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1.
Am J Surg Pathol ; 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34753864

RESUMO

The metastatic or recurrent potential of localized human papillomavirus-associated endocervical adenocarcinoma (HPVA EAC) is difficult to predict, especially based upon biopsy alone. Recent analyses of small cohorts indicate that high tumor nuclear grade (TNG) and the presence of necrotic tumor debris (NTD) from HPVA EACs in cervical biopsy specimens are highly predictive of nodal metastasis (NM). In the present study, we aimed to investigate how reliably tumoral morphologic features from cervical biopsy specimens predict NM or tumor recurrence (TR) and patient outcomes in a large cohort of endocervical adenocarcinoma patients. A cohort comprised of 397 patients with HPVA EAC treated at 18 institutions was identified, and cervical biopsies were paired with their associated complete tumor resections for a total of 794 specimens. A variety of tumoral histologic features were examined for each paired specimen, including TNG (assessed on a 3-tiered scale of increasing abnormalities-TNG1, TNG2, TNG3) and NTD (defined by the presence of necrotic and apoptotic tumor cells within tumor glandular lumens admixed with granular and eosinophilic amorphous material and inflammatory cells), which were correlated with outcomes. The distribution of TNG in biopsies was as follows: 86 (21.7%) TNG1, 223 (56.2%) TNG2, and 88 (22.2%) TNG3. NTD was identified in 176 (44%) of the biopsy specimens. The sensitivity, specificity, positive predictive value, and negative predictive value of a TNG1 assignment in the biopsy being predictive of the same assignment in the full resection were 0.82 (95% confidence interval [CI]: 0.7-0.9), 0.895 (0.86-0.93), 0.593 (0.48-0.696), and 0.96 (0.94-0.98), respectively. Respective values for an NTD-negative status were 0.89 (95% CI: 0.83-0.92), 0.715 (0.64-0.77), 0.72 (0.65-0.77), and 0.89 (0.83-0.93), respectively. Compared with the other cases in each category, both TNG1 and an NTD-negative status were each significantly associated with lower rates of NM (odds ratio for TNG1=0.245, 95% CI: 0.070-0.857, P=0.0277; for NTD=0.199, 95% CI: 0.094-0.421, P<0.0001) and TR (odds ratio for TNG1=0.225, 95% CI: 0.051-0.987, P=0.0479; for NTD=0.367, 95% CI: 0.171-0.786, P=0.0099) independent of depth of stromal invasion, lymphovascular invasion, tumor size, FIGO stage, and Silva pattern. Overall, 73/379 (19%) cases were both TNG1 and NTD-negative on the biopsy, and none of these 73 cases showed NM (0%), but a single case (1.4%) showed TR. In contrast, among the 324 biopsies with TNG2/3 and/or presence of NTD, 62 (19.1%) had NM, and 41 (12.9%) had TR. In summary, 2 variables in combination (ie, TNG1 and NTD-negative) identified a subset of HPVA EAC patients-∼19%-with a 0% frequency of nodal metastases and only 1.4% frequency of recurrence. Biopsies highly but imperfectly predicted these features. Nonetheless, these findings may potentially be of clinical utility in the risk stratification of patients with HPVA EACs. This may allow some patients with a minimal risk of nodal metastases and TR to be identified at the biopsy phase, thereby facilitating more personalized, possibly less aggressive treatment.

2.
Aging (Albany NY) ; 13(17): 21202-21215, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34520393

RESUMO

Most EEC cases are associated with activities of the mTOR pathway, which regulates protein synthesis, cell growth and autophagy. While Up-Frameshift 1(UPF1) is a key protein factor in the nonsense-mediated mRNA degradation pathway (NMD), its role in carcinogenesis of EEC remains unclear. In this study, we first evaluated the expression level of UPF1 in EEC tissues and cell lines. Then, we investigated the effect of UPF1 on cellular function and mTOR signaling pathway; these effects were further validated in vivo. Finally, its effect on autophagy was evaluated by western blot and GFP-mRFP-LC3 staining. UPF1 expression in the EEC tissue samples was significantly higher than that of matched normal tissue samples. Overexpression of UPF1 promoted migration and invasion of EEC cells. Conversely, depletion of UPF1 suppressed migration and invasion of EEC cells. In addition, overexpression of UPF1 increased the in vivo growth of our EEC xenograft tumors. Finally, UPF1 increased the activity of the mTOR/P70S6K/4EBP1 signaling pathway and inhibited autophagy in EEC cells. These findings suggest that UPF1 functions as an oncogene to promote EEC carcinogenesis. Our findings propose UPF1 as a new potential therapeutic target for EEC.

3.
Cancer Cell Int ; 21(1): 408, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34332611

RESUMO

BACKGROUND: Epigenetic modulation by noncoding RNAs substantially contributes to human cancer development, but noncoding RNAs involvement in bladder cancer remains poorly understood. This study investigated the role of long noncoding RNA (lncRNA) lnc-STYK1-2 in tumorigenesis in cancerous bladder cells. METHODS: Differential lncRNA and mRNA profiles were characterized by high-throughput RNA sequencing combined with validation via quantitative PCR. Bladder cancer cell proliferation was assessed through MTS, and bladder cancer cell migration and invasion were assessed through a Transwell system. The in vivo tumorigenesis of bladder cancer cells was evaluated using the cancer cell line-based xenograft model. The dual-luciferase reporter assay verified the association of miR-146b-5p with lnc-STYK1-2 and the target gene. Protein abundances and phosphorylation were detected by Western blotting. RESULTS: Alterations in lncRNA profiles, including decreased lnc-STYK1-2 expression, were detected in bladder cancer tissues compared with adjacent noncancerous tissues. lnc-STYK1-2 silencing effectively promoted proliferation, migration, and invasion in two bladder cancer cell lines, 5637 and T24, and their tumorigenesis in nude mice. lnc-STYK1-2 siRNA promoted miR-146b-5p and reduced ITGA2 expression in bladder cancer cells. Moreover, miR-146b-5p suppressed ITGA2 expression in bladder cancer cells through direct association. Also, lnc-STYK1-2 directly associated with miR-146b-5p. Finally, miR-146b-5p inhibitors abrogated the alterations in bladder cell functions, ITGA2 expression, and phosphorylation of AKT, STAT3, and P65 proteins in 5637 and T24 cells induced by lnc-STYK1-2 silencing. CONCLUSION: lnc-STYK1-2 inhibited bladder cancer cell proliferation, migration, and tumorigenesis by targeting miR-146b-5p to regulate ITGA2 expression and AKT/STAT3/NF-kB signaling.

5.
Medicine (Baltimore) ; 100(13): e24927, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33787580

RESUMO

RATIONALE: Usual-type endocervical adenocarcinoma (ECA), high-risk HPV associated, is the most common type of glandular carcinoma in the endocervix. Mucin-depleted usual-type ECA is 1 end of morphological lineage of usual-type ECA and morphologically may show endometrioid features, which could cause diagnostic challenge with uterine endometrioid adenocarcinoma (EEC) and primary endometrioid ECA, especially in the setting of small biopsy and endocervical curettage (ECC). PATIENT CONCERNS: A 37-year-old women presented with dyspareunia for 1 year, showing atypical glandular cell on a liquid-based Pap TCT examination and positive for HPV16 detection. ECC showed EEC in another hospital based on its "endometrioid" morphology and immunohistochemical profiles (ER/PR/PAX8 strongly positive, though p16 also strongly positive). DIAGNOSES: The specimen of hysterectomy in our hospital displayed a lesion confined to the uterine cervix showing the same morphology and immunohistochemical profiles as ECC. Finally, we successfully performed HPV RNAscope and detected high-risk human papilloma virus (HPV) E6/E7 mRNA particles in tumor cells in situ, which warranted usual-type ECA with mucin-depleted feature, a rare deviation of usual-type of ECA. INTERVENTIONS: The patient underwent total hysterectomy with lymph node dissection. OUTCOMES: To date, 14 months after surgery, the patient is well without recurrence or distant metastasis, and undergoes regular reexamination. LESSONS SUBSECTIONS: We report a rare case of mucin-depleted usual-type ECA showing overlapping morphological and immunohistochemical profiles with EEC. The pathological diagnosis was confirmed by high-risk HPV RNAscope detection which is superior than immunohistochemistry to identify usual-type ECA, warranting an important role in assisting the diagnosis of morphological vague cases.


Assuntos
Adenocarcinoma/diagnóstico , Carcinoma Endometrioide/diagnóstico , Neoplasias do Endométrio/diagnóstico , Testes de DNA para Papilomavírus Humano , Imuno-Histoquímica , Neoplasias do Colo do Útero/diagnóstico , Adenocarcinoma/virologia , Adulto , Carcinoma Endometrioide/virologia , Colo do Útero/virologia , Curetagem , Diagnóstico Diferencial , Neoplasias do Endométrio/virologia , Feminino , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/isolamento & purificação , Humanos , Teste de Papanicolaou , RNA Viral/análise , Neoplasias do Colo do Útero/virologia
6.
J Int Med Res ; 49(3): 3000605211000156, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33726531

RESUMO

OBJECTIVE: Many methods for tissue microarray (TMA) construction were described in previous reports. Because TMA-based methods are expensive and complicated, their widespread application may be restricted. This study aimed to develop a simple method for TMA construction. METHODS: High-density TMAs were constructed using simple equipment, and hematoxylin and eosin and immunohistochemical staining were performed to analyze the effect on the TMA block. RESULTS: A recipient block with 162 holes of 0.9 mm in diameter was prepared using a mini-drill and plastic mold. Tissue cores of 1.0 mm in diameter were obtained from multiple donor blocks with stainless-steel capillary tubes driven by the mini-drill. Under the fixation and guidance of the plastic mold, tissue cores could be easily injected into the holes in the recipient block by inserting a stainless-steel wire into the stainless-steel tube with the tissue core and then pressing using the stainless-steel wire. CONCLUSION: A high-density TMA block with 162 1.0-mm cores was created. This new modified technique could be a good alternative in many laboratories.


Assuntos
Projetos de Pesquisa , Humanos , Análise em Microsséries , Análise Serial de Tecidos
7.
BMC Cancer ; 21(1): 154, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33579221

RESUMO

BACKGROUND: Uterine serous carcinoma (USC) is an aggressive type of endometrial cancer that accounts for up to 40% of endometrial cancer deaths, creating an urgent need for prognostic biomarkers. METHODS: USC RNA-Seq data and corresponding patients' clinical records were obtained from The Cancer Genome Atlas and Genotype-Tissue Expression datasets. Univariate cox, Lasso, and Multivariate cox regression analyses were conducted to forge a prognostic signature. Multivariable and univariable cox regression analysis and ROC curve evaluated the prediction efficiency both in the training and testing sets. RESULTS: We uncovered 1385 genes dysregulated in 110 cases of USC tissue relative to 113 cases of normal uterine tissue. Functional enrichment analysis of these genes revealed the involvement of various cancer-related pathways in USC. A novel 4-gene signature (KRT23, CXCL1, SOX9 and ABCA10) of USC prognosis was finally forged by serial regression analyses. Overall patient survival (OS) and recurrence-free survival (RFS) were significantly lower in the high-risk group relative to the low-risk group in both the training and testing sets. The area under the ROC curve of the 4-gene signature was highest among clinicopathological features in predicting OS and RFS. The 4-gene signature was found to be an independent prognostic indicator in USC and was a superior predictor of OS in early stage of USC. CONCLUSIONS: Our findings highlight the potential of the 4-gene signature as a guide for personalized USC treatment.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Biomarcadores Tumorais/genética , Quimiocina CXCL1/genética , Cistadenocarcinoma Seroso/patologia , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição SOX9/genética , Neoplasias Uterinas/patologia , Idoso , Estudos de Casos e Controles , Biologia Computacional/métodos , Cistadenocarcinoma Seroso/genética , Bases de Dados Genéticas/estatística & dados numéricos , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Humanos , Queratinas Tipo I/genética , Prognóstico , Taxa de Sobrevida , Neoplasias Uterinas/genética
8.
Mol Pharm ; 18(3): 889-897, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33470823

RESUMO

Antibody-drug conjugates (ADCs) consist of a target-specific antibody that is covalently conjugated to a drug via a linker. ADCs are designed to deliver cytotoxic drugs (payloads), specifically to cancer cells, while minimizing systemic toxicity. Conventional cysteine conjugation typically results in the formation of ADC molecules containing a heterogeneous mixture of 2, 4, 6, and 8 drug-loaded species. The drug-to-antibody ratio (DAR) of the mixture represents the weighted average of these species. In this report, we have investigated the impact of the hydrophobicity of payloads and the overall drug loading on the in vitro binding and cytotoxicity of ADC species. Several ADCs were prepared by conventional cysteine conjugation using different payloads. ADC species with different DAR values were purified from the ADC mixture and characterized by standard analytical techniques. These ADC species were evaluated for target antigen binding using an immunoassay, enzyme-linked immunosorbent assay (ELISA). The potency was assessed using a cell-based cytotoxicity assay. These structure-function studies lead to a better understanding of factors that impact the in vitro target binding and cytotoxicity of ADC species. ADC species containing hydrophobic payloads with high DAR were found to have lower target binding by ELISA compared to that of the unconjugated antibody or the heterogeneous reference ADC with DAR ∼4. Under similar assay conditions, the ADCs conjugated to hydrophilic payloads did not show a significant impact on the target binding. The cytotoxic potency of ADC species increased with increasing level of drug loading in the cell-based cytotoxicity assay.


Assuntos
Antígenos/química , Antineoplásicos/química , Cisteína/química , Citotoxinas/química , Imunoconjugados/química , Anticorpos Monoclonais/química , Linhagem Celular Tumoral , Humanos , Interações Hidrofóbicas e Hidrofílicas/efeitos dos fármacos , Imunoensaio/métodos
9.
ACS Omega ; 5(41): 26441-26453, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33110972

RESUMO

Field experience shows that extending shut-in periods are conducive to increasing tight oil production after fracturing operations. Understanding the regularity of pressure decay is helpful to establish an appropriate shut-in time. However, the characteristics and influencing factors of pressure decay are unclear. This paper studies the porosity, permeability, mineral composition, and pore structure of samples in six different blocks. The pressure decay regularity is tested according to an independently designed indoor shut-in experimental device, and the oil distribution of experimental samples is monitored using nuclear magnetic resonance technology. The results show that the fracturing fluid enters the matrix pores under the action of percolation to slowly drive out the oil, causing the well pressure to decay over time. There are three types of pressure decay characteristics: concave type, fluctuation type, and quadratic type. Compared with conventional sandstone, the pressure decay rate of tight reservoirs is slower, and the pressure decay characteristics are more complicated. Clay mineral-rich reservoirs will swell when exposed to water. As a result, the strength of the framework will be weakened and collapsed. What's more, it will cause blockage of the throat, blocking the flow of oil and the decay of pressure. In addition, the rate of pressure decay is also related to the volume of fracturing fluid, initial borehole pressure, and formation closure stress. At a certain proppant thickness (fracture width), the larger the fracturing fluid volume, the larger the fracture surface area and the faster the pressure decay rate; Moreover, the greater the initial shut-in pressure, the greater the pressure difference and the faster the decay rate; the formation closure stress causes the core porosity and the permeability to decrease, resulting in a decrease in the decay rate. The experimental results are of great significance for establishing a proper shut-in time and enhancing the oil recovery of tight reservoirs.

10.
Cell Death Dis ; 11(7): 509, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32641685

RESUMO

SPEN family transcriptional repressor (SPEN), also known as the SMART/HDAC1-associated repressor protein (SHARP), has been reported to modulate the malignant phenotypes of breast cancer, colon cancer, and ovarian cancer. However, its role and the detail molecular basis in nasopharyngeal carcinoma (NPC) remain elusive. In this study, the SPEN mRNA and protein expression was found to be increased in NPC cells and tissues compared with nonmalignant nasopharyngeal epithelial cells and tissues. Elevated SPEN protein expression was found to promote the pathogenesis of NPC and lead to poor prognosis. Knockdown of SPEN expression resulted in inactivation ofPI3K/AKT and c-JUN signaling, thereby suppressing NPC migration and invasion. In addition, miR-4652-3p was found to be a downstream inducer of SPEN by targeting the homeodomain interacting protein kinase 2 (HIPK2) gene, a potential tumor suppressor that reduces the activation of epithelial-mesenchymal transition (EMT) signaling, thereby reducing its expression and leading to increased NPC migration, invasion, and metastasis. In addition, SPEN was found to induce miR-4652-3p expression by activating PI3K/AKT/c-JUN signaling to target HIPK2. Our data provided a new molecular mechanism for SPEN as a metastasis promoter through activation of PI3K/AKT signaling, thereby stimulating the c-JUN/miR-4652-3p axis to target HIPK2 in NPC.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Ligação a DNA/metabolismo , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/patologia , Invasividade Neoplásica , Metástase Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Transdução de Sinais
11.
Am J Surg Pathol ; 44(8): 1050-1060, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32384321

RESUMO

The prevalence and significance of programmed death-1 ligand (PD-L1) expression in different types of tubo-ovarian carcinoma have not been well defined. We evaluated PD-L1 expression and CD8 tumor-infiltrating lymphocyte (TIL) density in whole tissue sections of 189 cases of tubo-ovarian carcinoma, including high-grade serous carcinoma (HGSC, n=100), clear cell carcinoma (CCC, n=24), endometrioid carcinoma (EmC, n=40), and mucinous carcinomas (MC, n=25). Using the tumor proportion score (TPS) with a 1% cutoff, PD-L1 expression was present in 21% of HGSC, 16.7% of CCC, 2.5% of EmC, and 4% of MC. Using the combined positive score (CPS) with a cutoff of 1, PD-L1 expression was present in 48% of HGSC, 25% of CCC, 20% of EmC, and 24% of MC. HGSC demonstrated significantly higher CD8 TIL density than CCC (P=0.013238), EmC (P=0.01341), or MC (P=0.004556). In HGSC, CD8 TIL density was directly correlated with PD-L1 positivity using either TPS (P=0.0008) or CPS (P=0.00011). Survival analysis of patients with high stage (stage III to IV) HGSC revealed PD-L1 positivity by TPS to be associated with improved progression-free survival (adjusted hazard ratio: 0.4912 vs. 2.036, P=0.0378). Although not statistically significant, a similar trend was observed in overall survival (adjusted hazard ratio: 0.3387 vs. 2.953, P=0.0548). In contrast, with CPS, no significant difference was identified between PD-L1-positive and negative groups in either progression-free survival (P=0.5086) or overall survival (P=0.7823). Neoadjuvant chemotherapy was associated with higher PD-L1 expression by TPS (P=0.00407) but not CPS. No significant difference in PD-L1 expression was detected in tumors from patients with germline BRCA1/2 mutations compared with germline mutation-negative tumors by either TPS or CPS. In conclusion, the prevalence of PD-L1 expression is variable in different types of tubo-ovarian carcinoma and is highest in HGSC. In high-stage HGSC, PD-L1 positivity in tumor cells is associated with an increased immune response and improved survival.


Assuntos
Adenocarcinoma de Células Claras/imunologia , Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Linfócitos T CD8-Positivos/imunologia , Carcinoma Endometrioide/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Císticas, Mucinosas e Serosas/imunologia , Neoplasias Ovarianas/imunologia , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/terapia , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Císticas, Mucinosas e Serosas/mortalidade , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Císticas, Mucinosas e Serosas/terapia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Intervalo Livre de Progressão , Fatores de Tempo , Adulto Jovem
12.
J Cancer ; 11(10): 3052-3060, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226520

RESUMO

Nasopharyngeal carcinoma (NPC), is one of the most common malignant tumor in southern China and southeast Asia. MYH10 is a coding gene of the NMMHC-IIB protein. Previous studies have shown that MYH10 expression was up-regulated in breast cancer, glioma and meningioma. Moreover, it was targeted by miR200 family. However, no relevant studies have been found in NPC. In present study, we found in 48 NPC specimens, MYH10 level was lower in most cancer areas than that in the adjacent normal tissue. Moreover, the depletion of MYH10 can promote the migration and invasion of NPC. In addition, we demonstrated that miR-200a has the strongest regulation to MYH10 among miR-200 family. miR-200a mimics could decrease MYH10 expression, while miR-200a inhibitor increase MYH10 expression. Next, we found that miR-200a bound directly to MYH10 using Dual-luciferase reporter. Finally, it was demonstrated that siMYH10 could reverse the effect of miR-200a inhibitor on NPC cell migration and invasion. Taken together, it can be concluded that MYH10 is lowly expressed in NPC compared with adjacent tissues, and the loss of MYH10 can promote the migration and invasion of NPC cells; Among the miR-200 family, miR-200a has the strongest regulatory effect on MYH10; MYH10 is a direct target gene of miR200a, and miR200a targets MYH10 to regulate the migration and invasion of NPC cells.

13.
Am J Cancer Res ; 9(11): 2314-2330, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815037

RESUMO

Zinc finger E-box binding homeobox 1 (ZEB1), as a typical transcription inhibitory factor of E-cadherin, plays a major role in stimulating the invasion and metastasis of tumors via modulating the epithelial-mesenchymal transition (EMT) signal. However, its function and modulatory mechanisms in endometrial carcinoma (EC) remain unclear. In this study, silencing ZEB1 significantly reduced EC cell migration, invasion, and metastasis, as well as enhanced the sensitivity of EC cells to cisplatin (cDDP) in vitro and in vivo. Mechanism analysis indicated that ZEB1 interacts with hepatoma-derived growth factor (HDGF) and co-localizes in the nucleus. In addition, ZEB1 as a transcription factor binds to the promoter of HDGF to stimulate HDGF transcription. Furthermore, suppression of HDGF in ZEB1-overexpressed EC cells not only reduced the expression of ß-catenin, TCF4, and ZEB1, but also repressed ß-catenin translocation from the cytoplasm into the nucleus and further downregulated the combination with TCF4. Interestingly, the ß-catenin/TCF4 signaling feedback stimulates ZEB1 transcription and therefore constitutes a positive feedback loop. In clinical samples, ZEB1 positively correlates with HDGF expression, and co-expression of ZEB1 and HDGF promotes the pathogenesis of EC. In summary, our study demonstrated that the positive feedback loop of ZEB1/HDGF/ß-catenin/TCF4 plays an unfavorable role in the metastasis of endometrial carcinoma.

14.
J Cancer ; 10(25): 6252-6260, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772658

RESUMO

BACKGROUND: Phosphodiesterase 4D (PDE4D) has recently been reported as an oncogene in various types of human cancers. However, the expression and significance of PDE4D in pancreatic ductal adenocarcinoma (PDAC) have not been elucidated. Methods: Immunohistochemistry (IHC) was used to examine the expression of PDE4D in 104 clinicopathologically characterized PDAC cases. PDE4D expression in paired tumor tissues and adjacent noncancerous tissues were detected by western blotting and real time qRT-PCR. The correlation of PDE4D expression levels with clinicopathological features and prognosis in patients were analyzed by univariate and multivariate methods. Effect of PDE4D on pancreatic cancer cells was detected by cell migration and invasion assays. Results: We found that PDE4D was significantly up-regulated in PDAC tumor tissues compared to those paired adjacent noncancerous tissues at both protein and mRNA levels. High level of PDE4D was significantly associated with clinical stage (P = 0.004), T classification (P = 0.003), lymph node metastasis (P = 0.022) and liver metastasis (P = 0.038). Patients with higher levels of PDE4D had shorter overall survival time contrast with those with lower PDE4D expression (P = 0.002). Multivariate analysis indicated that PDE4D may be an independent prognostic factor for PDAC. PDE4D depletion significantly suppressed ß-catenin and Snail expression as well as the migration and invasion abilities of pancreatic cancer cells. Conclusions: Our study reveals that PDE4D up-regulated in PDAC was closely associated with poor prognosis of PDAC patients and multiple aggressive clinicopathological characteristics. PDE4D could be a useful prognostic biomarker and therapeutic target for PDAC.

15.
Artigo em Inglês | MEDLINE | ID: mdl-31754475

RESUMO

In this study, we present novel molecular mechanisms by which FOXO1 functions as a tumor suppressor to prevent the pathogenesis of nasopharyngeal carcinoma (NPC). First, we observed that FOXO1 not only controlled tumor stemness and metastasis, but also sensitized NPC cells to cisplatin (DDP) in vitro and in vivo. Mechanistic studies demonstrated that FOXO1-induced miR-200b expression through the GSK3ß/ß-catenin/TCF4 network-mediated stimulation of ZEB1, which reduced tumor stemness and the epithelial-mesenchymal transition (EMT) signal. Furthermore, we observed FOXO1 interaction with MYH9 and suppression of MYH9 expression by modulating the PI3K/AKT/c-Myc/P53/miR-133a-3p pathway. Decreased MYH9 expression not only reduced its interactions with GSK3ß, but also attenuated TRAF6 expression, which then decreased the ubiquitin-mediated degradation of GSK3ß protein. Increased GSK3ß expression stimulated the ß-catenin/TCF4/ZEB1/miR-200b network, which increased the downstream tumor stemness and EMT signals. Subsequently, we observed that chemically synthesized cinobufotalin (CB) strongly increased FOXO1-induced DDP chemosensitivity by reducing MYH9 expression, and the reduction in MYH9 modulated GSK3ß/ß-catenin and its downstream tumor stemness and EMT signal in NPC. In clinical samples, the combination of low FOXO1 expression and high MYH9 expression indicated the worst overall survival rates. Our studies demonstrated that CB potently induced FOXO1-mediated DDP sensitivity by antagonizing its binding partner MYH9 to modulate tumor stemness in NPC.

16.
EBioMedicine ; 48: 386-404, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31594754

RESUMO

BACKGROUND: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-related tumor. The role of EBV-encoding miR-BART22 is still unclear in NPC. This study aimed to identify the detailed mechanisms by which EBV-miR-BART22 functions as a tumor-promoting factor and evaluate the action of cinobufotalin in treating EBV-miR-BART22-overexpressing NPC cells. METHODS: Using real-time PCR, western blotting, immunohistochemistry, and In situ hybridization, we detected the expression of miR-BART22 and MAP2K4 in tissues and cells, as well as evaluated their clinical relevance in NPC patients. The effects of miR-BART22 on cell metastasis, stemness and DDP chemoresistance were examined by sphere formation assay, side population analysis, transwell, boyden, in vivo xenograft tumor mouse model et al. Western blotting, immunofluorescence staining, luciferase reporter assay, ChIP, EMSA and Co-IP assay et al. were performed to explore the detailed molecular mechanism of EBV-miR-BART22 in NPC. Finally, we estimated the effects and molecular basis of Cinobufotalin on EBV-miR-BART22-overexpressing NPC cells in vitro and in vivo assays. FINDINGS: We observed that EBV-miR-BART22 not only promoted tumor stemness and metastasis, but also enhanced the resistance to Cisplatin (DDP) in vitro and in vivo. Mechanistic analysis indicated that EBV-miR-BART22 directly targeted the MAP2K4 and upregulated non-muscle myosin heavy chain IIA (MYH9) expression by PI3K/AKT/c-Jun-induced transcription. Further, MYH9 interacted with glycogen synthase 3ß(GSK3ß) protein and induced its ubiquitin degradation by activating PI3K/AKT/c-Jun-induced ubiquitin transcription and the latter combined with increased TRAF6 E3 ligase, which further bound to GSK3ß protein. Reductions in the GSK3ß protein thus promoted ß-catenin expression and nuclear translocation, which induced tumor stemness and the epithelial-to-mesenchymal transition (EMT) signals. Furthermore, we observed that cinobufotalin, a new chemically synthesized compound, significantly suppressed EBV-miR-BART22-induced DDP chemoresistance by upregulating MAP2K4 to suppress MYH9/GSK3ß/ß-catenin and its downstream tumor stemness and EMT signals in NPC. Finally, clinical data revealed that increased miR-BART22 and reduced MAP2K4 expression caused the poor prognoses of NPC patients. INTERPRETATION: Our study provides a novel mechanism that cinobufotalin reversed the DDP chemoresistance and EMT induced by EBV-miR-BART22 in NPC.


Assuntos
Bufanolídeos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Herpesvirus Humano 4/genética , MicroRNAs/genética , RNA Viral , Linhagem Celular Tumoral , Glicogênio Sintase/metabolismo , Humanos , MAP Quinase Quinase 4/genética , Cadeias Pesadas de Miosina/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células-Tronco/metabolismo , beta Catenina/metabolismo
17.
BMC Nephrol ; 20(1): 224, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31215412

RESUMO

BACKGROUND: Primary hyperoxaluria (PH) is a rare inborn disorder of the metabolism of glyoxylate, which causes the hallmark production oxalate and forms insoluble calcium oxalate crystals that accumulate in the kidney and other organs. Since the manifestation of PH varies from recurrent nephrolithiasis, nephrocalcinosis, and end-stage renal disease with age at onset of symptoms ranging from infancy to the sixth decade, the disease remains undiagnosed until after kidney transplantation in some cases. CASE PRESENTATION: Herein, we report 3 cases of PH diagnosed after kidney transplantation failure, providing the comprehensive clinical course, the ultrasonic image of renal graft and pathologic image of the biopsy, highlighting the relevance of biopsy findings and the results of molecular genetic testing. We also focus on the treatment and the unfavorable outcome of the patients. Meanwhile, we review the literature and show the additional 10 reported cases of PH diagnosed after kidney transplantation. Additionally, we discuss the progressive molecular understanding of the mechanisms involved in PH and molecular therapy. CONCLUSIONS: Overall, the necessity of preoperative screening of PH in all patients even with a minor history of nephrolithiasis and the importance of proper treatment are the lessons we learn from the 3 cases, which prompt us to avoid tragedies.


Assuntos
Hiperoxalúria Primária/diagnóstico por imagem , Hiperoxalúria Primária/etiologia , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Falha de Tratamento , Adulto , Humanos , Transplante de Rim/tendências , Masculino
18.
Am J Surg Pathol ; 43(8): 1066-1073, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31045892

RESUMO

Progestin usage can alter the histologic and cytologic features of HSIL, which may potentially lead to the under-diagnosis of this precancerous lesion. The objective of the present study was to assess the relationship between the usage of progesterone-based contraceptives and the cytologic features of high-grade squamous intraepithelial lesion (HSIL) of the cervix. In this case-control study, we assembled 46 cases of cervical HSIL (CIN 3), including samples from 26 patients with known history of progestin usage (study group) and 20 samples from patients with no history of any exogenous hormone usage (control group). Cell image analysis was performed on all samples using a proprietary software. Immunohistochemical studies for Ki67, p16, estrogen receptor and progesterone receptor were performed on all cases, as was RNA in situ hybridization for HPV subtypes 16 and 18. Compared with the control group cases, the average nuclear size (21.5±1.80 µm) and the nuclear: cytoplasmic ratio (0.28±0.015) of HSILs in the study group cases were significantly smaller (P=0.026) and reduced (P=0.005), respectively. In addition, the study group cases showed reduced nuclear atypia and pleomorphism and significantly reduced mitotic figures (1.74±1.86/mm in study group versus 5.94±1.3/mm in control group, P<0.0001). The later was likely a consequence of the significantly reduced mitotic figures in the superficial and middle epithelial layers of the study group cases compared with their control group counterparts (0.73±0.88/mm vs. 7.3±2.6/mm, P<0.0001). Progestin usage has no discernible effects on p16 immunoreactivity, Ki67 proliferative index, hormone receptor expression, and HPV RNA levels of HSIL lesions. Being aware of progestin induced morphologic changes on those cervical precancerous lesions will be ultimately improve patient care quality in our daily practice.


Assuntos
Tamanho do Núcleo Celular/efeitos dos fármacos , Mitose/efeitos dos fármacos , Progestinas/uso terapêutico , Lesões Intraepiteliais Escamosas/patologia , Neoplasias do Colo do Útero/patologia , Adulto , Biomarcadores Tumorais/análise , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , China , DNA Viral/genética , Feminino , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Lesões Intraepiteliais Escamosas/metabolismo , Lesões Intraepiteliais Escamosas/virologia , Texas , Neoplasias do Colo do Útero/química , Neoplasias do Colo do Útero/virologia , Adulto Jovem
19.
Biomed Pharmacother ; 115: 108939, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079003

RESUMO

Family with sequence similarity 83 member B (FAM83B) has been recently identified as an oncogene involved in the development of various human cancers. However, the role of FAM83B in endometrial cancer tumorigenesis and metastasis is unclear. In this study, we found that the expression of FAM83B was upregulated in endometrial cancer tissues and cell lines. FAM83B expression in endometrial cancer tissues was significantly higher than that in normal tissues and higher FAM83B expression was closely related to poorly survival rate according to TCGA analysis. Moreover, FAM83B expression was correlated with International Federation of Gynecology and Obstetrics (FIGO)stage and myometrial invasion but had no significant correlation with age or histological grade. FAM83B knockdown inhibited endometrial cancer cell proliferation, migration, and invasion arrested the cell cycle at the G1/S stage and promoted apoptosis. FAM83B knockdown also inhibited endometrial cancer growth and lung metastasis in vivo. FAM83B knockdown silenced the PI3K/AKT/mTOR pathway and promoted autophagy. Furthermore, activation of the PI3K/AKT/mTOR pathway reversed FAM83B knockdown-induced autophagy promotion and inhibition of proliferation, migration, and invasion in endometrial cancer cells. Taken together, these results indicate that FAM83B promotes endometrial cancer cell proliferation and metastasis by inhibiting autophagy via activating the PI3K/AKT/mTOR pathway.


Assuntos
Proliferação de Células/genética , Neoplasias do Endométrio/metabolismo , Proteínas de Neoplasias/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias do Endométrio/genética , Feminino , Técnicas de Silenciamento de Genes , Humanos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Front Oncol ; 9: 211, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31032220

RESUMO

Background: Our previous work determined the correlation between high nuclear expression of hepatoma-derived growth factor (HDGF) and clinicopathological data of endometrial cancer (EC); however, the modulatory mechanisms and biological role of HDGF in EC have not been reported. Methods: Lentiviral particles carrying human HDGF short hairpin RNA (shHDGF-1, -2, and -3) vector and plasmids for HDGF, DDX5, and ß-catenin expression were, respectively introduced into EC cells to evaluate the effects and molecular mechanisms underlying EC cell proliferation, migration, invasion, and metastasis. Quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) and western blotting were used to determine HDGF and DDX5 expression. Co-immunoprecipitation (co-IP), mass spectrometry, and an immunofluorescence co-localization study were conducted to explore the relationship between HDGF, DDX5, and ß-catenin. Immunohistochemistry was used to analyze the clinical associations between HDGF and DDX5 in EC. Results: Knocking down HDGF expression significantly decreased EC cellular proliferation, migration, invasion in vitro, as well as tumorigenesis and metastasis in vivo. Conversely, HDGF overexpression reversed these effects. Stable knockdown-based HDGF suppression activated the PI3K/AKT signaling pathway, along with downstream ß-catenin-mediated cell cycle and epithelial-mesenchymal transition signaling. Furthermore, co-IP combined with mass spectrometry and an immunofluorescence co-localization study indicated that HDGF interacts with DDX5, whereas ß-catenin was associated with DDX5 but not HDGF. Overexpression of DDX5 reversed the suppression of shHDGF. Immunohistochemistry analysis showed that high expression of DDX5 constituted an unfavorable factor with respect to the clinicopathological characteristics of EC tissues and that HDGF and DDX5 high expression (HDGF+/DDX5+) led to a worse prognosis for patients with EC (P < 0.001). In addition, we found that the expression of HDGF and DDX5 was positively correlated in EC tissues (r = 0.475, P < 0.001). Conclusion: Our results provide novel evidence that HDGF interacts with DDX5 and promotes the progression of EC through the induction of ß-catenin.

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