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1.
Signal Transduct Target Ther ; 6(1): 368, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645784

RESUMO

The long-term immunity and functional recovery after SARS-CoV-2 infection have implications in preventive measures and patient quality of life. Here we analyzed a prospective cohort of 121 recovered COVID-19 patients from Xiangyang, China at 1-year after diagnosis. Among them, chemiluminescence immunoassay-based screening showed 99% (95% CI, 98-100%) seroprevalence 10-12 months after infection, comparing to 0.8% (95% CI, 0.7-0.9%) in the general population. Total anti-receptor-binding domain (RBD) antibodies remained stable since discharge, while anti-RBD IgG and neutralization levels decreased over time. A predictive model estimates 17% (95% CI, 11-24%) and 87% (95% CI, 80-92%) participants were still 50% protected against detectable and severe re-infection of WT SARS-CoV-2, respectively, while neutralization levels against B.1.1.7 and B.1.351 variants were significantly reduced. All non-severe patients showed normal chest CT and 21% reported COVID-19-related symptoms. In contrast, 53% severe patients had abnormal chest CT, decreased pulmonary function or cardiac involvement and 79% were still symptomatic. Our findings suggest long-lasting immune protection after SARS-CoV-2 infection, while also highlight the risk of immune evasive variants and long-term consequences for COVID-19 survivors.

2.
Bioengineered ; 12(1): 8570-8582, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34607512

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder. Studies have shown that long noncoding RNA SRY-box transcription factor 2 overlapping transcript (lncRNA SOX2-OT) is highly expressed in PD patients, but its specific functions and mechanisms require further research. To address this gap, this study utilized an in vitro PD cell model induced by 1-methyl-4-phenylpyridinium (MPP+). Cell viability, apoptosis, lactate dehydrogenase (LDH) activity, inflammatory factor secretion, and oxidative stress indicators were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-dipheyltetrazolium bromide assay, LDH assay, flow cytometry, enzyme linked immunosorbent assay (ELISA), and corresponding kits, respectively. Gene and protein expression were measured using quantitative real-time-PCR and western blotting, respectively. The results indicated that microRNA-942-5p (miR-942-5p) was a direct target of lncRNA SOX2-OT and nuclear apoptosis-inducing factor 1 (NAIF1) was a direct target of miR-942-5p. The expression levels of lncRNA SOX2-OT and NAIF1 were increased, and miR-942-5p expression was decreased in SH-SY5Y cells following MPP+ treatment. In addition, MPP+ treatment reduced SH-SY5Y cell viability, increased apoptosis; increased cleaved caspase-3 protein expression and cleaved caspase-3/caspase-3 ratio; enhanced lactate dehydrogenase viability; increased tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and reactive oxygen species, and decreased superoxide dismutase activity in SH-SY5Y cells were inhibited by SOX2-OT-siRNA, and these inhibitions were reversed by miR-942-5p inhibitor. Moreover, the protective role of miR-942-5p mimic in MPP+-induced SH-SY5Y cells was eliminated by the NAIF1 plasmid. Overall, lncRNA SOX2-OT-mediated regulation of oxidative stress, inflammation, and neuronal apoptosis were directly controlled by the miR-942-5p/NAIF1 signal axis in MPP+-induced SH-SY5Y cells.

3.
Aging (Albany NY) ; 13(17): 21483-21496, 2021 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-34511433

RESUMO

2,5-dimethyl celecoxib (DMC), a close derivative of celecoxib, has also been reported to have anticancer effects. However, the effects and underlying molecular mechanisms of DMC with respect to nasopharyngeal carcinoma are still largely unknown. In this study, we present that DMC has displayed anticancer potency in nasopharyngeal carcinoma in vitro and in vivo. Mechanistically, we found DMC induced apoptosis and autophagy for anticancer therapy against nasopharyngeal carcinoma. Furthermore, DMC-induced autophagy could remarkably attenuate after the treatment of reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) and c-Jun N-terminal kinase (JNK) inhibitor SP600125 (SP). Taken together, these results suggested DMC induced apoptosis and autophagic death via activation of ROS/JNK axis in NPC cells, which providing us new insights into developing potential therapeutic agents for nasopharyngeal carcinoma patients.

4.
Breast Cancer Res ; 23(1): 89, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488828

RESUMO

BACKGROUND: Telomere maintenance is crucial for the unlimited proliferation of cancer cells and essential for the "stemness" of multiple cancer cells. TAZ is more extensively expressed in triple negative breast cancers (TNBC) than in other types of breast cancers, and promotes proliferation, transformation and EMT of cancer cells. It was reported that TAZ renders breast cancer cells with cancer stem cell features. However, whether TAZ regulates telomeres is still unclear. In this study, we explored the roles of TAZ in the regulation of telomere maintenance in TNBC cells. METHODS: siRNA and shRNA was used to generate TAZ-depleted TNBC cell lines. qPCR and Southern analysis of terminal restriction fragments techniques were used to test telomere length. Co-immunoprecipitation, Western blotting, immunofluorescence, Luciferase reporter assay and Chromatin-IP were conducted to investigate the underlying mechanism. RESULTS: By knocking down the expression of TAZ in TNBC cells, we found, for the first time, that TAZ is essential for the maintenance of telomeres in TNBC cells. Moreover, loss of TAZ causes senescence phenotype of TNBC cells. The observed extremely shortened telomeres in late passages of TAZ knocked down cells correlate with an elevated hTERT expression, reductions of shelterin proteins, and an activated DNA damage response pathway. Our data also showed that depletion of TAZ results in overexpression of TERRAs, which are a group of telomeric repeat-containing RNAs and regulate telomere length and integrity. Furthermore, we discovered that TAZ maintains telomere length of TNBC cells likely by facilitating the expression of Rad51C, a crucial element of homologous recombination pathway that promotes telomere replication. CONCLUSIONS: This study supports the notion that TAZ is an oncogenic factor in TNBC, and further reveals a novel telomere-related pathway that is employed by TAZ to regulate TNBC.

5.
Cell Death Differ ; 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34462553

RESUMO

Bmf contributes to the onset of anoikis by translocating from cytoskeleton to mitochondria when cells lose attachment to the extracellular matrix. However, the structural details of Bmf cytoskeleton tethering and the control of Bmf release upon loss of anchorage remained unknown. Here we showed that cell detachment induced rapid and sustained activation of p38 MAPK in mammary epithelial cell lines. Inhibition of p38 signaling or Bmf knockdown rescued anoikis. Activated p38 MAPK could directly phosphorylate Bmf at multiple sites including a non-proline-directed site threonine 72 (T72). Crystallographic studies revealed that Bmf T72 directly participated in DLC2 binding and its phosphorylation would block Bmf/DLC2 interaction through steric hindrance. Finally, we showed that phosphomimetic mutation of T72 enhanced Bmf apoptotic activity in vitro and in a knock-in mouse model. This work unraveled a novel regulatory mechanism of Bmf activity during anoikis and provided structural basis for Bmf cytoskeleton tethering and dissociation.

6.
AMB Express ; 11(1): 121, 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34424425

RESUMO

Sulforaphane (SFN), an active compound in cruciferous vegetables, has been characterized by its antiproliferative capacity. We investigated the role and molecular mechanism through which SFN regulates proliferation and self-renewal of lung cancer stem cells. CD133+ cells were isolated with MACs from lung cancer A549 and H460 cells. In this study, we found that SFN inhibited the proliferation of lung cancer cells and self-renewal of lung cancer stem cells simultaneously. Meanwhile, the mRNA and protein expressions of Shh, Smo, Gli1 and PHC3 were highly activated in CD133+ lung cancer cells. Compared with siRNA-control group, Knock-down of Shh inhibited proliferation of CD133+ lung cancer cells, and decreased the protein expression of PHC3 in CD133+ lung cancer cells. Knock-down of PHC3 also affected the proliferation and decreased the Shh expression level in CD133+ lung cancer cells. In addition, SFN inhibited the activities of Shh, Smo, Gli1 and PHC3 in CD133+ lung cancer cells. Furthermore, the inhibitory effect of SFN on the proliferation of siRNA-Shh and siRNA-PHC3 cells was weaker than that on the proliferation of siRNA-control cells. Sonic Hedgehog signaling pathway might undergo a cross-talk with PHC3 in self-renewal of lung cancer stem cells. SFN might be an effective new drug which could inhibit self-renewal of lung cancer stem cells through the modulation of Sonic Hedgehog signaling pathways and PHC3. This study could provide a novel way to improve therapeutic efficacy for lung cancer stem cells.

7.
BMC Cancer ; 21(1): 760, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34193109

RESUMO

BACKGROUND: Breast cancer is the leading cause of cancer-related deaths in females worldwide. Formin-like protein 2 (FMNL2) is a member of formin family that governs cytokinesis, cell polarity, morphogenesis and cell division. To our knowledge, the function of FMNL2 in breast cancer proliferation still remains uncovered. METHODS: Tumor immune estimation resource (TIMER) analysis was used to detect the correlation between FMNL2 and Ki67 in breast cancer tissues. Quantitative real-time transcription polymerase chain reaction (qRT-PCR) and western blotting were performed to analyze the expression in human breast cancer cells. Moreover, RNA interference (RNAi) and plasmids were performed to silence and overexpress FMNL2 and p27. The CCK8, MTT, cell counting, colony formation, and 5-ethynyl-2-deoxyuridine (EdU) incorporation assays were used to detect cell proliferation, respectively. Flow cytometry analysis was used to detect cell cycle distribution. Further, the distribution of p27 was examined using immunofluorescence. RESULTS: We found that FMNL2 expression was positively associated with Ki67 among collected breast cancer tissues and in TCGA database. Compared to lower proliferative cells MCF7 and T47D, FMNL2 was overexpressed in highly proliferative breast cancer cells MDA-MB-231, BT549 and SUM159, accompanied by reduced levels of p27 and p21, and elevated CyclinD1 and Ki67 expression. FMNL2 silencing significantly inhibited the cell proliferation of MDA-MB-231 and BT549 cells. Meanwhile, FMNL2 overexpression distinctly promoted the cell proliferation of MCF7 cells. Furthermore, FMNL2 suppressed the nuclear levels of p27 and promoted p27 proteasomal degradation in human breast cancer cells. The ubiquitination of p27 was inhibited by FMNL2 silencing in BT549 cells. Besides, p27 silencing markedly elevated Ki67 expression and cell viability, which could be blocked by additionally FMNL2 silencing in MDA-MB-231 and BT549 cells. Furthermore, overexpression of p27WT significantly reversed the increased levels of FMNL2 and Ki67, cell viability and cell cycle progression induced by FMNL2 overexpression in MCF7 cells. More importantly, compared to p27WT group, those effects could be significantly reversed by p27△NLS overexpression. CONCLUSIONS: These results demonstrated that FMNL2 promoted cell proliferation partially by reducing p27 nuclear localization and p27 protein stability in human breast cancer cells, suggesting the pivotal role of FMNL2 in breast cancer progression.

8.
Drug Dev Res ; 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34196024

RESUMO

Sodium Danshensu, extracted from the root of the Salvia miltiorrhiza, has pleiotropic effects including anti-oxidation, anti-inflammation and anti-tumor. However, whether Sodium Danshensu has an anti-cancer effect in lung cancer remains to be elucidated. The present study aimed to illustrate the effects of Sodium Danshensu on lung cancer cells and the potential molecular mechanisms. BEAS-2B, A549, and NCI-H1299 cells were stimulated with 25, 50, and 100 µM Sodium Danshensu for 24, 48, and 72 h, and then cell viability, apoptosis, migration and invasion were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry and Transwell assays, respectively. Moreover, the levels of Proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 9 (MMP9), B-cell lymphoma-2 (Bcl-2) associated X (Bax), Bcl-2, phosphorylated (p)-phosphoinositide 3-kinase (PI3K), and p-Protein kinase B (AKT) in lung cancer cells were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) and/or Western blot assays. We observed that Sodium Danshensu suppressed cells viability, migration, and invasion, as well as promoted cells apoptosis in A549 and NCI-H1299 cells in a dose-dependent manner, while Sodium Danshensu had no cytotoxic effect on the proliferation activity of BEAS-2B cells. Moreover, the expression of PCNA, MMP9, Bcl-2 were decreased, but Bax was up-regulated in Sodium Danshensu-treated A549 and NCI-H1299 cells. Our findings also revealed that Sodium Danshensu inhibited PI3K/AKT pathway in A549 and NCI-H1299 cells. In conclusion, our study provided the first evidence that Sodium Danshensu suppressed the malignant biological behaviors of lung cancer cells, indicating that Sodium Danshensu might be a latent candidate for lung cancer therapy.

9.
J Hazard Mater ; 413: 125403, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-33930956

RESUMO

Stainless steel dust is a solid waste and contains a large number of valuable Fe, Cr, and Ni metal oxides, which should be recovered efficiently. Through direct reduction and self-pulverization separation, the goals of high metal recovery ratios and grades in the new process of comprehensive stainless steel dust utilization were achieved. Combined with theoretical analysis and experimental research, the effects of different conditions (FC/O ratio, reduction temperature, reduction time) on the reduction process and self-pulverization of reduction products were studied. The results showed that the optimal FC/O ratio was 0.8, reduction temperature was 1450 °C and reduction time was 20 min for the metal oxides in stainless steel dust to be completely reduced by carbon-thermal reduction; the self-pulverization holding temperature was 1100 °C, the holding time was 15 min, the conversion ratio of Ca3SiO5 to Ca2SiO4 reached the maximum, the content of γ-Ca2SiO4 in the reduced slag after cooling was increased, and a higher degree of self-pulverization was achieved. Fe-Cr-Ni-C alloy with an iron grade of 66.82%, chromium grade of 20.02% and nickel grade of 4.12% was manufactured successfully from stainless steel dust. The recoveries of iron, chromium and nickel in the stainless steel dust were 92.50%, 92.02% and 93.74%, respectively.

10.
Stem Cells ; 39(8): 1033-1048, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33754392

RESUMO

Revascularization of the islet transplant is a crucial step that defines the success rate of patient recovery. Bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to promote revascularization; however, the underlying cellular mechanism remains unclear. Moreover, our liquid chromatography-tandem mass spectrometry results showed that BMSCs could promote the expression of insulin gene enhancer binding protein-1 (ISL1) in islets. ISL1 is involved in islets proliferation and plays a potential regulatory role in the revascularization of islets. This study identifies the ISL1 protein as a potential modulator in BMSCs-mediated revascularization of islet grafts. We demonstrated that the survival rate and insulin secretion of islets were increased in the presence of BMSCs, indicating that BMSCs promote islet revascularization in a coculture system and rat diabetes model. Interestingly, we also observed that the presence of BMSCs led to an increase in ISL1 and vascular endothelial growth factor A (VEGFA) expression in both islets and the INS-1 rat insulinoma cell line. In silico protein structure modeling indicated that ISL1 is a transcription factor that has four binding sites with VEGFA mRNA. Further results showed that overexpression of ISL1 increased both the abundance of VEGFA transcripts and protein accumulation, while inhibition of ISL1 decreased the abundance of VEGFA. Using a ChIP-qPCR assay, we demonstrated that direct molecular interactions between ISL1 and VEGFA occur in INS-1 cells. Together, these findings reveal that BMSCs promote the expression of ISL1 in islets and lead to an increase in VEGFA in islet grafts. Hence, ISL1 is a potential target to induce early revascularization in islet transplantation.

11.
Int Urol Nephrol ; 53(11): 2311-2319, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33674949

RESUMO

BACKGROUND: Studies on the association of microalbuminuria with adverse outcomes in patients with hypertension remain controversial. This meta-analysis aimed to assess the predictive value of microalbuminuria in hypertensive patients. METHODS: PubMed and Embase databases were comprehensively searched for studies that published from their inceptions to July 10, 2020. Observational studies reporting the association of microalbuminuria (defined as urinary albumin excretion 30 and 300 mg/24 h urine or albumin/creatinine ratio 30-300 mg/g from a spot urine or equivalent value) with all-cause mortality or major adverse cardiovascular events (MACEs) in hypertensive patients were selected. RESULTS: Nine studies with a total of 19,893 hypertensive patients were included. When compared with those without microalbuminuria, hypertensive patients with microalbuminuria had an increased risk of all-cause mortality (risk ratio [RR] 1.68; 95% confidence interval [CI] 1.46-1.93) and MACEs (RR 1.40; 95% CI 1.22-1.62), respectively. Gender-specific analysis indicated that microalbuminuria was significantly associated with an increased risk of all-cause mortality (RR 1.61; 95% CI 1.17-2.21) in men but not in women (RR 1.18; 95% CI 0.78-1.80). CONCLUSION: This meta-analysis suggests that microalbuminuria is independently associated with higher risk of MACEs and all-cause mortality in hypertensive patients. Determination of microalbuminuria has potential to improve the risk classification of hypertension.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33547802

RESUMO

OBJECTIVE: To identify whether the time interval from insemination to ovulation (I-O interval) affects outcome after intrauterine insemination with donor sperm (IUI-D). METHODS: A retrospective study was conducted in a public assisted reproductive medicine center between January, 2014 and December, 2016 in Xi'an, China. The data were collected from the medical records and generalized estimating equations (GEEs) were used to evaluate the effects of various variables on IUI outcome. RESULTS: A total of 2091 IUI-D cycles from 1165 couples were included in this study. Multiple predictors were identified for (live birth rate) LBR. The I-O interval was the predictor for LBR. An I-O interval ≥19 h significantly decreased CPR (odds ratio [OR], 95% confidence interval [CI]: 0.29, 0.17-0.48) and LBR (OR, 95% CI: 0.32, 0.19-0.55). The presence of at least two follicles ≥18 mm on ovulation day significantly increased the LBR (OR, 95%CI: 1.27, 1.01-1.60). Women aged 35 years and older had a significantly decreased LBR (OR, 95% CI: 0.61, 0.38-0.98). CONCLUSION: The I-O interval, a new prognostic factor, in combination with the woman's age and number of mature follicles, can predict the outcome after IUI-D. IUI-D is best performed within 19 h of I-O interval for a higher probability of clinical pregnancy and live birth.

13.
Clin Exp Pharmacol Physiol ; 48(2): 279-287, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33030246

RESUMO

Nucleotide metabolism is the driving force of cell proliferation, and thymidylate synthase (TYMS) catalyzes a rate-limiting step in the initial synthesis of nucleotides. Previous studies reported that TYMS activity significantly affected the proliferation of tumour cells. However, the diagnostic and prognostic significance of TYMS expression in breast cancer remains unclear. Here, we used the Breast Cancer Integrative Platform (BCIP) to investigate the relationship between progression and prognosis of breast cancer with TYMS expression, and then verified the database analysis using immunohistochemical staining. Our results indicated TYMS expression was greater in breast cancer than adjacent normal tissues and greater in triple-negative breast cancer (TNBC) than non-TNBC tissues. TYMS expression also had significant positive correlations with histological grade, tumour size, and ER negativity, and PR negativity. The increased copy number of the TYMS gene appears to be the reason for its upregulation in breast cancer. Breast cancer patients with higher TYMS expression had poorer prognosis. Our data suggest that TYMS has potential use as a diagnostic and prognostic marker for breast cancer patients.

14.
J Cell Physiol ; 236(5): 3207-3219, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33107052

RESUMO

The primary cilium is an antennae-like structure extent outside the cell surface. It has an important role in regulating cell-signaling transduction to affect proliferation, differentiation and migration. Evidence is accumulating that ciliary defects lead to ciliopathies and ciliary deregulation also play crucial roles in cancer formation and progression. Interestingly, restoring the cilia can suppress proliferation in some cancer cell. However, t he role of primary cilia in cancer still be debated. In this article, we review the role of the primary cilium in cancer through architecture, signaling pathways, cilia assembly and disassembly regulators, and summarized the new findings of the primary cilium in tumor microenvironments and different cancers, highlighting novel possibilities for therapeutic target in cancer.

15.
Front Endocrinol (Lausanne) ; 11: 598948, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193111

RESUMO

Purpose: Cardiac comorbidity is one of the leading causes of death among acromegaly patients. We aimed to investigate the reversibility of acromegalic cardiac involvement after surgical treatment using the gold standard method, cardiovascular magnetic resonance, and to explore the effects of endocrine remission and gender on reversibility. Methods: In this single-center, prospective cohort study, fifty untreated acromegaly patients were enrolled. Comprehensive cardiac assessments were performed using a 3.0 T magnetic resonance scanner before and 3 and 12 months after transsphenoidal adenomectomy. Results: Preoperatively, left ventricular (LV) enlargement (13.0%), LV systolic dysfunction (6.5%), right ventricular (RV) enlargement (4.3%), RV systolic dysfunction (2.2%) and myocardial fibrosis (12.0%) were identified. On average, the LV and RV ejection fractions of acromegaly patients were higher than the healthy reference values. Male patients had thicker LV myocardia, wider ventricular diameters and more dilated pulmonary artery roots than female patients. After surgery, LV myocardial hypertrophy was reversed, the left atrium was remodeled, and ventricular systolic dysfunction recovered to normal. Cardiac alterations were detected early in the 3rd postoperative month and persisted until the 12th month. The interventricular septum was initially thickened in the 3rd postoperative month and then recovered at the 12th month. Notable postoperative cardiac reversibility was observed in male patients but did not occur in all female patients. Patients achieving endocrine remission with normalized hormone levels had thinner LV myocardia than patients without normalized hormone levels. Conclusion: Our findings demonstrated that some of the cardiac involvement in acromegaly patients is reversible after surgical treatment which lowers hormone levels. Endocrine remission and gender significantly impacted postoperative cardiac reversibility.


Assuntos
Acromegalia/cirurgia , Cardiomiopatias/prevenção & controle , Ecocardiografia/métodos , Imagem Cinética por Ressonância Magnética/métodos , Disfunção Ventricular Esquerda/prevenção & controle , Acromegalia/fisiopatologia , Adulto , Idoso , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/patologia , Adulto Jovem
16.
Onco Targets Ther ; 13: 11899-11912, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33239891

RESUMO

Background: Celastrol (Cela) was a natural compound that exerted anti-tumor activity in many cancer cells. Nevertheless, the molecular mechanism behind the anti-tumor role of Cela in non-small-cell lung carcinoma (NSCLC) remains to be clarified. Methods: Flow cytometry was used to analyze cell cycle progression and apoptosis. Colony formation assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay were used to analyze cell proliferation. Cell migration and invasion abilities were assessed by transwell assays. Quantitative real-time polymerase chain reaction (qRT-PCR) was implemented for the detection of RNA levels. Western blot assay was used for the determination of protein levels. Dual-luciferase reporter assay was conducted to confirm the interaction between microRNA-33a-5p (miR-33a-5p) and circular RNA SATB homeobox 2 (circ_SATB2) or E2F transcription factor 7 (E2F7). Xenograft tumor assay was conducted to test the roles of Cela and circ_SATB2 in NSCLC progression in vivo. Results: Cela hampered the malignant behaviors of NSCLC cells. Cela down-regulated circ_SATB2 level in NSCLC cells. Cela stimulation-induced suppressive influence in NSCLC progression was alleviated by circ_SATB2 accumulation. E2F7 interference overturned circ_SATB2-mediated effects in Cela-stimulated NSCLC cells. MiR-33a-5p was a target of circ_SATB2, and E2F7 was verified as a target of miR-33a-5p. Circ_SATB2 attenuated Cela-mediated effects through targeting miR-33a-5p in NSCLC cells. Cela-mediated suppressive effect on tumor growth was partly attenuated by the overexpression of circ_SATB2 in vivo. Conclusion: Cela suppressed NSCLC development through regulating circ_SATB2/miR-33a-5p/E2F7 signaling cascade.

17.
Front Genet ; 11: 931, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33005169

RESUMO

Introduction: The Pals1-associated tight junction (PATJ) is a Crumbs (CRB) complex component that regulates epithelial cell apico-basal polarity and directional migration. This study assessed PATJ expression in clear cell renal cell carcinoma (ccRCC) vs. normal tissues and associated with ccRCC progression and prognosis. Methods: The effects of PATJ knockdown were investigated on regulation of normal kidney epithelial cell viability and protein expression in vitro. The PATJ mRNA data in ccRCC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and analyzed with UALCAN, LinkedOmics, Kaplan-Meier Plotter, GEPIA, and SurvExpress tools. Immunohistochemistry was performed for PATJ in tissue microarray sections (n = 150 ccRCC and 30 normal renal specimens). Normal human kidney tubular epithelial cell (HKC) cells were transfected with PATJ and negative control siRNA for cell viability CCK-8 assay, flow cytometry, and western blots. Results: The data showed that PATJ mRNA and protein were downregulated in ccRCC tissues and cell lines. Downregulation of PATJ mRNA was associated with male patients, advanced tumor stages, grades, and ccB subtypes as well as poorer overall and disease-free survival of patients. Furthermore, PATJ protein was also significantly downregulated in ccRCC tissues and associated with advanced tumor pathologic, TNM stages and poorer overall. In vitro, knockdown of PATJ expression promoted HKC proliferation and the activation of mitogen-activated protein kinases (MAPK) pathway proteins. Conclusions: This study revealed that a decrease of PATJ in ccRCC, which was associated with male patients, advanced tumor, and poorer survival, suggesting that PATJ may be a useful prognostic biomarker and therapeutic target for ccRCC.

18.
J Mol Med (Berl) ; 98(11): 1573-1589, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32897390

RESUMO

Autophagy is a conserved self-degradation system closely related to cancer progression. Small molecule inhibitors of autophagy have proven to be efficient tools in cancer therapy and are in high demand. Here we report the discovery of two compounds (LZ02/01) capable of suppressing cancer cell proliferation via inhibiting autophagy flux and promoting apoptosis. Potential autophagy inhibitors were selected based on the pharmacophore model derived from the structures of known autophagy inhibitors. LZ02/01-mediated autophagy flux disruption and apoptosis promotion in breast and hepatocellular carcinoma cells (MCF-7 and Hep3B) were examined using a combination of molecular methods in vitro and in vivo. The synergistic tumor-suppressing effects of LZ02 and chloroquine were validated by adopting a xenograft mice model of human breast cancer. Two potential inhibitors (LZ02/01) targeting an autophagy pathway were discovered from the Enamine database. In both MCF-7 and Hep3B cells, LZ02 and LZ01 had the effect of causing the co-occurrence of autophagic flux inhibition and apoptosis induction, robustly suppressing the growth, proliferation, and cell cycle progression. Further tests revealed that FoxO3a and its downstream target genes regulating autophagy, apoptosis, and cell cycle progression were activated and overexpressed, suggesting such effects of LZ02/01 on autophagy and apoptosis were associated with the activation and overexpression of FoxO3a. In addition, LZ02/01-mediated apoptosis is not independent; it was verified to be promoted by autophagic flux inhibition. Meanwhile, synergistic effects on tumor growth reduction were detected in the xenograft mice model of human breast cancer simultaneously treated with LZ02 and chloroquine. Our findings suggest that LZ01 and LZ02 are potent in suppressing cancer cell proliferation and tumor growth through autophagic flux inhibition and apoptosis promotion. The synergistic anti-cancer effects of LZ02 with chloroquine may provide a rational basis for prospective cancer therapy. KEY MESSAGES: A ligand-based pharmacophore model of high quality is constructed to query hits and two novel scaffold lead compounds LZ01/02 were identified by high-throughput virtual screening. LZ01/02 works to inhibit autophagic flux by attenuating lysosome function. LZ01/02 induces apoptosis through autophagic flux inhibition and apoptosis is the main mechanism to inhibit MCF-7 and Hep3B cancer cell proliferation. The synergistic antitumor growth effects of LZ02 and chloroquine are verified in human xenograft model.

19.
Artigo em Inglês | MEDLINE | ID: mdl-32754907

RESUMO

It has been reported that loss of Hugl-2 contributes to tumour formation and progression in vitro and in vivo. However, whether Hugl-2 levels decrease during kidney renal clear cell carcinoma (KIRC) and the mechanism involved remain unknown. This study aimed to investigate whether DNA methylation of Hugl-2 reduces its expression, leading to the progression and poor prognosis of KIRC. Hugl-2 methylation and mRNA expression and KIRC clinicopathological data were extracted from The Cancer Genome Atlas (TCGA), and relationships among these factors were analyzed using UALCAN, MethHC, Wanderer and LinkedOmics web tools. We found that Hugl-2 mRNA and protein levels were reduced in KIRC tissues. Moreover, Hugl-2 mRNA levels were related to tumour grade and overall survival, and Hugl-2 methylation was increased in KIRC. According to the results of methylation-specific PCR, KIRC cells had higher Hugl-2 DNA methylation levels than HKC cells. Moreover, Hugl-2 DNA methylation correlated negatively with Hugl-2 mRNA and was also related to the pathology and T stage of KIRC patients. KIRC patients with high Hugl-2 DNA methylation also had shorter overall survival. Additionally, methylation of cg08827674, a Hugl-2 probe, was related to pathologic stage, T stage, neoplasm histologic grade, serum calcium level without laterality, M stage, N stage, and ethnicity. Furthermore, treatment with the DNA methylation inhibitor decitabine resulted in upregulation of Hugl-2 mRNA and protein levels in KIRC cell lines. These results indicate that Hugl-2 DNA methylation may be both a prognostic marker and a therapeutic target in KIRC.

20.
Cytoskeleton (Hoboken) ; 77(8): 303-312, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32748571

RESUMO

Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins are a large protein complex that is involved in the membrane fusion in vesicle trafficking, cell growth, cytokinesis, membrane repair, and synaptic transmission. As one of the SNARE proteins, SEC22B functions in membrane fusion of vesicle trafficking between the endoplasmic reticulum and the Golgi apparatus, antigen cross-presentation, secretory autophagy, and other biological processes. However, apart from not being SNARE proteins, there is little knowledge known about its two homologs (SEC22A and SEC22C). SEC22B alterations have been reported in many human diseases, especially, many mutations of SEC22B in human cancers have been detected. In this review, we will introduce the specific functions of SEC22B, and summarize the researches about SEC22B in human cancers and other diseases. These findings have laid the foundation for further studies to clarify the exact mechanism of SEC22B in the pathological process and to seek new therapeutic targets and better treatment strategies.

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