirurgia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Colo/patologia , Neoplasias do Colo/cirurgia , Técnicas de Apoio para a Decisão , Feminino , Humanos , Excisão de Linfonodo , Linfonodos/cirurgia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nomogramas , Estudos Retrospectivos , Adulto Jovem
18.
Pharmacology ; 104(3-4): 113-125, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31167205

RESUMO

The breast cancer is the leading cause of death in women. Therefore, objective of the present study was to examine the antibreast cancer effect of glabridin (GBN) and to evaluate its mechanism of action. In this study, we have demonstrated that GBN causes reduction of cellular viability of human breast cancer SK-BR-3 in MTT assay. Results from Hoechst 33342 and propidium iodide staining assay suggested that GBN causes significant enhancement in the apoptosis. At the molecular level, in western blot analysis, GBN causes significant increase in c-PARP and c-caspases 3, 8, and 9 concentrations in a dose-dependent manner in breast cancer cells. The GBN further showed reduced level of p-epidermal growth factor receptor, p-AKT, p-ERK1/2, and cyclin D1 as the concentration rose in treated cells. Subsequent to this, GBN showed beneficial effect in 7,12-dimethylbenz[a]anthracene-induced breast cancer in experimental mice as confirmed by increase in body weight, reduction in tumor volume, oxidative stress, and dose-dependent restoration of all tested enzymes (phase I and II) in the treated group. GBN may, thus, play a protective role as an antibreast cancer drug for the prevention of breast cancer.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Isoflavonas/farmacologia , Fenóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Feminino , Humanos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
19.
Breast Cancer Res Treat ; 176(1): 109-117, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30989461

RESUMO

PURPOSE: Targeting DNA repair mechanisms to induce apoptosis may be a promising strategy for breast cancer treatment. Olaparib is proved to have anticancer effect by inhibiting DNA repairing protein poly (ADP-ribose) polymerase (PARP). However, the cytotoxicity of olaparib is very limited to homologous recombination-proficient cells. This study aims to examine the effect and mechanism of olaparib treatment in breast cancer cell lines. METHODS: We investigated the cytotoxic effect of various doses of olaparib treatment to MCF-7 and ZR-75-1 cells in vitro. mRNA and protein levels of PARP and APE1 were examined by real-time PCR and western blot, respectively. APE1-deficient cell lines were created by RNA interference and used for in vitro cytotoxicity study as well as in vivo study. RESULTS: 2 µM or higher concentrations of olaparib lead to significant cell death and ROS production. Moreover, olaparib treatment not only inhibits PARP1, but also reduces the expression of APE1 in both mRNA and protein levels. Deficiency of APE1 resulted in increased sensitivity of MCF-7 and ZR-75-1 cells to olaparib treatment. In vivo study showed that reduction of APE1 significantly reduced the volume and weight of MCF-7 xenografted tumors when treated with olaparib, which suggests the synergistic function of inhibition of APE1 in promoting antitumor effects of olaparib treatment. CONCLUSION: To acquire better benefits for HR-proficient breast cancer patients, developing chemotherapeutic drugs antagonize APE1 would be an effective strategy to improve the clinical outcome of PARP inhibitors.


Assuntos
Neoplasias da Mama/genética , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ftalazinas/farmacologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Biomed Pharmacother ; 113: 108655, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30849637

RESUMO

In this study, we aimed to explore the expression profiles of some known functional lncRNAs in esophageal adenocarcinoma (EAD) and to screening the potential prognostic makers, using data from The Cancer Genome Atlas (TCGA)-esophageal carcinoma (ESCA). Results showed that DLEU2 is a high potential OS related marker among 73 functional lncRNAs. DLEU2 and its intronic miR-15a and miR-16-1 expression were significantly upregulated in EAD compared with adjacent normal tissues. However, miR-15a and miR-16-1 expression were only weakly correlated with DLEU2 expression. Univariate and multivariate analysis confirmed that DLEU2 expression, but not miR-15a or miR-16-1 expression is an independent prognostic marker in terms of OS (HR:1.688, 95%CI: 1.085-2.627, p = 0.020) in EAD patients. The exon 9 of DLEU2 is very strongly co-expressed with DLEU2 (Pearson's r = 0.96) and showed better predictive value than total DLEU2 expression in predicting the OS of EAD patients. Multivariate analysis confirmed its independent prognostic value (HR:1.970, 95%CI: 1.266-3.067, p = 0.003), after adjustment of histologic grade, pathological stages and the presence of residual tumor. By checking the methylation status of DLEU2 gene, we excluded the possibility of the influence of two CpG sites near the DLEU2 exon 9 locus on its expression. In addition, although copy number alterations (CNAs) were observed DLEU2 gene, heterozygous loss (-1), low-level copy gain (+1) and high-level amplification (+2) had no significant association with DLEU2 transcription. Based on these findings, we infer that DLEU2 exon 9 expression might serve as a valuable biomarker of unfavorable OS in EAD patients.


Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/biossíntese , Neoplasias Esofágicas/metabolismo , Éxons/genética , RNA Longo não Codificante/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Ilhas de CpG/genética , Epigênese Genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Feminino , Humanos , Modelos Lineares , Masculino , Prognóstico , RNA Longo não Codificante/genética , Análise de Sobrevida , Transferases , Proteínas Supressoras de Tumor/genética , Regulação para Cima
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