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Objective To evaluate the value of magnetic resonance imaging(MRI)in prenatal diagnosis of fetal Chiari malformation.Methods The prenatal MRI findings of 27 cases of Chiari malformation confirmed by follow-up in Obstetrics and Gynecology Hospital,Fudan University from Feb 2010 to Feb 2022 were retrospectively analyzed and compared with ultrasound findings.Results Twenty-seven pregnant women,aged from 16-36 years(average 28.0 years)and 27 fetuses with gestation from 15.3-38.4 weeks(average 24.3 weeks)were studied.There were 18 cases of Chiari Ⅱ(Chiari malformation type Ⅱ,CMⅡ),3 cases of Chiari Ⅲ(CMⅢ),6 cases of Chiari Ⅳ(CMⅣ).CMⅡ and CMⅢ images showed brain herniation,descending pons,narrowing or disappearance of the posterior fossa cistern and the fourth ventricle,the subarachnoid space disappears.There were 17 cases of hydrocephalus,2 cases of cerebrospinal fluid loss,17 cases of"lemon head"and"banana cerebellar"signs,4 cases of encephalocele,15 cases of spinal bifida,3 cases of lower spinal cord and 2 cases of spinal cavity,4 cases of spinal angular deformity and 6 cases of other malformations.In CMⅣ,there were 2 cases of undeveloped cerebellum and 4 cases of cerebellum and brainstem dysplasia,hydrocephalus in 5 cases,posterior fossa cistern widening in 4 cases,and other malformations in 4 cases.MRI showed the posterior fossa structure and spinal cord more clearly than ultrasound,and could find lesions not detected by ultrasound.Conclusion Prenatal MRI can be used as a complementary examination of ultrasound,which can improve the accuracy of diagnosis of Chiari malformation,reduce the rate of missed diagnosis,and clarify the classification of Chiari malformation.
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Osteosarcoma is a common malignant tumor in children and adolescents, known for its aggressive invasion and distant metastasis, leading to a poor prognosis. Matrix metalloproteinases (MMPs) can degrade the extracellular matrix and basement membranes through their proteolytic activity, thereby promoting osteosarcoma metastasis. Chemokine ligand 2 (CCL2) is a well-studied chemokine that plays a significant role in the cell motility of many cancers. However, its specific involvement in osteosarcoma metastasis is not fully understood. The aim of this study is to examine the role of miRNAs in CCL2-mediated MMP expression and cell motility in human osteosarcoma. The analysis of immunohistochemistry data and databases associated a positive correlation between CCL2 or MMP-3 levels with the metastasis of osteosarcoma patients. The in vivo lung metastatic osteosarcoma model also demonstrated similar effects, showing higher levels of CCL2 and MMP-3 in lung metastatic osteosarcoma tissues. The stimulation of osteosarcoma cells with CCL2 enhanced migration and invasion abilities through the upregulation of MMP-3 synthesis. Our results also indicate that CCL2 enhances MMP-3-dependent cell motility by inhibiting miR-3659 synthesis. Therefore, CCL2 represents a promising therapeutic target for treating metastasis in osteosarcoma.
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Bladder cancer (BC) cells exhibit a high basal level of autophagy activity, which contributes to the development of a protective mechanism for cellular survival against current treatments. HsamicroRNA34a (miR34a) presents antitumor function in several types of cancer. However, the functional mechanism of miR34a in regulating tumor aggressiveness and protective autophagy of BC remains largely unknown. First, transfected BC cells with miR34a mimic exhibited LC3II and p62 accumulation through immunofluorescence staining. It was demonstrated that syntaxin 17 (STX17), which is required for autophagosomelysosome fusion, was downregulated upon miR34a mimic treatment. Mechanistically, miR34a reduced the expression of STX17 proteins that directly bind on STX17 3'untranslated regions and thus suppressed STX17 mRNA translation to eventually inhibit protective autophagy in BC. Cell viability and colony formation assays revealed that overexpression of miR34a in BC cells enhances the chemosensitivity of cisplatin, doxorubicin, epirubicin and mitomycin C. Furthermore, miR34a inhibited cell proliferation and triggered G0/G1 cell cycle arrest by inhibiting cyclin D1 and cyclin E2 protein expression. Moreover, miR34a suppressed cell motility through the downregulation of epithelialmesenchymal transition. In summary, miR34a inhibits cell proliferation, motility and autophagy activity in BC, which can benefit BC treatment.
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MicroRNAs , Neoplasias da Bexiga Urinária , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Proliferação de Células/genética , Ciclo Celular/genética , Autofagia/genética , Linhagem Celular Tumoral , Apoptose/genéticaRESUMO
Bone metastases during lung cancer are common. Bone sialoprotein (BSP), a non-collagenous bone matrix protein, plays important functions in bone mineralization processes and in integrin-mediated cell-matrix interactions. Importantly, BSP induces bone metastasis in lung cancer, but the underlying mechanisms remain unclear. This study therefore sought to determine the intracellular signaling pathways responsible for BSP-induced migration and invasion of lung cancer cells to bone. Analyses of the Kaplan-Meier, TCGA, GEPIA and GENT2 databases revealed that high levels of BSP expression in lung tissue samples were associated with significantly decreased overall survival (hazard ratio = 1.17; p = 0.014) and with a more advanced clinical disease stage (F-value = 2.38, p < 0.05). We also observed that BSP-induced stimulation of matrix metalloproteinase (MMP)-14 promoted lung cancer cell migration and invasion via the PI3K/AKT/AP-1 signaling pathway. Notably, BSP promoted osteoclastogenesis in RAW 264.7 cells exposed to RANKL and BSP neutralizing antibody reduced osteoclast formation in conditioned medium (CM) from lung cancer cell lines. Finally, at 8 weeks after mice were injected with A549 cells or A549 BSP shRNA cells, the findings revealed that the knockdown of BSP expression significantly reduced metastasis to bone. These findings suggest that BSP signaling promotes lung bone metastasis via its direct downstream target gene MMP14, which reveals a novel potential therapeutic target for lung cancer bone metastases.
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Neoplasias Ósseas , Neoplasias Pulmonares , Camundongos , Animais , Sialoproteína de Ligação à Integrina/genética , Sialoproteína de Ligação à Integrina/metabolismo , Sialoglicoproteínas/genética , Sialoglicoproteínas/metabolismo , Metaloproteinase 14 da Matriz , Fosfatidilinositol 3-Quinases , Linhagem Celular Tumoral , Neoplasias Ósseas/metabolismoRESUMO
Lung cancer is an extremely common cancer and metastatic lung cancer has a greatly low survival rate. Lymphangiogenesis is essential for the development and metastasis of lung cancer. The adipokine angiopoietin-like protein 2 (ANGPTL2) regulates tumor progression and metastasis, although the functions of ANGPTL2 in lung cancer are unknown. Analysis of data from TCGA genomics program, the GEPIA web server and the Oncomine database revealed that higher levels of ANGPTL2 expression were correlated with progressive disease and lymph node metastasis. ANGPTL2 enhanced VEGF-A-dependent lymphatic endothelial cell (LEC) tube formation and migration. Integrin α5ß1, p38 and nuclear factor (NF)-κB signaling mediated ANGPTL2-regulated lymphangiogenesis. Importantly, overexpression ANGPTL2 facilitated tumor growth and lymphangiogenesis in vivo. Thus, ANGPTL2 is a promising therapeutic object for treating lung cancer.
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Neoplasias Pulmonares , Linfangiogênese , Humanos , Proteína 2 Semelhante a Angiopoietina , Fator A de Crescimento do Endotélio Vascular , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Transdução de Sinais , NF-kappa B/metabolismo , Linhagem Celular TumoralRESUMO
Background: Metastatic prostate cancer (PCa) predicts a poor prognosis and lower likelihood of survival. Osteoblasts (OBs) are known to be responsible for the synthesis and mineralization of bone, although it is unclear as to whether PCa in the prostate gland cooperates with OBs in bone to promote PCa malignant transformation. We aimed to elucidate how primary PCa cells cooperate with distal OBs and contribute to the vicious cycle that leads to metastatic PCa. Methods: N-cadherin, E-cadherin, and Twist protein expression were measured by Western blot. Twist translocation into the nucleus was detected by the immunofluorescence (IF) assay. Enzyme-linked immunosorbent assay (ELISA) detected protein levels in human serum samples. Levels of candidate protein expression were examined by the human cytokine array. Prostate tumor growth and metastasis were analyzed by orthotopic and metastatic prostate cancer models, respectively. Immunohistochemistry (IHC) staining was used to observe ADAM metallopeptidase domain 9 (ADAM9) and WNT1 inducible signaling pathway protein 1 (WISP-1) expression in tissue. Results: Our in vitro and in vivo analyses have now discovered that primary PCa expressing ADAM9 protein enables the transformation of OBs into PCa-associated osteoblasts (PCa-OBs), inducing WISP-1 secretion from PCa-OBs in the bone microenvironment. The upregulation of WISP-1 in bone provided feedback to primary PCa and promoted PCa cell aggressiveness via epithelial-mesenchymal transition (EMT) activity. Elevated levels of WISP-1 expression were detected in the serum of patients with PCa. ADAM9 levels were overexpressed in tumor tissue from PCa patients; ADAM9 blockade interrupted OB-induced release of WISP-1 and also suppressed primary tumor growth and distal metastasis in orthotopic PCa mouse models. Conclusion: Our study suggests that the ADAM9/WISP-1 axis assists with metastatic PCa progression. Thus, targeting the ADAM9/WISP-1 axis may help to prevent the malignant phenotypes of PCa cells.
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Proteínas ADAM , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Proteínas ADAM/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Osteoblastos/metabolismo , Neoplasias da Próstata/metabolismo , Microambiente Tumoral , Regulação para CimaRESUMO
INTRODUCTION: Cigarette smoking is the main risk factor for lung cancer. MSCs in the TME promoting tumor angiogenesis, growth, and metastasis. SIBLING proteins enable cancer cells to extend, invade and metastasize. OBJECTIVES: Cigarette smoke promotes the progression and metastasis of lung cancer, although how this occurs is poorly understood. We evaluated the impact of whether cigarette smoking motivates SIBLING protein expression and is involved in MSC-mediated lung tumor metastasis. METHODS: We investigated the expression of OPN in the Gene Expression Omnibus (GEO) databases and confirmed the results by immunohistochemistry (IHC), qPCR and Western blotting (WB) of lung cancer cells and tissues. The effect of OPN on the recruitment and adhesion of mesenchymal stem cells (MSCs) to lung cancer cells and lung cancers metastasis was investigated by Transwell, adhesion assays. A series of in vitro and in vivo experiments were conducted to demonstrate the mechanisms by which OPN modulates recruitment and adhesion of MSCs to lung cancer cells and lung cancer metastasis. RESULTS: Cigarette smoke extract (CSE) and benzo[α]pyrene (B[α]P) increased levels of OPN expression and facilitated the recruitment and adhesion of MSCs to lung cancer cells via JAK2/STAT3 signaling. We also observed that OPN promotes tumor-associated MSC (TA-MSC) formation through the OPN receptor (integrins αvß1, αvß3, αvß5 or CD44), inducing lung cancer cell migration and invasion. In an orthotopic mouse model of lung cancer, increases in OPN expression promoted by cigarette smoke upregulated MSC recruitment and facilitated lung cancer metastasis. Knockdown of OPN expression inhibited cigarette smoke-induced lung cancer metastasis in vivo. CONCLUSION: Cigarette smoke increases OPN expression through the JAK2/STAT3 signaling pathway to attract MSC cell recruitment and promote lung cancer metastasis. Our findings offer important insights into how lung cancer metastasis develops in smokers.
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Fumar Cigarros , Neoplasias Pulmonares , Células-Tronco Mesenquimais , Camundongos , Animais , Osteopontina/genética , Osteopontina/metabolismo , Osteopontina/farmacologia , Fumar Cigarros/efeitos adversos , Neoplasias Pulmonares/genética , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Transdução de Sinais , Nicotiana/metabolismo , Processos NeoplásicosRESUMO
Prostate cancer commonly affects the urinary tract of men and metastatic prostate cancer has a very low survival rate. Apelin belongs to the family of adipokines and is associated with cancer development and metastasis. However, the effects of apelin in prostate cancer metastasis is undetermined. Analysis of the database revealed a positive correlation between apelin level with the progression and metastasis of prostate cancer patients. Apelin treatment facilitates cell migration and invasion through inhibiting tissue inhibitor of metalloproteinase 2 (TIMP2) expression. The increasing miR-106a-5p synthesis via c-Src/PI3K/Akt signaling pathway is controlled in apelin-regulated TIMP2 production and cell motility. Importantly, apelin blockade inhibits prostate cancer metastasis in the orthotopic mouse model. Thus, apelin is a promising therapeutic target for curing metastatic prostate cancer.
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Adipocinas , Apelina , MicroRNAs , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Adipocinas/genética , Adipocinas/fisiologia , Apelina/genética , Apelina/fisiologia , Linhagem Celular Tumoral , MicroRNAs/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Inibidor Tecidual de Metaloproteinase-2/genética , Movimento Celular , Metástase NeoplásicaRESUMO
A high basal level of autophagic flux in bladder cancer (BC) cells prevents cell death and weakens chemotherapy efficacy. However, how autophagy influences cancer-associated immunosuppression in BC remains undetermined. In this study, we observed a negative correlation between the autophagy-related markers LC3-II and programmed death ligand-1 (PD-L1) in BC cells. The autophagy inhibitors chloroquine (CQ) and bafilomycin A1 (Baf-A1) increased PD-L1 expression in BC cells through the ERK-JNK-c-Jun signal-transduction pathway. Moreover, the treatment of BC cells with CQ and Baf-A1 inhibited hsa-microRNA-34a (miR-34a) expression and miR-34a overexpression in BC cells prevented the autophagy blockade-induced PD-L1 expression; a negative correlation between miR-34a and PD-L1 expression was observed during treatment with autophagy inhibitors. Furthermore, miR-34a overexpression induced the cytotoxic activity of natural killer cells against BC cells. Our results provide evidence that autophagy blockade and its regulatory pathway affect cancer-associated immunosuppression through PD-L1 elevation. Thus, the coadministration of autophagy inhibitors and a PD-L1 immune checkpoint blockade provides a potential therapeutic approach for treating BC.
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MicroRNAs , Neoplasias da Bexiga Urinária , Autofagia , Antígeno B7-H1/metabolismo , Humanos , Terapia de Imunossupressão , MicroRNAs/metabolismo , Regulação para Cima , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genéticaRESUMO
Bladder cancer (BC) is the second most common urologic cancer in western countries. New strategies for managing high-grade muscle-invasive bladder cancer (MIBC) are urgently required because MIBC has a high risk of recurrence and poor survival. A growing body of evidence indicates that microRNA has potent antitumorigenic properties in various cancers, and thus, therapeutic strategies based on microRNA may show promising results in cancer therapy. Analysis of The Cancer Genome Atlas (TCGA) database indicated that hsa-miR-30a-3p is downregulated in human BC. Our in vitro investigation demonstrated that hsa-miR-30a-3p suppresses the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 and reduces the cell invasive potential of BC cells. Furthermore, hsa-miR-30a-3p directly targets ATG5, ATG12, and Beclin 1; this in turn improves the chemosensitivity of BC cells to cisplatin through the repression of protective autophagy. In a tumor-xenograft mice model, hsa-miR-30a-3p suppressed muscle invasion. Cotreatment with hsa-miR-30a-3p enhanced the antitumor effect of cisplatin in reducing tumor growth in BC. The current study provides a novel strategy of using hsa-miR-30a-3p as an adjuvant or replacement therapy in future BC treatment.
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MicroRNAs , Neoplasias da Bexiga Urinária , Animais , Autofagia/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Feminino , Humanos , Masculino , Metaloproteinase 2 da Matriz , Camundongos , MicroRNAs/metabolismo , Músculos/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genéticaRESUMO
Objective:To explore the value of apparent diffusion coefficient (ADC) and renal volume in assessing fetal kidney development and disease.Methods:From January 2016 to October 2020, 84 fetuses with congenital anomalies of the kidney and urinary tract (CAKUT) were identified with MRI (CAKUT group), and 97 fetuses with no significant abnormalities on MRI or postnatal follow-up (control group) from the Obstetrics and Gynecology Hospital of Fudan University were enrolled and analyzed retrospectively. ADC value and renal volume were measured to compare the two groups, and the relationship was analyzed between these two parameters in the control group with gestational age, location (left or right kidney), and fetal gender. Two independent or paired sample t-tests, and linear correlation analyses, were adopted for the statistical analysis. Results:(1) There were 84 pregnant women in the CAKUT group, including a twin pregnancy, with an average age of (29±4) years old, ranging from 21 to 39 years old. The gestational age at MRI was (26±4) weeks with a range of 21-34 weeks. Of the 85 fetuses, 52 were male (61.2%), and 33 were female (38.8%). The polycystic dysplastic kidney was found in 32 cases (37.6%), hydronephrosis in 29 cases (34.1%), and an isolated kidney in 24 cases (28.2%). There were 97 singleton pregnancies in the control group, including 45 (46.4%) male and 52 (53.6%) female fetuses. The average maternal age was (30±5) years old, with a range of 19-41 years old, and the gestational week at MRI was (27±4) weeks, with a range of 21-34 weeks. (2) In the control group, the mean ADC value and renal volume were (1.255±0.112)×10 -3 mm2/s and (4 747±2 479) mm 3, which were negatively ( R 2=0.30, P<0.01) and positively correlated ( R 2=0.80, P<0.01) with the gestational age, respectively. There was no significant difference between ADC value and renal volume between different fetal gender in the control group. (3) The ADC value and the renal volume of fetuses with polycystic dysplastic kidney [(1.720±0.200) ×10 -3 mm2/s and (8 154±8 337) mm 3] were higher than those in the control group ( t=-13.11 and-3.08, P<0.001 and P=0.004). Compared with the control group, ADC of fetuses with hydronephrosis [(1.333±0.171) ×10 -3 mm2/s] was higher ( t=-3.90, P<0.001); and the renal volume [(7 201±4 460) mm 3] was larger but without statistical significance. The fetuses with an isolated kidney had an increasing trend in renal volume [(5 239±4 244) mm 3] and a decreasing trend in the ADC value [(1.239±0.125) ×10 -3 mm2/s] when compared with the normal fetuses, but neither difference was significant. Conclusions:In normal fetuses, the ADC value decreases, and the renal volume increases with the gestational age. Fetuses with CAKUT may have a larger kidney than normal.
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Osteoblasts and osteoclasts are major cellular components in the bone microenvironment and they play a key role in the bone turnover cycle. Many risk factors interfere with this cycle and contribute to bone-wasting diseases that progressively destroy bone and markedly reduce quality of life. Melatonin (N-acetyl-5-methoxy-tryptamine) has demonstrated intriguing therapeutic potential in the bone microenvironment, with reported effects that include the regulation of bone metabolism, acceleration of osteoblastogenesis, inhibition of osteoclastogenesis and the induction of apoptosis in mature osteoclasts, as well as the suppression of osteolytic bone metastasis. This review aims to shed light on molecular and clinical evidence that points to possibilities of melatonin for the treatment of both osteoporosis and osteolytic bone metastasis. It appears that the therapeutic qualities of melatonin supplementation may enable existing antiresorptive osteoporotic drugs to treat osteolytic metastasis.
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Antioxidantes/farmacologia , Neoplasias Ósseas/prevenção & controle , Melatonina/farmacologia , Osteoclastos/efeitos dos fármacos , Osteogênese , Osteoporose/prevenção & controle , Animais , Neoplasias Ósseas/secundário , Humanos , Osteoclastos/citologia , Osteoporose/patologiaRESUMO
Bladder cancer (BC), one of the most common urological neoplastic disorders in men, has an extremely low survival rate because of its tendency to metastasize. The anticancer drugs chloroquine (CQ) and hydroxy CQ (HCQ) might inhibit tumor progression and invasiveness. However, the mechanism by which CQ and HCQ influence BC is undetermined. In this study, CQ and HCQ treatments inhibited the migration and invasion of two BC cell types (5637 and T24) through expression modulation of matrix metalloproteinase-2 (MMP-2), which belongs to the matrix MMP family and is a key mediator of cancer progression. Moreover, additional data revealed that the migrative and invasive effects of BC cells treated with CQ or HCQ were abolished after treatment with rapamycin, which induces autophagy, demonstrating that CQ and HCQ functions in BC are based on autophagy inhibition. In conclusion, our research demonstrated that CQ and HCQ regulated cell motility in BC through MMP-2 downregulation by targeting autophagy functions, providing a novel therapeutic strategy for BC treatment.
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Metaloproteinase 2 da Matriz , Neoplasias da Bexiga Urinária , Autofagia , Cloroquina , Humanos , Hidroxicloroquina , Masculino , Metaloproteinase 2 da Matriz/genética , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
Bladder cancer (BC) is the second most common urological tumour in Western countries. Approximately, 80% of patients with BC will present with non-muscle invasive bladder cancer (NMIBC), whereas a quarter will have muscle invasive disease (MIBC) at the time of BC diagnosis. However, patients with NMIBC are at risk of BC recurrence or progression into MIBC, and an MIBC prognosis is determined by the presence of progression and metastasis. Matrix metalloproteinase 2 (MMP2), a type of matrix metalloproteinase (MMP), plays a major role in tumour invasion and is well-characterized in BC prognosis. In BC, the mechanisms regulating MMP2 expression, and, in turn, promote cancer invasion, have hardly been explored. Thrombospondin-4 (THBS4/TSP4) is a matricellular glycoprotein that regulates multiple biological functions, including proliferation, angiogenesis, cell adhesion and extracellular matrix modelling. Based on the results of a meta-analysis in the Gene Expression Profiling Interactive Analysis 2 database, we observed that TSP4 expression levels were consistent with overall survival (OS) rate and BC progression, with the highest expression levels observed in the advanced stages of BC and associated with poor OS rate. In our pilot experiments, incubation with recombinant TSP4 promoted the migration and invasion in BC cells. Furthermore, MMP2 expression levels increased after recombinant TSP4 incubation. TSP4-induced-MMP2 expression and cell motility were regulated via the AKT signalling pathway. Our findings facilitate further investigation into TSP4 silencing-based therapeutic strategies for BC.
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Bladder cancer (BC), a common urologic cancer, is the fifth most frequently diagnosed tumor worldwide. hsamiR34a displays antitumor activity in several types of cancer. However, the functional mechanisms underlying hsamiR34a in BC remains largely unknown. We observed that hsamir34a levels were significantly and negatively associated with clinical disease stage as well as regional lymph node metastasis in human BC. In a series of in vitro investigations, overexpression of hsamiR34a inhibited cell migration and invasion in BC cell lines 5637 and UMUC3 as detected by Transwell assays. We further found that hsamiR34a inhibited cell migration and invasion by silencing matrix metalloproteinase2 (MMP2) expression and thus interrupting MMP2mediated cell motility. Our analysis of BC datasets from The Cancer Genome Atlas database revealed a negative correlation between hsamiR34a and MMP2. Moreover, higher MMP2 protein expression was observed in the BC tissues when compared with that noted in the normal tissue. MMP2 levels were also significantly associated with clinical disease stage and poor survival rate in human BC. These findings indicate that MMP2 plays a critical role in regulating BC progression. Therefore, hsamiR34a is a promising treatment to target MMP2 for the prevention and inhibition of cell migration and invasion in BC.
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Movimento Celular/genética , Genes Supressores de Tumor/fisiologia , Metaloproteinase 2 da Matriz/genética , MicroRNAs/metabolismo , Neoplasias da Bexiga Urinária/patologia , Linhagem Celular Tumoral , Bases de Dados Genéticas , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Metaloproteinase 2 da Matriz/metabolismo , MicroRNAs/genética , Invasividade Neoplásica/genética , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/mortalidadeRESUMO
Cancer-related bone erosion occurs frequently in bone metastasis and is associated with severe complications such as chronic bone pain, fractures, and lower survival rates. In recognition of the fact that the darkness hormone melatonin is capable of regulating bone homeostasis, we explored its therapeutic potential in bone metastasis. We found that melatonin directly reduces osteoclast differentiation, bone resorption activity and promotes apoptosis of mature osteoclasts. We also observed that melatonin inhibits RANKL production in lung and prostate cancer cells by downregulating the p38 MAPK pathway, which in turn prevents cancer-associated osteoclast differentiation. In lung and prostate bone metastasis models, twice-weekly melatonin treatment markedly reduced tumor volumes and numbers of osteolytic lesions. Melatonin also substantially lowered the numbers of TRAP-positive osteoclasts in tibia bone marrow and RANKL expression in tumor tissue. These findings show promise for melatonin in the treatment of bone metastases.
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Neoplasias Ósseas/tratamento farmacológico , Melatonina/farmacologia , Osteoclastos/efeitos dos fármacos , Ligante RANK/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Animais , Células da Medula Óssea/efeitos dos fármacos , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Osteoclastos/patologia , Osteólise/tratamento farmacológico , Osteólise/patologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Células RAW 264.7/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fosfatase Ácida Resistente a Tartarato/genéticaRESUMO
Autophagy plays a dual function in cancer progression; autophagy activation can support cancer cell survival or contribute to cell death. Miconazole, a Food and Drug Administration-approved antifungal drug, has been implicated in oncology research recently. Miconazole was found to exert antitumor effects in various tumors, including bladder cancer (BC). However, whether it provokes protective autophagy has been never discussed. We provide evidence that miconazole induces protective autophagy in BC for the first time. The results indicated that 1A/1B-light chain 3 (LC3)-II processing and p62 expression were elevated after miconazole exposure. Also, adenosine monophosphate-activated protein kinase phosphorylation was increased after miconazole treatment. We also confirmed the autophagy-promoting effect of miconazole in the presence of bafilomycin A1 (Baf A1). The result indicates that a combination treatment of miconazole and Baf A1 improved LC3-II processing, confirming that miconazole promoted autophagic flux. The acridine orange, Lysotracker, and cathepsin D staining results indicate that miconazole increased lysosome formation, revealing its autophagy-promoting function. Finally, miconazole and autophagy inhibitor 3-methyladenine cotreatment further reduced the cell viability and induced apoptosis in BC cells, proving that miconazole provokes protective autophagy in BC cells. Our findings approve that miconazole has an antitumor effect in promoting cell apoptosis; however, its function of protective autophagy is needed to be concerned in cancer treatment.
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Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Miconazol/farmacologia , Neoplasias da Bexiga Urinária/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Lisossomos/metabolismo , Macrolídeos/administração & dosagem , Macrolídeos/farmacologia , Miconazol/administração & dosagem , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Fosforilação , Proteínas Quinases/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
Prostate cancer has high metastatic potential. Men with higher urinary levels of the sleep hormone melatonin are much less likely to develop advanced prostate cancer compared with men with lower levels of melatonin. Melatonin has shown anticancer activity in experimental investigations. Nevertheless, the therapeutic effect of melatonin in metastatic prostate cancer has largely remained a mystery. Analyses of Gene Expression Omnibus data and human tissue samples indicated that levels of matrix metallopeptidase 13 (MMP-13) expression are higher in prostate cancer patients than in healthy cancer-free individuals. Mechanistic investigations revealed that melatonin inhibits MMP-13 expression and the migratory and invasive capacities of prostate cancer cells via the MT1 receptor and the phospholipase C, p38, and c-Jun signaling cascades. Importantly, tumor growth rate and metastasis to distant organs were suppressed by melatonin in an orthotopic prostate cancer model. This is the first demonstration showing that melatonin impedes metastasis of prostate cancer by suppressing MMP-13 expression in both in vitro and in vivo models. Thus, melatonin is promising in the management of prostate cancer metastasis and deserves to undergo clinical investigations.
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Metaloproteinase 13 da Matriz/metabolismo , Melatonina/farmacologia , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Masculino , Camundongos SCID , Modelos Biológicos , Invasividade Neoplásica , Metástase Neoplásica , Proteínas Proto-Oncogênicas c-jun/metabolismo , Receptores de Melatonina/metabolismo , Fosfolipases Tipo C/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Oral squamous cell carcinoma (OSCC) is an aggressive tumor that has a poor prognosis, with high levels of local invasion and lymph node metastasis. Vascular endothelial growth factor A (VEGF-A) plays essential roles in OSCC tumor angiogenesis and metastasis. Monocyte chemoattractant protein-1 (MCP-1, CCL2) is implicated in various inflammatory conditions and pathological processes, including oral cancer. The existing evidence has failed to confirm any correlation between MCP-1 or VEGF-A expression and OSCC angiogenesis. In this study, high expression levels of MCP-1 and VEGF-A were positively correlated with disease stage in patients with OSCC. In oral cancer cells, MCP-1 increased VEGF-A expression and subsequently promoted angiogenesis; miR-29c mimic reversed MCP-1 activity. We also found that MCP-1 modulated VEGF-A expression and angiogenesis through CCR2/ILK/MEK1/2 signaling. Ex vivo results of the chick embryo chorioallantoic membrane (CAM) assay revealed the angiogenic qualities of MCP-1, with increased numbers of visible blood vessel branches. Our data suggest that MCP-1 is a new molecular therapeutic target for the inhibition of angiogenesis and metastasis in OSCC.