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1.
Exp Ther Med ; 22(5): 1270, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34594407

RESUMO

Brain disorders, such as Alzheimer's and Parkinson's disease and cerebral stroke, are an important contributor to mortality and disability worldwide, where their pathogenesis is currently a topic of intense research. The mechanisms underlying the development of brain disorders are complex and vary widely, including aberrant protein aggregation, ischemic cell necrosis and neuronal dysfunction. Previous studies have found that the expression and function of growth differentiation factor-15 (GDF15) is closely associated with the incidence of brain disorders. GDF15 is a member of the TGFß superfamily, which is a dimer-structured stress-response protein. The expression of GDF15 is regulated by a number of proteins upstream, including p53, early growth response-1, non-coding RNAs and hormones. In particular, GDF15 has been reported to serve an important role in regulating angiogenesis, apoptosis, lipid metabolism and inflammation. For example, GDF15 can promote angiogenesis by promoting the proliferation of human umbilical vein endothelial cells, apoptosis of prostate cancer cells and fat metabolism in fasted mice, and GDF15 can decrease the inflammatory response of lipopolysaccharide-treated mice. The present article reviews the structure and biosynthesis of GDF15, in addition to the possible roles of GDF15 in Alzheimer's disease, cerebral stroke and Parkinson's disease. The purpose of the present review is to summarize the mechanism underlying the role of GDF15 in various brain disorders, which hopes to provide evidence and guide the prevention and treatment of these debilitating conditions.

2.
JAMA Netw Open ; 4(10): e2128217, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34609494

RESUMO

Importance: Few studies have examined the clinicopathological characteristics and prognoses of patients with hepatoid adenocarcinoma of the stomach (HAS). Objective: To explore the clinicopathological characteristics and prognoses of patients with HAS and develop a nomogram to predict overall survival (OS). Design, Setting, and Participants: This prognostic study involved a retrospective analysis of data from 315 patients who received a diagnosis of primary HAS between April 1, 2004, and December 31, 2019, at 14 centers in China. Main Outcomes and Measures: OS and prognostic factors. Patients were randomly assigned to a derivation cohort (n = 220) and a validation cohort (n = 95). A nomogram was developed based on independent prognostic factors identified through a multivariable Cox mixed-effects model. Results: Among 315 patients with HAS (mean [SD] age, 61.9 [10.2] years; 240 men [76.2%]), 137 patients had simple HAS (defined as the presence of histologically contained hepatoid differentiation areas only), and 178 patients had mixed HAS (defined as the presence of hepatoid differentiation areas plus common adenocarcinoma areas). Patients with simple HAS had a higher median preoperative α-fetoprotein level than those with mixed HAS (195.9 ng/mL vs 48.9 ng/mL, respectively; P < .001) and a higher rate of preoperative liver metastasis (23 of 137 patients [16.8%] vs 11 of 178 patients [6.2%]; P = .003). The 3-year OS rates of patients with simple vs mixed HAS were comparable (56.0% vs 60.0%; log-rank P = .98). A multivariable Cox analysis of the derivation cohort found that the presence of perineural invasion (hazard ratio [HR], 2.13; 95% CI, 1.27-3.55; P = .009), preoperative carcinoembryonic antigen levels of 5 ng/mL or greater (HR, 1.72; 95% CI, 1.08-2.74; P = .03), and pathological node category 3b (HR, 3.72; 95% CI, 1.34-10.32; P = .01) were independent risk factors for worse OS. Based on these factors, a nomogram to predict postoperative OS was developed. The concordance indices of the nomogram (derivation cohort: 0.72 [95% CI, 0.66-0.78]; validation cohort: 0.72 [95% CI, 0.63-0.81]; whole cohort: 0.71 [95% CI, 0.66-0.76]) were higher than those derived using the American Joint Committee on Cancer's AJCC Cancer Staging Manual (8th edition) pathological tumor-node-metastasis (pTNM) staging system (derivation cohort: 0.63 [95% CI, 0.57-0.69]; validation cohort: 0.65 [95% CI, 0.56-0.75]; whole cohort: 0.64 [95% CI, 0.59-0.69]) and those derived using a clinical model that included pTNM stage and receipt of adjuvant chemotherapy (derivation cohort: 0.64 [95% CI, 0.58-0.69]; validation cohort: 0.65 [95% CI, 0.56-0.75]; whole cohort: 0.64 [95% CI, 0.59-0.69]). Based on the nomogram cutoff of 10 points, the whole cohort was divided into high-risk and low-risk groups. The 3-year OS rate of patients in the high-risk group was significantly lower than that of patients in the low-risk group (29.7% vs 75.9%, respectively; log-rank P < .001), and the 3-year prognosis of high-risk and low-risk groups could be further distinguished into pTNM stage I to II (33.3% vs 80.2%; exact log-rank P = .15), stage III (34.3% vs 71.3%; log-rank P < .001), and stage IV (15.5% vs 70.3%; log-rank P = .009). Conclusions and Relevance: This study found that perineural invasion, preoperative carcinoembryonic antigen levels of 5 ng/mL or greater, and pathological node category 3b were independent risk factors associated with worse OS. An individualized nomogram was developed to predict OS among patients with HAS. This nomogram had good prognostic value and may be useful as a supplement to the current American Joint Committee on Cancer TNM staging system.

4.
Front Oncol ; 11: 727698, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34422671

RESUMO

Background: Long non-coding RNAs (lncRNAs) display regulatory function flexibly in tumor onset and developments. Our study aimed to delve into the roles of lncRNA LINC01569 (LINC01569) in colorectal cancer (CRC) progression to study the potential mechanisms. Methods: The genetic expression profiles of miR-381-3p and LINC01569 were measured by RT-PCR. The subcellular localization of LINC01569 in CRC cells was identified using subcellular fractionation location. Loss-of-function assays were performed to explore the potential effects of LINC01569 on CRC progression. Dual-luciferase reporter analysis was employed to verify the binding connections among LINC01569, miR-381-3p, and RAP2A. Results: LINC01569 expression was distinctly increased in CRC. Curiously, if LINC01569 is removed, CRC cells will not migrate, proliferate, and invade remarkably. Molecular mechanism exploration uncovered that LINC01569 acted as a ceRNA competing with RAP2A to bind with miR-381-3p. Furthermore, rescue experiments corroborated the fact that miR-381-3p suppression reversed the inhibitory actions of LINC01569 knockdown on the expression of RAP2A and CRC progression. Conclusion: Overall, our findings indicate that LINC01569 plays a key role in CRC development by means of aiming at the miR-381-3p/RAP2A axis and can be equivalent to an underlying medicinal target to save CRC patients.

5.
Clin Chim Acta ; 521: 251-257, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34331952

RESUMO

Atherosclerosis constitutes the pathological basis of life-threatening events, including heart attack and stroke. Midkine is a heparin-binding growth factor and forms a small protein family with pleiotrophin. Under inflammatory or hypoxic conditions, midkine expression is up-regulated. Upon binding to its receptors, midkine can activate multiple signal pathways to regulate cell survival and migration, epithelial-to-mesenchymal transition, and oncogenesis. Circulating midkine levels are significantly increased in patients with essential hypertension, obesity or severe peripheral artery disease. Importantly, midkine exerts a proatherogenic effect by altering multiple pathophysiological processes involving atherogenesis, including macrophage lipid accumulation, vascular inflammation, neointima formation, insulin resistance and macrophage apoptosis. Midkine represents a potential therapeutic target for atherosclerosis-associated diseases. This review described the structure characteristics, expression patterns and signal transduction pathways of midkine with an emphasis on its role in atherosclerosis.


Assuntos
Aterosclerose , Citocinas , Fatores de Crescimento de Fibroblastos , Humanos , Macrófagos , Midkina , Transdução de Sinais
6.
Cell Biol Int ; 45(11): 2226-2237, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34288211

RESUMO

Prevention of ATP binding cassette transporter A1 (ABCA1)-dependent cholesterol efflux leads to lipid accumulation in macrophages and atherosclerosis development. C1q tumor necrosis factor-related protein 1 (CTRP1), a conserved paralog of adiponectin, has been shown to aggravate atherosclerosis via its proinflammatory property. However, very little is known about its effects on ABCA1 expression and macrophage lipid accumulation. In the current studies, we found that CTRP1 downregulated ABCA1 expression, inhibited cholesterol efflux to apoA-I and promoted lipid accumulation in THP-1 macrophage-derived foam cells. Forkhead box O1 (FoxO1), a transcriptional repressor of ABCA1, was identified as a direct target of miR-424-5p. Mechanistically, CTRP1 attenuated miR-424-5p levels and then augmented FoxO1 expression in the nucleus, which led to downregulation of ABCA1 expression and inhibition of cholesterol efflux. In conclusion, these findings suggest that CTRP1 restrains cholesterol efflux and facilitates macrophage lipid accumulation through the miR-424-5p/FoxO1/ABCA1 signaling pathway, thereby providing a novel mechanistical insight into its proatherosclerotic action.

7.
J Org Chem ; 86(10): 7021-7027, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33881865

RESUMO

Hypermonins A-D (1-4), four rearranged nor-polycyclic polyprenylated acylphloroglucinols (PPAPs) with unprecedented skeletons, together with two new biosynthesis related PPAPs (5 and 6) were isolated and identified from the flowers of Hypericum monogynum. Hypermoins A-D represented the first examples of highly modified norPPAPs characterized by a rare 7/6/6/5-tetracyclic system. From the biogenic synthesis pathway analysis, all isolates shared the same biosynthetic intermediate, and the addition of two methyls or one methyl to this intermediate through methyltranferase could generate different types of PPAPs (1-7). Their planner structures as well as absolute configuration were confirmed via spectroscopic analysis, ECD calculation, and X-ray crystallography. All isolates potentially reversed multidrug resistance (MDR) activity in both two cancer cells, HepG2/ADR and MCF-7/ADR. Specifically, hypermoin E (5) and hyperielliptone HA (7) were found to be the best MDR modulators with the reversal fold ranging from 41 to 236, which is higher than the positive control verapamil.


Assuntos
Hypericum , Cristalografia por Raios X , Flores , Estrutura Molecular , Floroglucinol/farmacologia
8.
J Immunol Res ; 2021: 6647292, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33681387

RESUMO

There are multiple tumor-infiltrating lymphocytes (TILs) and relevant immune checkpoints existing in gastrointestinal stromal tumor (GIST), which provides opportunities and rationales for developing effective immunotherapies. Recent studies have suggested that checkpoint TIM-3/Gal-9 plays a pivotal role on immune response in multiple tumors, similar to the PD-1/PD-L1, emerging as a potential therapeutic target. However, their functions in GIST are unrevealed. Hence, the expression of immune checkpoints TIM-3 and Gal-9, as well as the infiltration of CD8+ T cells and NK cells, is described in 299 cases of GIST specimens. The results showed that TIM-3 and Gal-9 are mainly expressed in TILs, rarely in tumor cells. Expression levels of TIM-3 and Gal-9 significantly differ in varying risks of GIST and exert opposite distribution trends. Indicated by prognosis analysis, high TIM-3 expression of TILs was associated with improved outcome, while low expression levels of TIM-3 in combination with low amounts of CD8+ and CD56+ TILs predict extremely poor survival. The integrated analysis of TIM-3+, CD8+, and CD56+ TILs as one biomarker is a reliable independent predictor of prognosis. In conclusion, low densities of TIM-3+ TILs are associated with poor survival, and integrated immune biomarkers lead to superior predictors of GIST prognosis.


Assuntos
Tumores do Estroma Gastrointestinal/etiologia , Tumores do Estroma Gastrointestinal/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos T Citotóxicos/metabolismo , Adulto , Idoso , Biomarcadores Tumorais , Feminino , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Citotóxicos/imunologia , Carga Tumoral
9.
Org Biomol Chem ; 19(1): 216-219, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33180084

RESUMO

Hypsampsone A (1) and hyperhexanone F (2), two novel seco-polycyclic polyprenylated acylphloroglucinols, were isolated from Hypericum sampsonii. Hypsampsone A (1) features the first spirocyclic system fused with 5/6/5/5 tetracyclic skeleton. Hyperhexanone F (2) represents the second novel 1,2-seco-bicyclo[3.3.1]-PPAP skeleton. Their structures were established by extensive spectroscopic analysis, computer-assisted structure elucidation software, and calculated electronic circular dichroism spectra. A plausible biogenetic pathway of 1 was also proposed. Compounds 1 and 2 showed moderate multidrug resistance reversal activity to adriamycin (ADR) resistant cancer cell lines, HepG2/ADR and MCF-7/ADR, with the fold-reversals ranging from 16 to 38 at noncytotoxic concentration of 10 µM.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Hypericum/química , Floroglucinol/química , Floroglucinol/farmacologia , Prenilação , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células Hep G2 , Humanos , Células MCF-7 , Modelos Moleculares , Conformação Molecular
10.
EBioMedicine ; 49: 157-171, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31678002

RESUMO

BACKGROUND: Liver is one of the most preferred destinations of distant metastasis in gastric cancer (GC). As effective treatment is still limited, the prognosis of GC patients bearing liver metastasis is poor. We filter out lysyl oxidase (LOX) to study its function in the tumor microenvironment (TME) and seek for potential therapeutic targets. METHODS: Transcription analysis on 6 cases of liver metastasis of GC patients with respective paired primary tumors and adjacent normal livers was performed. The filtration out of LOX was done using 5 datasets. 69 GC liver metastasis tissues were utilized to perform immunohistochemistry (IHC) and analyze prognosis. Computed Tomography (CT) combined 3D organ reconstruction bioluminescence imaging was performed to precisely evaluate the metastatic tumor burden on liver of intrasplenic injection mouse model. Human and mouse cancer associated fibroblasts (CAFs) in liver metastasis were separated to culture to study the interaction of LOX and TGF-ß1. Patients-derived xenograft (PDX) model was established using liver metastasis of patients to evaluate the therapeutic value of LOX inhibitor ß-aminopropionitrile (BAPN). RESULTS: CAFs-derived LOX at liver metastatic niche of GC promotes niche formation and outgrowth thus predicts poor prognosis. Meanwhile tumor cells in niche secrete TGF-ß1 to nourish CAFs and stimulate them to produce more LOX in turn. The mechanism involved in LOX-mediated proliferation facilitation is enhancement of Warburg effect. The inhibitor of LOX, BPAN could hamper the effect brought by LOX in vivo and in vitro. INTERPRETATION: Our study has unveiled a positive feedback loop between CAFs and tumor cells in liver metastasis niche of GC. The core molecule is LOX which facilitates Warburg effect. Targeting LOX with its inhibitor BAPN might serve as a potential therapeutic strategy. FUND: This research was supported by the National Natural Science Foundation of China (31872740), the 100-member plan of the Shanghai Municipal Commission of Health and Family Planning (2017BR043), Shanghai Science and Technology Commission Project(17ZR1416800), Renji Hospital Training Fund (PYMDT-003, PYIII-17-015), National Natural Science Foundation of China (81672358), the Shanghai Municipal Education Commission-Gao feng Clinical MedicineGrant Support (20181708), Program of Shanghai Academic/Technology Research Leader(19XD1403400), Science and Technology Commission of Shanghai Municipality (18410721000), Shanghai Municipal Health Bureau (2018BR32), China Postdoctoral Science Foundation (2018M640403), National Natural Science Foundation of China (81701945) and Youth project of Shanghai Municipal Health Commission(20164Y0045).


Assuntos
Fibroblastos Associados a Câncer/enzimologia , Fibroblastos Associados a Câncer/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Proteína-Lisina 6-Oxidase/metabolismo , Neoplasias Gástricas/patologia , Aminopropionitrilo/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Glicólise , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais , Células Estromais/patologia , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima
11.
World J Gastrointest Oncol ; 11(10): 898-908, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31662828

RESUMO

BACKGROUND: Tumor budding, is a promising prognostic hallmark in many cancers, and can help us better assess the degree of malignancy in gastric cancer (GC) and in colorectal cancer. In the past few years, several articles on the relationship between tumor budding and GC have been published, but different results have been observed. As the relationship between tumor budding and GC remains controversial, we integrated the data from 7 eligible studies to conduct a systematic review and meta-analysis. AIM: To systematically evaluate the prognostic and pathological impact of tumor budding in GC. METHODS: Literature searches were conducted in the PubMed, Cochrane Library, EMBASE and Web of Science databases, and 7 cohort studies involving 2178 patients met our criteria and included in the analysis. The patients were divided into those with high-grade tumor budding and those with low-grade tumor budding, and the cut-off values for tumor budding varied across the included studies. The hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to estimate the impact of tumor budding on overall survival (OS) in GC patients. The odds ratios (ORs) with 95%CIs were used to determine the correlation between tumor budding and pathological parameters (tumor stage, tumor differentiation, lymphovascular invasion, lymph node metastasis) of GC. RESULTS: Seven studies involving 2178 patients were included in the meta-analysis. The combined ORs suggested that high-grade tumor budding was significantly associated with tumor stage (OR = 6.63, 95%CI: 4.01-10.98, P < 0.01), tumor differentiation (OR = 3.74, 95%CI: 2.68-5.22, P < 0.01), lymphovascular invasion (OR = 7.85, 95%CI: 5.04-12.21, P < 0.01), and lymph node metastasis (OR = 5.75, 95%CI: 3.20-10.32, P < 0.01). Moreover, high-grade tumor budding predicted a poor 5-year OS (HR = 1.79, 95%CI: 1.53-2.05, P < 0.01) in patients with GC and an adverse 5-year OS (HR = 1.93, 95%CI: 1.45-2.42, P < 0.01) in patients with intestinal-type GC. CONCLUSION: High-grade tumor budding suggested a poor prognosis in patients with GC or intestinal-type GC.

12.
Mol Cancer ; 18(1): 129, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455334

RESUMO

Following publication of the original article [1], authors reported Pro. Gang Zhao has to be considered as another corresponding author, according to his important contribution.

13.
Mol Cancer ; 18(1): 115, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272462

RESUMO

BACKGROUND: UCA1 is a long non-coding RNA which was found overexpressed in various human cancers including gastric cancer (GC). It is identified that UCA1 promotes GC cells proliferation, migration and invasion, however, the role of UCA1 during the processes of immune escape is still not unclear. METHODS: We collected 40 paired GC and non-tumor tissue samples. The level of UCA1 in GC and control tissue samples were determined by in situ hybridization and qRT-PCR. Cell viability was determined by MTT assay. GC cells' migration capacities were examined by transwell assay. To understand the roles of UCA1 during immune escape, wildtype or UCA1 KO GC cells co-cultured with peripheral blood mononuclear cells or cytokine-induced killer cells in vitro. Mouse model was used to examine the function of UCA1 in vivo. RESULTS: UCA1 promoted GC cells proliferation and migration, and inhibit apoptosis. UCA1 repressed miR-26a/b, miR-193a and miR-214 expression through direct interaction and then up-regulated the expression of PDL1. UCA1-KO GC cells could induce a higher IFNγ expression when co-cultured with peripheral blood mononuclear cells (PBMCs), and have a lower survival rate when co-cultured with cytokine-induced killer (CIK) cells in vitro. UCA1-KO GC cells formed smaller tumors, had higher miR-26a, -26b, -193a and - 214 level, reduced cell proliferation and increased apoptosis in xenograft mouse model. CONCLUSIONS: UCA1 overexpression protected PDL1 expression from the repression of miRNAs and contributed to the GC cells immune escape. UCA1 could serve as a potential novel therapeutic target for GC treatment.

14.
J Exp Clin Cancer Res ; 37(1): 308, 2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30541591

RESUMO

BACKGROUND: Recent observations indicate a decreased cancer risk in patients with Alzheimer's disease (AD). AD is a severe neurodegenerative disorder characterized by progressive cognitive decline. The 8q24 region has been shown to be involved in AD aetiology. We aimed to identify and explore the potential oncogenes or antioncogenes on chromosome 8q24. METHODS: We compared expression of genes on Chromosome 8q24 in 32 pairs of samples from The Cancer Genome Atlas (TCGA) database. We conducted bioinformatics analysis of the commonly used gastric cancer databases and performed clinical verification of gastric cancer samples, combined with assessment of biological function both in vitro and in vivo to determine the relationship between upregulated expression of GRINA and gastric cancer progression. We also explored the molecular mechanism of GRINA upregulation and its function in gastric cancer development and progression. RESULTS: The expression of GRINA in cancer tissues was significantly higher than that in normal tissues. GRINA indicated poor prognosis in gastric cancer. GRINA promoted the proliferation, migration and invasion capacity of gastric cancer cells. GRINA was transcriptionally mediated by c-Myc and promotes cell cycle transition. GRINA knockdown decreased PI3K/Akt/mTOR signaling and glycolytic metabolism in gastric cancer cells. The apoptosis rate was significantly increased in gastric cancer cell lines after knockdown of GRINA. The expression of pro-apoptotic protein Bax was significantly upregulated, whereas the anti-apoptotic protein Bcl-2 was significantly downregulated in GRINA silenced cells. CONCLUSIONS: Human gastric cancers have increased levels of GRINA, which promotes growth of gastric cancer and inhibits tumor cells apoptosis.


Assuntos
Receptores de N-Metil-D-Aspartato/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Apoptose/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Progressão da Doença , Feminino , Glicólise , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , Estudos Retrospectivos , Transdução de Sinais , Neoplasias Gástricas/patologia , Transfecção
15.
J Cancer ; 9(2): 346-357, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29344281

RESUMO

Krt17 is a 48kDa protein member of keratin family. Previous literatures have demonstrated Krt17 may play a promotive role in the progression of various malignancies. However, the exact function of Krt17 in the carcinogenesis and the progression of gastric cancer (GC) remains unknown. In the present study, the expression of Krt17 in 20 fresh GC and matched normal tissues were detected and Krt17 was found to be significantly increased in GC tissues compared to normal tissues. And then the immunochemistry was performed to investigate the Krt17 expression in 569 GC tissue specimens, we found that the expression of Krt17 was remarkably positively correlated with the tumor size (P < 0.01), depth of invasion (T) (P < 0.001), lymph node metastasis (N) (P < 0.001), tumor node metastasis (TNM) stage (P < 0.001) and vascular invasion (P < 0.05). High expression of Krt17 predicted a poor prognosis of GC patients. In addition, we showed silencing of Krt17 inhibited GC cell proliferation, migration and invasion, and induced cell apoptosis by altering Bcl2 family protein expression and cleaved caspase3 upregulation. Moreover, silencing of Krt17 led to cell cycle arrest at G1/S stage by decreasing cyclin E1 and cyclin D expression. In conclusion, our findings revealed Krt17 can be used as a novel predictive biomarker, thus providing a novel therapeutic target for GC patients.

16.
Am J Transl Res ; 9(9): 4317-4330, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28979705

RESUMO

The mammalian target of rapamycin (mTOR) kinase acts downstream of phosphoinositide 3-kinase/Akt and plays an important role in tumor growth and progression of gastric cancer. It is well characterized that mTOR complex1 (mTORC1) controls cell metabolism and proliferation, whereas the contribution of mTOR complex2 (mTORC2) and its key component, Rictor, remains poorly understood. Therefore, we investigated clinical significance of Rictor expression by immunohistochemical analysis of 391 tissue samples from gastric cancer patients. In addition, the roles of Rictor in cell proliferation, apoptosis, migration and invasion in vitro were evaluated by RNA interference. The results showed that over expression of Rictor was associated with increased tumor size, depth of tumor invasion, lymph node metastasis and advanced TNM stage, together with poorer overall and relapse-free survival. Stable sh-RNA mediated down-regulation of Rictor significantly inhibited SGC7901 and MGC803 gastric cancer cells proliferation, migration and invasion. Furthermore, Rictor knockdown attenuated cell cycle progression and enhanced apoptosis, synergistic with treatment of mTORC1 inhibitor rapamycin owing to abrogating the feedback activation of Akt. Our findings identify Rictor as an important mediator of tumor progression and metastasis, providing the rationale for targeting both mTORC1 and mTORC2 as part of therapeutic strategy for gastric cancer.

17.
Biomed Pharmacother ; 93: 470-479, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28667916

RESUMO

Intervertebral disc degeneration (IDD) is thought to be the most common cause of low back pain. Dysregulation of microRNAs (miRNAs) is involved in the development of IDD. The aim of this study was to explore the influence of miR-210 on type II collagen (Col II) and aggrecan expression and possible mechanisms in human degenerated nucleus pulposus (NP) cells. Our results showed that miR-210 levels were significantly increased in degenerated NP tissues compared with healthy controls, and positively correlated with disc degeneration grade. By gain-of-function and loss-of-function studies in human degenerated NP cells, miR-210 was shown to inhibit autophagy and then upregulate MMP-3 and MMP-13 expression, leading to increased degradation of Col II and aggrecan. Autophagy-related gene 7 (ATG7) was identified as a direct target of miR-210. Knockdown of ATG7 by small interfering RNA (siRNA) abrogated the effects of miR-210 inhibitor on MMP-3, MMP-13, Col II and aggrecan expression. Taken together, these results suggest that miR-210 inhibits autophagy via silencing of ATG7, leading to increased Col II and aggrecan degradation in human degenerated NP cells.


Assuntos
Proteína 7 Relacionada à Autofagia/genética , Autofagia/genética , Matriz Extracelular/metabolismo , Degeneração do Disco Intervertebral/genética , Degeneração do Disco Intervertebral/patologia , MicroRNAs/metabolismo , Núcleo Pulposo/patologia , Adolescente , Adulto , Idoso , Agrecanas/metabolismo , Proteína 7 Relacionada à Autofagia/metabolismo , Sequência de Bases , Colágeno Tipo II/metabolismo , Inativação Gênica , Humanos , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , MicroRNAs/genética , Pessoa de Meia-Idade , Regulação para Cima/genética , Adulto Jovem
18.
Int J Clin Exp Pathol ; 10(9): 9878-9888, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-31966876

RESUMO

OBJECTIVE: To observe the expression of THY-1 (CD90) in gastric tumour cells and its effect on the growth of gastric cancer and to provide new evidence for the development of possible targets for the treatment of gastric cancer. METHODS: The effect of THY-1 on the proliferative ability of HGC-27, MGC-803 and AGS gastric cancer cells was examined by CCK-8 and cell cycle assays. The effect of THY-1 on the ability of gastric cancer cells to avoid apoptosis was analysed by Annexin V/PI double staining. The effect of THY-1 on the tumourigenic ability of gastric cancer cells in vivo was explored by subcutaneous tumour formation assay in nude mice. RESULTS: The CCK-8 assay showed that the proliferative activity of HGC-27 and MGC-803 gastric cancer cells was significantly limited after THY-1 interference in vitro (P < 0.01); however, exogenous THY-1 significantly promoted the growth of AGS gastric cancer cells (P = 0.003). The cell cycle assay showed that exogenous THY-1 reduced the G0/G1 phase arrest of AGS cells and facilitated cell entry into S phase, which accelerated cell division and proliferation (P = 0.008). After interference in the expression of the THY-1 gene, HGC-27 cells showed significant G0/G1 arrest, while the percentage of S phase cells decreased, and cell proliferation was inhibited (P < 0.001). The apoptosis assay showed that the average apoptosis rate of AGS cells was significantly lower in the overexpression group versus the control group (7.89 ± 1.08% vs. 11.90 ± 0.45%, P = 0.004). In contrast, the average apoptosis rate of HGC-27 cells was significantly increased in the interference group versus the control group (37.88 ± 5.47% vs. 22.84 ± 1.50%, P = 0.01). The subcutaneous tumour formation assay in nude mice revealed that at week 3, tumour volume and weight reached 1018.33 ± 521.48 mm3 and 81.47 ± 41.72 mg, respectively, in the control group, while tumour volume and weight were only 213.72 ± 111.94 mm3 and 17.10 ± 9.00 mg, respectively, in the interference group; the differences between the two groups were statistically significant (P < 0.01). CONCLUSIONS: THY-1 promoted the proliferation of gastric cancer cells and reduced the apoptosis rate of gastric cancer cells with a lack of nutrient supply. Moreover, THY-1 promoted subcutaneous tumour formation and growth in nude mice, as indicated by the results of the subcutaneous tumour formation assay.

19.
Mater Sci Eng C Mater Biol Appl ; 72: 177-184, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-28024574

RESUMO

Gastrointestinal stromal tumors (GIST) are one of the most common forms of mesenchymal cancers of the gastrointestinal tract. Although chemotherapeutic drugs inhibited the proliferation of GIST, however, sizable proportion of people developed resistance and therefore difficult to treat. In the present study, O-carboxymethyl chitosan (OCMC)-tocopherol polymer conjugate was synthesized and formulated into stable polymeric nanoparticles. The main aim of present study was to increase the therapeutic efficacy of miR-218 in GIST. The mean size of nanoparticles was ~110nm with a spherical shape. The miR-218 NP has been shown inhibit the cell proliferation and exhibited a superior cell apoptosis. The miR-218 NP inhibited the cell invasion and promoted the apoptosis of GIST cancer cells. In the present study, we have successfully showed that KIT1 is the target gene of miR-218 as shown by the luciferase reporter assay. These findings collectively suggest the miR-218 loaded nanoparticle by virtue of effective transfection could act as a tumor suppressor miRNA in the treatment of GIST.


Assuntos
Quitosana/análogos & derivados , MicroRNAs/química , Nanopartículas/química , Tocoferóis/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Quitosana/química , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Humanos , MicroRNAs/metabolismo , Nanopartículas/toxicidade , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo
20.
Sci Rep ; 6: 27435, 2016 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-27272474

RESUMO

To discover new biomarkers for gastric cancer (GC) diagnose and treatment, we screened the lncRNAs in GC tissues from 5 patients. We found 6 lncRNAs had altered expression, and in the same time, the levels of their neighboring genes (located near 300 kb upstream or downstream of lncRNA locus) were significantly changed. After confirming the results of microarray by qRT-PCR in 82 GC patients, the biological function of LINC00628 was examined through cell proliferation and apoptosis, cell migration and invasion, colony formation assay and cell cycle detection. We confirmed that LINC00628 functions as a GC suppressor through suppressing proliferation, migration and colony formation of cancer cells. Furthermore, LINC00628 can also suppress the tumor size in mouse xenograft models. Although LINC00628 can modulate LRRN2 expression, the GC suppressor function of LINC00628 is not LRRN2 dependent. The result of mRNA microarray indicated that LINC00628 perform GC inhibitor function through long-range modulating cell cycle related genes. Importantly, we confirmed that LINC00628 mainly located in the nucleus and interacted with EZH2, and modulated genes expression by regulating H3K27me3 level. This research shed light on the role of dysregulated LINC00628 during GC process and may serve as a potential target for therapeutic intervention.


Assuntos
Genes Supressores de Tumor , Genes cdc , RNA Longo não Codificante/genética , Neoplasias Gástricas/patologia , Moléculas de Adesão Celular Neuronais/genética , Proliferação de Células , Humanos , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias Gástricas/genética , Taxa de Sobrevida
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