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1.
Cell Biol Int ; 46(4): 599-610, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-34957655

RESUMEN

In most cases of cervical cancer, the high risk of the disease is caused by the human papilloma virus (HPV). Surgery or radiation usually benefits patients with early cervical cancer, while the metastatic one is uncurable and new therapeutic strategies and approaches are required. In this study, HPV16 E6 silence or overexpression were carried out to evaluate the possible mechanisms of HPV16 E6 function in cervical cancer cells with different HPV16 E6 expression background. HPV16 E6-positive cervical cancer cell Siha exerts significantly stronger cell invasion and migration potentials than the HPV16 E6-negative C33A cells. HPV16 E6 silence significantly weakened the potentials of cell invasion and migration, cell proliferation and stemness characteristic in Siha cells. Meanwhile, the overexpression of HPV16 E6 effectively promoted the cell proliferation and stemness characteristic in C33A cells. Our data also indicated a positive association between HPV16 E6 and the levels of epithelial to mesenchymal transition (EMT), and cell stemness. The ectopic expression of OCT4 could effectively reverse the inhibitory roles of HPV16 E6 silence on cell migration, invasion, and stemness in Siha cells. More interestingly, we found that HPV16 E6 might promote the OCT4 expression by impairing the direct binding of p53 on the promoter and activate its transcription. Taken together, our results indicated that HPV16 E6 could promoted the potential cell proliferation, migration, and invasion of human cervical cancer cells by modulating EMT and cell stemness. Our data provide a novel mechanism for how HPV16 E6 acts as a key risk factor for cervical cancer development and progression.


Asunto(s)
Neoplasias del Cuello Uterino , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Transición Epitelial-Mesenquimal , Femenino , Papillomavirus Humano 16/metabolismo , Humanos , Neoplasias del Cuello Uterino/metabolismo
2.
Horm Metab Res ; 54(2): 113-118, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35130572

RESUMEN

The function of miR-551b has been widely reported in various human cancers, and its dysregulation in papillary thyroid cancer (PTC) has also been disclosed, implying its potential regulator role in PTC. The aim of the study was to evaluate the function of miR-551b in PTC development and its potential mechanism. miR-551b was evaluated in PTC tissues and cells by RT-qPCR and associated with the clinicopathological features of patients. The biological effect of miR-551b on cellular processes of PTC was assessed with the CCK8 proliferation assay and the Transwell migration and invasion assay. The potential molecular mechanism was estimated with the dual-luciferase reporter assay. miR-551b was significantly upregulated in PTC, which showed a close relationship with the malignancy and development of PTC patients. miR-551b served as a prognostic biomarker negatively related to patients' survival together with the TNM stage. The overexpression of miR-551b exerted promoted effect on the development-related cellular processes of PTC, which was reversed by the overexpression of ERBB4. In conclusion, miR-551b could predict the poor prognosis of PTC patients and serve as a tumor promoter via suppressing ERBB4.


Asunto(s)
MicroARNs , Neoplasias de la Tiroides , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , Pronóstico , Receptor ErbB-4/genética , Cáncer Papilar Tiroideo/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología
3.
J Ovarian Res ; 15(1): 55, 2022 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-35513870

RESUMEN

BACKGROUND: Increasing evidence has indicated that Maelstrom (MAEL) plays an oncogenic role in various human carcinomas. However, the exact function and mechanisms by which MAEL acts in epithelial ovarian cancer (EOC) remain unclear. RESULTS: This study demonstrated that MAEL was frequently overexpressed in EOC tissues and cell lines. Overexpression of MAEL was positively correlated with the histological grade of tumors, FIGO stage, and pT/pN/pM status (p < 0.05), and it also acted as an independent predictor of poor patient survival (p < 0.001). Ectopic overexpression of MAEL substantially promoted invasiveness/metastasis and induced epithelial-mesenchymal transition (EMT), whereas silencing MAEL by short hairpin RNA effectively inhibited its oncogenic function and attenuated EMT. Further study demonstrated that fibroblast growth factor receptor 4 (FGFR4) was a critical downstream target of MAEL in EOC, and the expression levels of FGFR4 were significantly associated with MAEL. (P < 0.05). CONCLUSION: Our findings suggest that overexpression of MAEL plays a crucial oncogenic role in the development and progression of EOC through the upregulation of FGFR4 and subsequent induction of EMT, and also provide new insights on its potential as a therapeutic target for EOC.


Asunto(s)
Transición Epitelial-Mesenquimal , Neoplasias Ováricas , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proteínas de Unión al ADN , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Ováricas/patología , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/metabolismo , Factores de Transcripción
4.
Oncol Rep ; 47(6)2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35514319

RESUMEN

Icariin (ICA) is one of the main bioactive monomer belonging to the flavonoid glycosides that has been widely studied in multiple diseases, including lung cancer. Although ICA has shown anticancer effects, its specific molecular mechanism of action remains to be elucidated. In the present study, the expression of microRNA (miR)­205­5p and Phosphatase and tensin homolog deleted on chromosome ten (PTEN) in human lung cancer and bronchial cells were analyzed. Cell viability, colony formation, migration, invasion, apoptosis and cell cycle distribution were investigated in vitro. In addition, the function of ICA on tumor growth was determined using a xenotransplantation model. The results showed that ICA decreased the viability of lung cancer cells. In addition, miR­205­5p was upregulated in lung cancer tissues but downregulated following ICA treatment, while PTEN showed a significantly lower expression in lung cancer cells. miR­205­5p could increase cancer cell proliferation, migration, invasion and cell cycle progression while suppressing cell apoptosis. Importantly, rescue experiment results showed that ICA could target the miR­205­5p/PTEN axis to affect the PI3K/Akt signaling, thereby suppressing the malignant cell phenotype of lung cancer. Finally, animal experiments confirmed that ICA could inhibit lung cancer growth in vivo. Taken together, our findings suggest that miR­205­5p is a key gene targeted by ICA to inhibit lung cancer progression.


Asunto(s)
Neoplasias Pulmonares , MicroARNs , Animales , Apoptosis/genética , Movimiento Celular/genética , Proliferación Celular/genética , Flavonoides , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo
5.
Cell Commun Signal ; 20(1): 63, 2022 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-35538545

RESUMEN

BACKGROUND: The tumor microenvironment consists of stromal cells, extracellular matrix, and physicochemical properties (e.g., oxygenation, acidification). An important element of the tumor niche are cancer-associated fibroblasts (CAFs). They may constitute up to 80% of the tumor mass and share some features with myofibroblasts involved in the process of wound healing. CAFs can facilitate cancer progression. However, their interaction with melanoma cells is still poorly understood. METHODS: We obtained CAFs using conditioned media derived from primary and metastatic melanoma cells, and via co-culture with melanoma cells on Transwell inserts. Using 2D and 3D wound healing assays and Transwell invasion method we evaluated CAFs' motile activities, while coverslips with FITC-labeled gelatin, gelatin zymography, and fluorescence-based activity assay were employed to determine the proteolytic activity of the examined cells. Western Blotting method was used for the identification of CAFs' markers as well as estimation of the mediators of MMPs' (matrix metalloproteinases) expression levels. Lastly, CAFs' secretome was evaluated with cytokine and angiogenesis proteomic arrays, and lactate chemiluminescence-based assay. RESULTS: Acquired FAP-α/IL6-positive CAFs exhibited elevated motility expressed as increased migration and invasion ratio, as well as higher proteolytic activity (area of digestion, MMP2, MMP14). Furthermore, fibroblasts activated by melanoma cells showed upregulation of the MMPs' expression mediators' levels (pERK, p-p38, CD44, RUNX), enhanced secretion of lactate, several cytokines (IL8, IL6, CXCL1, CCL2, ICAM1), and proteins related to angiogenesis (GM-CSF, DPPIV, VEGFA, PIGF). CONCLUSIONS: Observed changes in CAFs' biology were mainly driven by highly aggressive melanoma cells (A375, WM9, Hs294T) compared to the less aggressive WM1341D cells and could promote melanoma invasion, as well as impact inflammation, angiogenesis, and acidification of the tumor niche. Interestingly, different approaches to CAFs acquisition seem to complement each other showing interactions between studied cells. Video Abstract.


Asunto(s)
Interleucina-6 , Melanoma , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Fibroblastos/metabolismo , Gelatina/metabolismo , Humanos , Interleucina-6/metabolismo , Lactatos/metabolismo , Melanoma/patología , Factor de Crecimiento Placentario/metabolismo , Proteómica , Microambiente Tumoral
6.
Int J Biol Sci ; 18(7): 3082-3101, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35541892

RESUMEN

Gastric cancer is anatomically proximal to peritoneum. Gastric cancer peritoneal metastasis is a complex biological process which is corresponded with disharmony within dysfunctional adipose tissue and metabolism reprogramming. Laminin gamma 1 (LAMC1) is highly expressed in cancer cells of peritoneal metastatic sites, however, the mechanism of LAMC1-metiated gastric cancer metastases to adipose tissue-rich peritoneum remains unclear. In our study, immunohistochemical staining, single cell sequencing, a co-culture model, luciferase reporter, RNA immunoprecipitation (RIP), Chromatin immunoprecipitation (CHIP) and single-molecular magnetic tweezers assays were conducted, and our results showed that LAMC1 related to Perilipin-1 content was highly expressed in peritoneal metastatic sites and mainly secreted by tumor cells. Gastric cancer cells secreted LAMC1 in an autocrine manner to detached from the primary site and promoted preadipocytes mature, rupture and release of free fatty acids (FFAs) in the peritoneal microenvironment to form pre-metastatic niche by the paracrine pathway. Reversely, differentiated preadipocyte-derived conditioned medium inhibited glycolysis and enhanced fatty acid oxidation (FAO) rate to promote cell proliferation, mesenchymal-epithelial transformation which led to tumor peritoneal colonization. In terms of biological mechanisms, one of differentiated preadipocyte-derived FFAs, palmitic acid-activated STAT3 inhibited miR-193a-3p by binding to its promoter directly; Using single-molecular magnetic tweezers, this binding manner was proved to be stable, reversable and ATP-dependent. Moreover, miR-193a-3p regulated LAMC1 in a post-translational manner. Furthermore, high LAMC1 expression in serum predicted a higher risk of peritoneal metastasis. In conclusion, our results illustrated that palmitic acid/p-STAT3/miR-193a-3p/LAMC1 pathway promotes preadipocyte differentiation, pre-metastatic niche formation and gastric cancer cell colonization to peritoneum.


Asunto(s)
Adipocitos , Laminina , MicroARNs , Neoplasias Peritoneales , Neoplasias Gástricas , Adipocitos/metabolismo , Adipocitos/patología , Diferenciación Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Humanos , Laminina/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Ácidos Palmíticos , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/metabolismo , Neoplasias Peritoneales/patología , Peritoneo/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Microambiente Tumoral
7.
Int J Biol Sci ; 18(7): 2867-2881, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35541899

RESUMEN

Background: There is increasing evidence that tumour-associated macrophages (TAMs) are critical in the formation of lung metastases. However, the molecular mechanisms of tumour interactions with TAMs via EMT are largely unknown. Methods: The mechanism of lung metastasis was studied in patient tissues. The mechanism of SNAIL regulation of the interaction between mesenchymal cells and M2 macrophages was elucidated using coculture of M2 macrophages and Transwell assays in vitro and in vivo in nude mice and NOD-SCID mice. Results: We demonstrated for the first time that SNAIL and CXCL2 were abnormally overexpressed in colorectal cancer, especially lung metastasis, and were associated with poor prognosis in colorectal cancer patients. We demonstrated that SNAIL promoted the secretion of CXCL2 by mesenchymal cells and induced the activation of M2 macrophages. We found that CXCL2 attracted M2-type macrophages to infiltrate and promote tumour metastasis. Conclusion: These findings suggest that SNAIL promotes epithelial tumour transformation, and that transformed mesenchymal cells secrete CXCL2, which promotes M2 macrophage infiltration and tumour cell metastasis. These findings elucidate the tumour-TAM interaction in the metastatic microenvironment, which is mediated by tumour-derived CXCL2 and affects lung metastasis. This study also provides a theoretical basis for the occurrence of secondary lung cancer.


Asunto(s)
Neoplasias Colorrectales , Neoplasias Pulmonares , Factores de Transcripción de la Familia Snail , Animales , Línea Celular Tumoral , Movimiento Celular , Quimiocina CXCL2 , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Transición Epitelial-Mesenquimal/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Macrófagos , Ratones , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Microambiente Tumoral
8.
Bioengineered ; 13(5): 11822-11831, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35543351

RESUMEN

Cell migration inducing hyaluronidase 1 (CEMIP) mediates catabolism of hyaluronan, and participates in the cell metastasis, invasion, and motility. Dysregulated CEMIP expression was associated with progression and prognosis of tumors. The role of CEMIP in papillary thyroid carcinoma (PTC) remains unknown. Our study showed that CEMIP was upregulated in both tissues and cells of PTC. Silencing of CEMIP reduced cell proliferation and suppressed migration and invasion of PTC. Protein expression of phosphorylated STAT3 (Signal Transducer And Activator Of Transcription 3) (p-STAT3), AKT (p-AKT) and p65 (p-p65) were decreased by CEMIP silencing in PTC cells. Pyruvate dehydrogenase kinase 4 (PDK4) over-expression attenuated CEMIP silencing-induced decrease in p-STAT3, p-AKT and p-p65. Silencing of CEMIP-induced decrease in cell proliferation and metastasis in PTC were restored by over-expression of STAT3. CEMIP functioned as an oncogenic gene in PTC through PDK4-mediated activation of STAT3/AKT/NF-κB pathway.


Asunto(s)
Hialuronoglucosaminidasa , Neoplasias de la Tiroides , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Humanos , Hialuronoglucosaminidasa/genética , Hialuronoglucosaminidasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genética , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/patología
9.
Bioengineered ; 13(5): 11867-11880, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35543375

RESUMEN

Lung adenocarcinoma (LUAD) is the main histological type of lung cancer, which is the leading cause of cancer-related deaths. Accumulating evidence has displayed that UBE2T is related to tumor progression. However, its role in LUAD has not been fully elucidated. The expression of UBE2T was detected in LUAD tissues by qRT-PCR, western blotting, and immunohistochemistry. UBE2T shRNAs were transfected into LUAD cells to analyze the consequent alteration in function through CCK-8 assay, Edu assay, transwell assay, and TUNEL staining. The potential mechanism of UBE2T was analyzed through GEPIA and verified using ChIP, EMSA, and GST pull-down assays. Furthermore, a xenograft mouse model was used to assess UBE2T function in vivo. Results showed that UBE2T level was significantly elevated in LUAD tissues and high UBE2T expression was associated with poor overall survival and disease-free survival. Results from the loss-of-function experiments in vitro showed that UBE2T modulated LUAD cell proliferation, migration, invasion, and apoptosis. The mechanism analysis demonstrated that silence of UBE2T increased FBLN5 expression and inhibited the activation of p-ERK, p-GSK3ß, and ß-catenin. Moreover, following knockdown of UBE2T, the cell proliferation, migration, and invasion were decreased, and sh-FBLN5 partially reverse the decrease. In in vivo experiments, it was found that UBE2T knockdown inhibits the tumor growth in LUAD. Immunohistochemically, there was a reduction in Ki67 and an increase in FBLN5 in UBE2T shRNA-treated tumor tissues. In conclusion, UBE2T might be a potential biomarker of LUAD, and targeting the UBE2T/FBLN5 axis might be a novel treatment strategy for LUAD.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Animales , Proteínas de Unión al Calcio , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Proteínas de la Matriz Extracelular , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Proteínas Recombinantes , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/metabolismo
10.
BMC Oral Health ; 22(1): 160, 2022 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-35524329

RESUMEN

BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most common neck and head malignancies, and the prognosis is not good. Studies shown that the long non-coding RNA (lncRNA) TFAP2A-AS1 is involved in the progression of multiple cancers. However, the role of lncRNA TFAP2A-AS1 in OSCC remains unclear. We aimed to explore the functions and expression in OSCC. METHODS: The lncRNA profiles for OSCC patients were acquired from the TCGA. Based on these data, the data mining of TFAP2A-AS1 in patients with OSCC were performed. The functions of TFAP2A-AS1 were determined by bioinformatics analysis. The expression and roles in cell growth were tested by RT-qPCR and MTS assay. Cell invasion and migration were tested by wound healing and transwell assays. RESULTS: The consequences displayed that TFAP2A-AS1 was upregulated in the TCGA datasets. The expression of TFAP2A-AS1 was higher in OSCC samples. Bioinformatics analysis shown that TFAP2A-AS1 might be associated with the P53 signaling pathway. Cell culture experiments indicated that deficiency of TFAP2A-AS1 inhibited cell growth, invasion, and migration, and overexpression of it could opposite results in SCC-25 cells. CONCLUSION: The results suggested that TFAP2A-AS1 was overexpressed in OSCC cells, which could facilitate OSCC cell proliferation, migration, and invasion.


Asunto(s)
Neoplasias de la Boca , ARN Largo no Codificante , Carcinoma de Células Escamosas de Cabeza y Cuello , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Biología Computacional , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , ARN Largo no Codificante/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología
11.
BMC Cancer ; 22(1): 525, 2022 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-35534807

RESUMEN

BACKGROUND: Recently, increasing evidence has indicated that platelet-activating factor acetylhydrolase 1b catalytic subunit 3 (PAFAH1B3) plays an important role in several cancers. However, its role in lung adenocarcinoma (LUAD) has not been reported until now. METHODS: The expression of PAFAH1B3 in LUAD was determined by using the Gene Expression Profiling Interactive Analysis (GEPIA) database and real-time PCR (RT-PCR), western blot and immunohistochemical (IHC) analyses. A chi-square test was used to investigate the correlation between PAFAH1B3 expression and clinical parameters. Cox regression and Kaplan-Meier analysis were performed to analyze the prognostic value of PAFAH1B3. The CCK-8 assay, clone formation assay, transwell invasion assay and flow cytometry were conducted to detect cell proliferation, clone formation, invasion and the cell cycle. The xenograft tumor model was constructed to explore the function of PAFAH1B3 in vivo. Western blot and IHC analyses were performed to detect epithelial-to-mesenchymal transition (EMT)-related markers. Immune Cell Abundance Identifier (ImmuneCellAI) and IHC analyses were used to analyze the effect of PAFAH1B3 on immune cell infiltration. RESULTS: Our study showed that the expression of PAFAH1B3 was upregulated in LUAD tissues and cells compared with noncancerous tissues and cells. Additionally, the results indicated that the expression of PAFAH1B3 was positively correlated with distant metastasis, TNM stage and poor clinical outcome and it was an independent prognostic risk factor for LUAD. In addition, silencing PAFAH1B3 suppressed cell proliferation, colony formation, and invasion and increased the cell population in the G0-G1 phases in vitro. Furthermore, our results showed that knockdown of PAFAH1B3 increased the epithelial marker E-cadherin level and decreased the mesenchymal marker N-cadherin level in vitro and in vivo. We also proved that PAFAH1B3 downregulation inhibited tumorigenesis and neutrophil infiltration in the xenograft tumor model. CONCLUSION: Our studies indicate that PAFAH1B3, a prognostic risk factor, promotes proliferation, invasion and EMT and affects immune infiltrates in LUAD.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/patología , Pronóstico
12.
J Exp Clin Cancer Res ; 41(1): 170, 2022 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-35534866

RESUMEN

BACKGROUND: Melanoma is a type of malignant tumor with high aggressiveness and poor prognosis. At present, metastasis of melanoma is still an important cause of death in melanoma patients. However, the potential functions and molecular mechanisms of most circular RNAs (circRNAs) in melanoma metastasis remain unknown. METHODS: circRNAs dysregulated in melanoma cell subgroups with different metastatic abilities according to a screening model based on repeated Transwell assays were identified with a circRNA array. The expression and prognostic significance of circZNF609 in skin cutaneous melanoma and acral melanoma cells and tissues were determined by qRT-PCR, nucleoplasmic separation assays and fluorescence in situ hybridization. In vitro wound healing, Transwell and 3D invasion assays were used to analyse melanoma cell metastasis ability. Tail vein injection and intrasplenic injection were used to study in vivo lung metastasis and liver metastasis, respectively. The mechanism of circZNF609 was further evaluated via RNA immunoprecipitation, RNA pull-down, silver staining, and immunofluorescence colocalization assays. RESULTS: circZNF609 was stably expressed at low levels in melanoma tissues and cells and was negatively correlated with Breslow depth, clinical stage and prognosis of melanoma patients. circZNF609 inhibited metastasis of acral and cutaneous melanoma in vivo and in vitro. Mechanistically, circZNF609 promoted the binding of FMRP protein and RAC1 mRNA, thereby enhancing the inhibitory effect of FMRP protein on the stability of RAC1 mRNA and ultimately inhibiting melanoma metastasis. CONCLUSIONS: Our findings revealed that circZNF609 plays a vital role in the metastasis of acral and cutaneous melanoma through the circRNF609-FMRP-RAC1 axis and indicated that circZNF609 regulates the stability of RAC1 mRNA by combining with FMRP, which might provide insight into melanoma pathogenesis and a new potential target for treatment of melanoma.


Asunto(s)
Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil , Melanoma , MicroARNs , Neoplasias Cutáneas , Proteína de Unión al GTP rac1 , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/genética , Proteína del Retraso Mental del Síndrome del Cromosoma X Frágil/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Ligandos , Melanoma/genética , MicroARNs/genética , ARN Circular/genética , ARN Mensajero/genética , Neoplasias Cutáneas/genética , Proteína de Unión al GTP rac1/genética , Proteína de Unión al GTP rac1/metabolismo
13.
Proc Natl Acad Sci U S A ; 119(20): e2123511119, 2022 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-35537053

RESUMEN

SignificanceHere we show that most chemokine receptors (CRs) form heteromeric complexes with α1-adrenergic receptors (ARs) in recombinant systems and that such heteromers are detectable in human monocytes and in the human monocytic leukemia cell line THP-1. Furthermore, we provide evidence that α1B/D-ARs control the function of their CR heteromerization partners. Our findings suggest that heteromeric complexes between α1B/D-ARs and CRs are necessary for normal function of CR heteromerization partners, indicate receptor heteromerization as a molecular mechanism by which stress hormones regulate leukocyte trafficking in health and disease, and offer opportunities to modulate leukocyte and/or cancer cell trafficking in disease processes.


Asunto(s)
Movimiento Celular , Leucocitos , Receptores Adrenérgicos alfa 1 , Receptores CXCR4 , Membrana Celular/metabolismo , Humanos , Leucocitos/metabolismo , Neoplasias , Receptores Adrenérgicos alfa 1/genética , Receptores Adrenérgicos alfa 1/metabolismo , Receptores CXCR4/metabolismo , Transducción de Señal
14.
Acta Biochim Biophys Sin (Shanghai) ; 54(3): 361-369, 2022 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-35538031

RESUMEN

Pancreatic cancer is highly lethal due to its aggressive invasive properties and capacity for metastatic dissemination. Additional therapeutic targets and effective treatment options for patients with tumours of high invasive capacity are required. Ras-related protein-2a (RAP2) is a member of the GTP-binding proteins. RAP2 has been reported to be widely upregulated in many types of cancers via regulating cytoskeleton reorganization, cell proliferation, migration, and adhesion, as well as inflammation. As a member of the RAS oncogene family, which has been demonstrated to drive pancreatic cancer oncogenesis and many other malignancies, the physiological roles of RAP2 in pancreatic cancer have seldom been discussed. In the present study, we explored the correlation between RAP2 expression and the prediction of overall survival of pancreatic cancer patients. Mechanistic studies were carried out to shed light on the role of RAP2 in pancreatic cancer invasion and how RAP2 is regulated in the invasive process. Our results demonstrated that patients with higher RAP2 expression showed unfavourable prognoses. studies demonstrated that silencing of inhibited the invasion of pancreatic cancer cells. Moreover, our results demonstrated that transforming growth factor-ß1 (TGF-ß1), an inducer of the metastatic potential of pancreatic cancer cells, regulates the expression of RAP2 via the transcription factor c-Myc. In conclusion, the present study uncovered RAP2 as a novel predictive marker and therapeutic target for pancreatic cancer.


Asunto(s)
Neoplasias Pancreáticas , Factor de Crecimiento Transformador beta1 , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Humanos , Invasividad Neoplásica , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Regulación hacia Arriba , Proteínas de Unión al GTP rap/genética , Proteínas de Unión al GTP rap/metabolismo
15.
Acta Biochim Biophys Sin (Shanghai) ; 54(3): 378-387, 2022 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-35538035

RESUMEN

Long non-coding RNA (lncRNA) LINC00891 knockdown is associated with poor prognosis of lung adenocarcinoma, but the underlying mechanism remains to be further explored. Here, we found that LINC00891 expression is downregulated in lung cancer tissues and cell lines compared with that in adjacent normal tissues and normal lung epithelial cells. LINC00891 overexpression impedes cell proliferation, invasion, migration and epithelial-to-mesenchymal transition (EMT) process in lung cancer cells. Mechanistic research showed that GATA2 directly binds to LINC00891 promoter and transcriptionally regulates LINC00891 expression. Meanwhile, GATA2 was identified as a target of miR-128-3p, and it is negatively regulated by miR-128-3p. Moreover, overexpression of GATA2 suppresses lung cancer cell proliferation, invasion, migration, and EMT process. Furthermore, LINC00891 restrains the RhoA pathway activity, and treatment with CCG-1423 (a specific RhoA pathway inhibitor) antagonizes the promoting effect of LINC00891 knockdown on cell malignant behaviors. Additionally, silencing of LINC00891 promotes xenograft tumor growth, which can be reversed by administration with CCG-1423. In summary, LINC00891 regulated by the miR-128-3p/GATA2 axis restrains lung cancer cell malignant progression and hinders xenograft tumor growth by suppressing the RhoA pathway.


Asunto(s)
Factor de Transcripción GATA2 , Neoplasias Pulmonares , MicroARNs , ARN Largo no Codificante , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Transición Epitelial-Mesenquimal/genética , Factor de Transcripción GATA2/genética , Factor de Transcripción GATA2/metabolismo , Humanos , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Transducción de Señal , Proteína de Unión al GTP rhoA/genética , Proteína de Unión al GTP rhoA/metabolismo
16.
Nat Commun ; 13(1): 2543, 2022 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-35538070

RESUMEN

Bone metastases occur in 50-70% of patients with late-stage breast cancers and effective therapies are needed. The expression of enhancer of zeste homolog 2 (EZH2) is correlated with breast cancer metastasis, but its function in bone metastasis hasn't been well-explored. Here we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFß) signaling. EZH2 induces cancer cell proliferation and osteoclast maturation, whereas EZH2 knockdown decreases bone metastasis incidence and outgrowth in vivo. Mechanistically, EZH2 transcriptionally increases ITGB1, which encodes for integrin ß1. Integrin ß1 activates focal adhesion kinase (FAK), which phosphorylates TGFß receptor type I (TGFßRI) at tyrosine 182 to enhance its binding to TGFß receptor type II (TGFßRII), thereby activating TGFß signaling. Clinically applicable FAK inhibitors but not EZH2 methyltransferase inhibitors effectively inhibit breast cancer bone metastasis in vivo. Overall, we find that the EZH2-integrin ß1-FAK axis cooperates with the TGFß signaling pathway to promote bone metastasis of breast cancer.


Asunto(s)
Neoplasias Óseas , Neoplasias de la Mama , Proteína Potenciadora del Homólogo Zeste 2 , Quinasa 1 de Adhesión Focal , Proteína-Tirosina Quinasas de Adhesión Focal , Integrina beta1 , Factor de Crecimiento Transformador beta , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Femenino , Quinasa 1 de Adhesión Focal/metabolismo , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Humanos , Integrina beta1/genética , Integrina beta1/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo
17.
Neoplasia ; 29: 100802, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35500545

RESUMEN

The molecular mechanism of myeloid sarcoma (MS) formation remains nuclear. Our clinical and mouse model findings from a previous study revealed that cooperation of KMT2A (MLL) translocation (MLL-t) with activating N-/K-RAS mutations promoted MS formation in a shorter latency. To improve the understanding of MS formation, in this study, we performed imaging cell trafficking analysis and demonstrated that cells harboring cooperating mutations migrated more slowly to omental adipose tissues and more cells were retained in adipose tissues in vivo. Comparison of transcriptome profiling among three pairs of mouse MLL/AF10(OM-LZ) leukemia cell lines harboring activating and wild-type KRAS identified 77 differentially expressed genes (DEGs) with >1.5-fold change. Functional annotation of these 77 DEGs using Gene Ontology (GO) enrichment analysis followed by cluster analysis revealed that GO terms related to development/differentiation have the highest enrichment score. The roles of Hoxa10 and Hoxa11, two genes which mapped to this cluster, were further characterized. Silencing Hoxa10 and Hoxa11 in cells harboring cooperating mutations prolonged the survival and reduced MS formation, respectively, in the recipient mice. Data of imaging cell trafficking as well as competitive engraftment and clonal expansion analyses indicated that silencing or overexpressing Hoxa11 in mouse leukemia cells affected cell migration and retention in omental adipose tissue. Although silencing Hoxa11 in leukemia cells did not affect Cxcr4 expression, it resulted in increased transwell migration, motility in confined spaces 3 µm in size, and cell protrusion. Our results revealed that Hoxa10 plays an important role in survival and Hoxa11 contributes to MS formation in MLL-t acute myeloid leukemia with activating KRAS mutation.


Asunto(s)
Proteínas de Homeodominio/metabolismo , Leucemia Mieloide Aguda , Sarcoma Mieloide , Animales , Movimiento Celular/genética , Proteínas de Homeodominio/genética , Humanos , Ratones , Mutación , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Factores de Transcripción/genética
19.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(4): 407-415, 2022 Apr 28.
Artículo en Inglés, Chino | MEDLINE | ID: mdl-35545336

RESUMEN

OBJECTIVES: Bladder cancer is one of the most common urothelial tumors with high incidence and mortality rates. Although it has been reported that microRNA (miR)-133b can regulate tumorigenesis of bladder cancer, the mechanism remains unclear. Sex-determining region Y-box transcription factor 4 (SOX4) exhibits an important role in tumorigenesis, but it is unclear whether SOX4 and miR-133b are associated with regulation of pathogenesis of bladder cancer. This study aims to determine the expressions of SOX4 and miR-133b in bladder cancer tissues and cells, investigate their effects on the proliferation, colony formation, and invasion of bladder cancer cells, and to explore the association between miR-133b and SOX4 in regulating biological featurss of bladder cancer cells. METHODS: The bladder cancer and adjacent tissue samples of 10 patients who underwent surgical resection in the Second Xiangya Hospital of Central South Universty from Januray to June 2015 were obtained. The levels of miR-133b were tested by real-time PCR, and the protein levels of SOX4 were evaluated using Western blotting in bladder cancer tissues, matched adjacent tissues, and cell lines. The correlation between miR-133b expression and SOX4 expression in bladder cancer tissues was analyzed. Using the online database TargetScan, the relationship between SOX4 and miR-133b was predicted. MiR-133b mimics, miR-133b inhibitor, and short hairpin RNA (shRNA)-SOX4 were transfected into T24 cells by Lipofectamine 2000. The relationship between miR-133b and SOX4 was also verified by a dual-luciferase reporter assay. The proliferation of T24 cells cultured for 0, 12, 48, 72, and 96 h was evaluated by cell counting kit-8 (CCK-8) assay. The colony formation capacity of bladder cancer cells was tested after 14-day culture, and cell invasion capacity was evaluated with Transwell invasion assay. RESULTS: Bladder cancer tissue and bladder cancer cells had low level of miR-133b but high level of SOX4, compared with matched adjacent tissues and normal bladder epithelial cells. A negative correlation between miR-133b mRNA and SOX4 protein levels in bladder cancer tissues was also found (r=-0.84). The results of online database TargetScan showed that miR-133b targets at SOX4, and overexpression of miR-133b significantly attenuated the expression of SOX4 in T24 cells. Both overexpression of miR-133b and knockdown of SOX4 significantly inhibited the proliferation, colony formation, and invasion capacity of bladder cancer cells in vitro. SOX4 down-regulation restored the effects of miR-133b inhibitor on the proliferation, colony formation, and invasion capacity of T24 cells. CONCLUSIONS: The up-regulation of SOX4 contributes to the progression of bladder cancer, and miR-133b can regulate the proliferation, colony formation, and invasion of bladder cancer cells via inhibiting SOX4.


Asunto(s)
MicroARNs , Neoplasias de la Vejiga Urinaria , Carcinogénesis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Células Epiteliales/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , MicroARNs/metabolismo , Factores de Transcripción SOXC/genética , Factores de Transcripción SOXC/metabolismo , Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/genética
20.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(2): 143-152, 2022 Feb 28.
Artículo en Inglés, Chino | MEDLINE | ID: mdl-35545404

RESUMEN

OBJECTIVES: Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer, with highmorbidity and mortality rate. Nove drug development for NSCLC is urgently needed.This study aims to investigate the activity of lathyrol derivatives and the mechanism for its inhibitory effect on the growth of NSCLC cells. METHODS: Three lathyrol derivatives were synthesized from lathyrol and their structures were verified by nuclear magnetic resonance. MTT assay was used to detect the effects of the lathyrol derivatives on the proliferation activity of NSCLC cells (A549 and H1299 cells), and the compound with the best activity was selected for subsequent experiments. Colony forming assay, wound-healing assay, and transwell assay were applied to detect in vitro cell proliferation, migration and invasion ability in A549 and H1299 cells, respectively. Quantitative real-time RT-PCR and Western blotting were performed to detect mRNA and protein levels of E-cadherin, N-cadherin, ß-catenin, and MMP2 in A549 cells, respectively. RESULTS: Three lathyrol derivatives inhibited the growth of A549 and H1299 cells in a dose-dependent manner, and they showed a weak inhibitory effect on normal cells Beas-2B and 16HBE, indicating that they possessed certain selective toxic effects. Therefore, C-5 benzoylated lathyrol with the best activity was selected as the ideal drug for the subsequent experiments. Compared with the control group, the number and size of cell clusters in the treatment group of A549 and H1299 cells were significantly decreased, the relative mobility were significantly decreased, and the number of invaded cells were significantly decreased (all P<0.05), indicating that the in vitro cell proliferation, migration and invasion ability were decreased. The mRNA levels of integrin α2, integrin ß1, MMP2, MMP9, ß-catenin, and N-cadherin were decreased, while the expression of E-cadherin was increased (all P<0.05). The protein levels of N-cadherin, ß-catenin, MMP2, and integrin αV were decreased, while the expression of E-cadherin was increased (all P<0.05). CONCLUSIONS: The lathyrol derivatives synthesized in this study possess good inhibitory activity against NSCLC. Among them, C-5 benzoylated lathyrol significantly inhibits the proliferation, migration, and invasion ability of NSCLC cells in vitro through regulating the process of epithelial-mesenchymal transition.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Cadherinas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Transición Epitelial-Mesenquimal , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Metaloproteinasa 2 de la Matriz/genética , ARN Mensajero , beta Catenina/genética
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