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1.
Cell Death Dis ; 14(3): 195, 2023 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-36914619

RESUMO

Cell-in-cell structures (CICs) refer to a type of unique structure with one or more cells within another one, whose biological outcomes are poorly understood. The present study aims to investigate the effects of CICs formation on tumor progression. Using genetically marked hepatocellular cancer cell lines, we explored the possibility that tumor cells might acquire genetic information and malignant phenotypes from parental cells undergoing CICs formation. The present study showed that the derivatives, isolated from CICs formed between two subpopulations by flow cytometry sorting, were found to inherit aggressive features from the parental cells, manifested with increased abilities in both proliferation and invasiveness. Consistently, the CICs clones expressed a lower level of E-cadherin and a higher level of Vimentin, ZEB-1, Fibronectin, MMP9, MMP2 and Snail as compared with the parental cells, indicating epithelial-mesenchymal transition. Remarkably, the new derivatives exhibited significantly enhanced tumorigenicity in the xenograft mouse models. Moreover, whole exome sequencing analysis identified a group of potential genes which were involved in CIC-mediated genetic transfer. These results are consistent with a role of genetic transfer by CICs formation in genomic instability and malignancy of tumor cells, which suggest that the formation of CICs may promote genetic transfer and gain of malignancy during tumor progression.


Assuntos
Transição Epitelial-Mesenquimal , Esferoides Celulares , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Células Clonais , Transição Epitelial-Mesenquimal/genética , Células-Tronco Neoplásicas/metabolismo
2.
Front Mol Biosci ; 9: 808152, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35372504

RESUMO

Background: Golgi phosphoprotein 3 (GOLPH3) overexpression was recently reported to be associated with a poor clinical outcome in patients with colorectal cancer (CRC). However, the underlying molecular mechanism through which GOLPH3 promotes CRC metastasis remains poorly understood. Methods: In vitro genetic ablation of GOLPH3 was performed using siRNA transfection, and a stably overexpressed GOLPH3 colon cancer cell line was constructed using the lentivirus system. Cell invasion and migration assays were conducted with or without Matrigel. Immunoblotting, qRT-PCR, immunofluorescence and immunohistochemistry were utilized to study the expression level of GOLPH3, ZEB1, integrin α3 and phosphorylation level of STAT3, AKT/mTOR and Raf/MEK/ERK pathways. Co-immunoprecipitation was used to investigate the interaction between GOLPH3 and p-STAT3 (Tyr705) or total STAT3. Results: Overexpression of GOLPH3 was found in CRC tissues and colon cancer cell lines. Knockdown of GOLPH3 using siRNAs significantly suppressed the invasion and migration of HCT116 and HCT8 cells. In contrast, the overexpression of GOLPH3 promoted the migratory and invasive ability of colon cancer cells. The phosphorylation level of STAT3 as well as the protein and mRNA levels of ZEB1 and integrin α3, were significantly decreased after GOLPH3 knockdown. Moreover, Integrin α3 expression was correlated with GOLPH3 expression in CRC tissues. Co-immunoprecipitation assay revealed that GOLPH3 interacted with pSTAT3 (Tyr705) and total STAT3. Our further experiments suggested that GOLPH3 facilitated IL-6 induced STAT3 activation and subsequently induced transcription of integrin α3 and ZEB1, which promoted the metastasis and progression of CRC. Conclusion: Our current work demonstrates that GOLPH3 facilitates STAT3 activation and regulates the expression of EMT transcription factor ZEB1 and Integrin α3 in colon cancer cells. These findings indicate that GOLPH3 plays a critical role in CRC metastasis and might be a new therapeutic target for CRC treatment.

3.
Front Oncol ; 10: 575358, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33134174

RESUMO

Overexpression of Golgi phosphoprotein 3 (GOLPH3) predicts poor prognosis and is a potential therapeutic target in pancreatic ductal adenocarcinoma (PDAC). However, its role and underlying molecular mechanisms in the progression of PDAC remain unknown. In the present study, using high-throughput bimolecular fluorescence complementation (BiFC) analysis, we identified that stress-inducible protein-1 (STIP1) interacts with GOLPH3 and confirmed the interaction using co-localization and co-immunoprecipitation. The levels of GOLPH3 and STIP1 in PDAC tissues and adjacent non-cancerous pancreatic tissues were determined using immunohistochemistry (IHC) and quantitative real-time reverse transcription PCR. Real-time Quantitative-telomere repeat amplification (Q-TRAP) was applied to detect relative telomerase activity, and cell proliferation was measured when small interfering RNAs targeting GOLPH3 or STIP1 were transfected into PDAC cell lines. BALB/c nude mice were used to assess tumor growth inhibition of BXPC3 cells stably transfected with GOLPH3 short hairpin RNA. In summary, GOLPH3 was found to interact with STIP1 and both proteins were overexpressed and co-localized in PDAC tissues and cell lines. Moreover, suppression of GOLPH3 expression using shRNAs in PANC1 and BXPC3 cells inhibited tumor cell proliferation both in vitro and in vivo. Mechanistically, GOLPH3 interacts with STIP1 to activate telomerase reverse transcriptase (hTERT) and telomerase activity by c-Myc, and then upregulates cell cycle-related signaling proteins, including cyclin D1, to promote tumor cell growth, suggesting that disrupting the interaction between STIP1 and GOLPH3 would be a promising new strategy to treat PDAC.

4.
Cell Death Dis ; 11(3): 187, 2020 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-32179733

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is associated with metaplastic changes in the pancreas but the transcriptional program underlying these changes is incompletely understood. The zinc finger transcription factor, PRDM3, is lowly expressed in normal pancreatic acini and its expression increases during tumorigenesis. Although PRDM3 promotes proliferation and migration of PDAC cell lines, the role of PRDM3 during tumor initiation from pancreatic acinar cells in vivo is unclear. In this study, we showed that high levels of PRDM3 expression in human pancreas was associated with pancreatitis, and well-differentiated but not poorly differentiated carcinoma. We examined PRDM3 function in pancreatic acinar cells during tumor formation and pancreatitis by inactivating Prdm3 using a conditional allele (Ptf1aCreER;Prdm3flox/flox mice) in the context of oncogenic Kras expression and supraphysiological cerulein injections, respectively. In Prdm3-deficient mice, KrasG12D-driven preneoplastic lesions were more abundant and progressed to high-grade precancerous lesions more rapidly. This is consistent with our observations that low levels of PRDM3 in human PDAC was correlated significantly with poorer survival in patient. Moreover, loss of Prdm3 in acinar cells elevated exocrine injury, enhanced immune cell activation and infiltration, and greatly increased acinar-to-ductal cell reprogramming upon cerulein-induced pancreatitis. Whole transcriptome analyses of Prdm3 knockout acini revealed that pathways involved in inflammatory response and Hif-1 signaling were significantly upregulated in Prdm3-depleted acinar cells. Taken together, our results suggest that Prdm3 favors the maintenance of acinar cell homeostasis through modulation of their response to inflammation and oncogenic Kras activation, and thus plays a previously unexpected suppressive role during PDAC initiation.


Assuntos
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Proteína do Locus do Complexo MDS1 e EVI1/metabolismo , Pancreatite/genética , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Pessoa de Meia-Idade
5.
J Biomed Nanotechnol ; 15(8): 1812-1823, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31219012

RESUMO

Golgi phosphoprotein 3 (GOLPH3), a proto-oncogene product, is significantly increased during the progression of several types of cancer. However, its biological role and underlying mechanism in the development of renal cell carcinoma (RCC) remain poorly understood. In this study, GOLPH3 was found to be highly expressed in RCC specimens compared to the corresponding non-tumor tissues. In vitro, ectopic overexpression of GOLPH3 substantially promoted the proliferative and invasive capacity of RCC cells, while the depletion of GOLPH3 significantly inhibited proliferation and invasion of RCC cells. Furthermore, the average tumor volume was significantly increased in mice injected with 769-P cells highly expressing GOLPH3, whereas GOLPH3 knockdown reduced the tumor growth rate. Mechanistically, using a high-throughput phospho-proteome array verified by Western blotting, we have identified that phosphorylated proteins (FAK, Raf1, MEK, and GSK3ß) were upregulated, activating, in turn, FAK/Raf1/MEK and Wnt/ß-catenin signaling pathways in RCC cells. Taken together, our findings demonstrate that GOLPH3, whose expression is related to enhanced cell proliferation and invasion via activation of GOLPH3-FAK/Raf1/MEK axis or Wnt/ß-catenin signaling pathways, may provide a new therapeutic target to treat renal cell carcinoma.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Proteínas de Membrana/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Camundongos , Fenótipo , Fosfoproteínas , Proto-Oncogene Mas , Via de Sinalização Wnt
6.
Oncol Rep ; 40(5): 2628-2636, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30226561

RESUMO

Macrophage migration inhibitory factor (MIF) is a pro­inflammatory cytokine that serves important roles in cancer. MIF overexpression is frequently observed in numerous human cancer types, including pancreatic carcinoma. However, the prognostic value and function of MIF in pancreatic ductal adenocarcinoma (PDAC) have not been fully elucidated. In the present study, upregulation of MIF expression in PDAC tissue compared with adjacent normal tissue was observed. Furthermore, MIF overexpression was identified to be significantly associated with poor survival rates in patients with PDAC. Multivariate Cox regression analysis confirmed that MIF was an independent risk factor for poor survival. Functional analyses demonstrated that MIF knockdown significantly inhibited the proliferation and invasion of pancreatic cancer cells in vitro compared with control cells. IN addition, mechanistic investigations revealed that silencing MIF leads to inhibition of AKT serine/threonine kinase and extracellular­signal­regulated kinase activation, and suppression of cyclin D1 and matrix metalloproteinase­2 expression, which may suppress tumor proliferation and invasion. These results highlight the importance of MIF overexpression in PDAC aggressiveness, and indicate that MIF may be a potential therapeutic target for pancreatic cancer.


Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/genética , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Adenocarcinoma/patologia , Adulto , Idoso , Apoptose/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Ciclina D1/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Metaloproteinase 2 da Matriz/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Intervalo Livre de Progressão
7.
J Diabetes Res ; 2018: 1082561, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29670912

RESUMO

PURPOSE: To investigate the effects of sleeve gastrectomy (SG) on glucose metabolism and changes in glucagon-like peptide 1 (GLP-1) in Goto-Kakizaki (GK) rats. METHODS: GK rats were randomly assigned to one of three groups: SG, SG pair-fed plus sham surgery (PF-sham), and ad libitum-fed no surgery (control). Food intake, body weight, blood glucose, GLP-1 and insulin levels, and GLP-1 expression in the jejunum and ileum were compared. RESULTS: The SG rats exhibited lower postoperative food intake, body weight, and fasting glucose than did the control rats (P < 0.05). SG significantly improved glucose and insulin tolerance (P < 0.05). Plasma GLP-1 levels were higher in SG rats than in control or PF-sham rats in the oral glucose tolerance test (OGTT) (P < 0.05). Blood glucose levels expressed as a percentage of baseline were higher in SG rats than in control rats after exendin (9-39) administration (P < 0.05). The levels of GLP-1 expression in the jejunum and ileum were higher in SG rats than in PF-sham and control rats (P < 0.05). CONCLUSIONS: Improvement of glucose metabolism by SG was associated with increased GLP-1 secretion. SG contributes to an increase in plasma GLP-1 levels via increased GLP-1 expression in the mucosa of the jejunum and/or ileum.


Assuntos
Glicemia/metabolismo , Ingestão de Alimentos/fisiologia , Gastrectomia/métodos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Resistência à Insulina/fisiologia , Animais , Glicemia/efeitos dos fármacos , Peso Corporal/fisiologia , Teste de Tolerância a Glucose , Íleo/metabolismo , Insulina/sangue , Jejuno/metabolismo , Masculino , Fragmentos de Peptídeos/farmacologia , Ratos
8.
J Anat ; 205(2): 147-56, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15291797

RESUMO

Using stereological methods, especially the optical disector for unbiased estimation of nuclear number, our recent study demonstrated that long-term (6 or 12 months) vasectomy in the rhesus monkey had no significant effects on spermatogenesis (Peng et al. Reproduction 2002, 124, 847-856). This study aimed to determine the scenario in the rabbit using the same morphometric methodology. Three groups of normal male Japanese white rabbits (aged 4-5 months) were subjected to unilateral vasectomy; 10 days, 6 months and 12 months later both testes and epididymides were removed. Testicular and epididymal methacrylate-embedded sections were obtained for stereology. Vasectomy-induced damage to spermatogenesis was observed, primarily sloughing of spermatogenic cells with a greater reduction in the number of advanced (adluminal) cells. The damage was most severe at 10 days, occurring in all the testes on the vasectomized side and involving sloughing of even type A spermatogonia, the number of which returned to normal at 6 and 12 months. Damage was less severe at 6 and 12 months, being found in half of the testes of the vasectomy side, in which the total numbers of later germ cell types were 24.0-59.1% (spermatocytes) and 0.3-11.6% (spermatids) of control at 6 months, and 20.1-22.1% (spermatocytes) and 0.4-12.0% (spermatids) of control at 12 months. By contrast, Sertoli cell number per testis was unchanged following vasectomy in any group. Epididymis on the vasectomy side, especially at 10 days and 6 months, appeared larger than on the contralateral side, but this difference was not statistically significant, and no sperm granuloma was seen in the epididymis.


Assuntos
Espermatogênese/fisiologia , Vasectomia , Animais , Contagem de Células , Epididimo/anatomia & histologia , Epididimo/citologia , Masculino , Coelhos , Túbulos Seminíferos/anatomia & histologia , Túbulos Seminíferos/citologia , Espermatócitos/citologia , Espermatozoides/citologia , Testículo/anatomia & histologia , Testículo/citologia , Fatores de Tempo
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