scholarly journals The Macro-Autophagy-Related Protein Beclin-1 Immunohistochemical Expression Correlates With Tumor Cell Type and Clinical Behavior of Uveal Melanoma

2020 ◽  
Vol 10 ◽  
Author(s):  
Giuseppe Broggi ◽  
Antonio Ieni ◽  
Daniela Russo ◽  
Silvia Varricchio ◽  
Lidia Puzzo ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Human Cancer ◽  
Malignant Neoplasm ◽  
Disease Free Survival ◽  
Beclin 1 ◽  
Survival Times ◽  
Immunohistochemical Expression ◽  
Prognostic Role ◽  
Long Time ◽  
Related Proteins

Uveal melanoma, in spite of its rarity, represents the most common primitive intraocular malignant neoplasm of the adults; it affects choroid, ciliary bodied and iris and remains clinically silent for a long time, being accidentally discovered by routine ophthalmic exams. Prognosis of uveal melanoma is poor and frequently characterized by liver metastases, within 10–15 years from diagnosis. Autophagy is a multi-step catabolic process by which cells remove damaged organelles and proteins and recycle nutrients. It has been hypothesized that in early stages of tumorigenesis autophagy has a tumor suppressor role while, in more advanced stages, it may represent a survival mechanism of neoplastic cells in response to stress. Several proteins related to autophagy cascade have been investigated in numerous subtypes of human cancer, with overall controversal results. In this paper we studied the immunohistochemical expression of 3 autophagy related proteins (Beclin-1, p62 and ATG7) in a cohort of 85 primary uveal melanoma treated by primary enucleation (39 with metastasis and 46 non metastatic) and correlated their expression with clinico-pathological parameters and blood vascular microvessel density, in order to investigate the potential prognostic role of autophagy in this rare neoplasm. We found that high immunohistochemical levels of Beclin-1 correlated with a lower risk of metastasis and higher disease-free survival times, indicating a positive prognostic role for Beclin-1 in uveal melanoma. No statistically significative differences regarding the expression of ATG7 and p62 between metastatic and non metastatic patients was detected.

scholarly journals Immunoexpression of Macroh2a in Uveal Melanoma

2019 ◽  
Vol 9 (16) ◽  
pp. 3244 ◽  
Author(s):  
Salvatorelli ◽  
Puzzo ◽  
Bartoloni ◽  
Palmucci ◽  
Longo ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Uveal Melanoma ◽  
Metastatic Disease ◽  
Cutaneous Melanoma ◽  
High Expression ◽  
Melanoma Metastasis ◽  
Proper Treatment ◽  
Immunohistochemical Expression ◽  
Prognostic Role

MacroH2A is a histone variant whose expression has been studied in several neoplasms, including cutaneous melanomas (CMs). In the literature, it has been demonstrated that macroH2A.1 levels gradually decrease during CM progression, and a high expression of macroH2A.1 in CM cells relates to a better prognosis. Although both uveal and cutaneous melanomas arise from melanocytes, uveal melanoma (UM) is biologically and genetically distinct from the more common cutaneous melanoma. Metastasis to the liver is a frequent occurrence in UM, and about 40%–50% of patients die of metastatic disease, even with early diagnosis, proper treatment, and close follow-up. We wanted to investigate macroH2A.1 immunohistochemical expression in UM. Our results demonstrated that mH2A.1 expression was higher in metastatic UM (21/23, 91.4%), while only 18/32 (56.3%). UMs without metastases showed mH2A.1 staining. These data could suggest a possible prognostic role for mH2A.1 and could form a basis for developing new pharmacological strategies for UM treatment.

scholarly journals Autophagy-Related Proteins Are Differentially Expressed in Adrenal Cortical Tumor/Pheochromocytoma and Associated with Patient Prognosis

2021 ◽  
Vol 22 (19) ◽  
pp. 10490
Author(s):  
Hye Min Kim ◽  
Ja Seung Koo
Keyword(s):  
Adrenal Gland ◽  
Disease Free Survival ◽  
Beclin 1 ◽  
Gland Tumor ◽  
Adrenal Cortical Adenoma ◽  
Single Positive ◽  
Adrenal Cortical Tumor ◽  
Patient Prognosis ◽  
Cox Analysis ◽  
Related Proteins

The aim of this research was to evaluate the expression and concomitant implications of LC3A, LC3B, beclin-1, and p62, which are key components of autophagy in human adrenal gland tumors. Tissue microarray was made for 321 cases of adrenal gland tumor (adrenal cortical adenoma (ACA): 115, adrenal cortical carcinoma (ACC): 17, and pheochromocytoma (PCC): 189). Immunohistochemical staining was performed for beclin-1, p62, LC3A, and LC3B, and the results were compared with the patients’ clinicopathologic parameters. LC3A, LC3B, beclin-1, and LC3B isolated single positive cells (ISPC) positivity rates were higher in PCC than in adrenal cortical tumor (ACT), whereas p62 positivity was lower in PCC than in ACT. The proportion of positive LC3B (ISPC) was higher in ACC than in ACA. In addition, the proportion of cells positive for p62 and LC3B (ISPC) was significantly higher in PCCs with a GAPP score of ≥3. In univariate Cox analysis, p62 positivity (p = 0.014) and the presence of p62 (ISPC) (p = 0.001) were associated with shorter disease-free survival in PCC. Moreover, p62 positivity was predictive of shorter overall survival (OS) in patients with PCC by multivariate analysis (relative risk, 6.240; 95% CI, 1.434–27.15; p = 0.015). Differences were found in the expression of autophagy-related proteins according to adrenal gland tumor types. Compared to ACT, the proportion of LC3A, LC3B, beclin-1, and LC3B (ISPC) positivity was higher in PCC, whereas p62 positivity was lower. Similarly, p62 positivity in PCC was associated with patient prognosis of OS.

scholarly journals Prognostic Value of the Immunohistochemical Expression of Serine and Arginine-Rich Splicing Factor 1 (SRSF1) in Uveal Melanoma: A Clinico-Pathological and Immunohistochemical Study on a Series of 85 Cases

2021 ◽  
Vol 11 (17) ◽  
pp. 7874
Author(s):  
Giuseppe Broggi ◽  
Luca Falzone ◽  
Matteo Fallico ◽  
Andrea Russo ◽  
Michele Reibaldi ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Rna Binding ◽  
Metastatic Potential ◽  
Splicing Factor ◽  
Survival Times ◽  
Immunohistochemical Expression ◽  
Free Survival ◽  
Metastatic Risk ◽  
Factor Α ◽  
Splicing Factor 1

Uveal melanoma (UM) is the most frequent primary ocular malignancy of adults; it exhibits an almost invariably poor prognosis with onset of liver metastases within 10–15 years after the diagnosis. Serine and arginine-rich splicing factor 1 (SRSF1) is an RNA-binding protein with proto-oncogene functions, including stimulation of angiogenesis, cell migration and cell growth; regarding the complex regulation of tumor angiogenesis, it has been suggested that SRSF1 regulates the alternative splicing of vascular endothelial growth factor-α, promoting the formation of its pro-angiogenic isoform. The immunohistochemical expression of SRSF1 on a series of 85 primary UMs, including 39 metastasizing and 46 non-metastasizing cases, was investigated; to clarify the potential pathogenetic role of SRSF1 in this tumor and its effect on angiogenesis, we correlated our immunohistochemical findings with the clinico-pathological features, the prognostic data and blood vascular microvessel density (MVD) findings of the cases from our series. Cases with higher immunohistochemical expression of SRSF1 also had higher MVD, higher metastatic potential and shorter metastasis-free survival; conversely, cases with lower SRSF1 immunoexpression showed lower MVD, lower metastatic risk and longer metastasis-free survival times. Our results suggested that SRSF1 has a negative prognostic role and a pro-angiogenic function in UM.

scholarly journals AMBRA1 attenuates the proliferation of uveal melanoma cells

Open Medicine ◽  
2021 ◽  
Vol 17 (1) ◽  
pp. 1-14
Author(s):  
Binbin Zhao ◽  
Yun Yang ◽  
Biyun Cun ◽  
Ping Chen
Keyword(s):  
Cell Division ◽  
Cell Growth ◽  
Tumor Suppressor ◽  
Uveal Melanoma ◽  
Human Cancer ◽  
Therapeutic Targets ◽  
E3 Ligase ◽  
Beclin 1 ◽  
Dependent Manner ◽  
The Stability

Abstract Uveal melanoma (UVM) is the most common primary intraocular malignancy in adults with high metastasis rates. D-type cyclins (CCNDs) are central regulators of the cell division cycle and are among the most frequently deregulated therapeutic targets in human cancer. Recently, the E3 ligase adaptor, autophagy and beclin 1 regulator 1 (AMBRA1), was reported to regulate the stability of CCNDs, including CCND1, but its role in UVM has not been demonstrated. AMBRA1 is lowly expressed in UVM cells, and the ablation of AMBRA1 promotes the proliferation of 92.1 and OMM1 cells, whereas ectopically expressing AMBRA1 attenuates the proliferation of UVM cells. Further studies found that AMBRA1 promotes the ubiquitination and degradation of CCND1, and AMBRA1 regulates the proliferation of UVM cells in a CCND1-dependent manner. Thus, this study suggests that AMBRA1 serves as an important tumor suppressor by limiting UVM cell growth.

Proline-Directed Protein Kinase FA Is a Powerful and Independent Prognostic Predictor for Progression and Patient Survival of Hepatocellular Carcinoma

2006 ◽  
Vol 24 (23) ◽  
pp. 3780-3788 ◽  
Author(s):  
Yu-Chen Hsu ◽  
Hsiao-Hui Fu ◽  
Yung-Ming Jeng ◽  
Po-Huang Lee ◽  
Shiaw-Der Yang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Protein Kinase ◽  
Patient Survival ◽  
Human Cancer ◽  
Disease Free Survival ◽  
Prognostic Role ◽  
Free Survival ◽  
Disease Free

Purpose Molecular, cellular, and animal studies have established that overexpressed proline-directed protein kinase FA (PDPK FA) is essential for the development of tumorigenesis, invasion, and metastasis of human cancer cells. However, the prognostic role of PDPK FA in cancer patients remains largely unknown. In this study, association of PDPK FA expression with poor prognosis of hepatocellular carcinoma (HCC) patients was examined. Patients and Methods PDPK FA expression in the resected tumors of 134 HCC patients (112 men and 22 women) with ages ranging from 33 to 83 years (mean, 55 years) was analyzed by immunohistochemistry. Highly condensed cytoplasmic and nuclear PDPK FA associated with tumor cells was used as the major scoring parameter for positive PDPK FA expression. Results Approximately 68% of the patients (91 of 134) exhibited positive PDPK FA expression. Patients with positive PDPK FA showed poorer disease-free survival and overall survival (P < .001). Cox multivariate regression analysis further established PDPK FA as the strongest independent prognosticator for progression and patient survival of HCC (hazard ratio [HR], 2.878; 95% CI, 1.634 to 5.067 for disease-free survival; and HR, 5.035; 95% CI, 2.137 to 11.866 for overall survival; P < .001). Conclusion Consistent with PDPK FA’s essential role in the development of highly malignant phenotypes, the present study establishes the potential prognostic role of PDPK FA in progression and patient survival of surgically resected primary HCC. Taken together, PDPK FA represents a new modifiable signal-transducing target for prognostic prediction and adjuvant treatment of patients with aggressive HCC after hepatic resection.

Bioinformatics Analysis Identifies CPZ as a Tumor Immunology Biomarker For Gastric Cancer

2020 ◽  
Vol 15 ◽  
Author(s):  
Yuan Gu ◽  
Ying Gao ◽  
Xiaodan Tang ◽  
Huizhong Xia ◽  
Kunhe Shi
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Signaling Pathway ◽  
Tumor Immunology ◽  
Bioinformatics Analysis ◽  
Human Cancer ◽  
Disease Free Survival ◽  
Kaplan Meier ◽  
Potential Biomarker ◽  
Pathway Regulation

Background: Gastric cancer (GC) is one of the most common malignancies worldwide. However, the biomarkers for the prognosis and diagnosis of Gastric cancer were still need. Objective: The present study aimed to evaluate whether CPZ could be a potential biomarker for GC. Method: Kaplan-Meier plotter (http://kmplot.com/analysis/) was used to determine the correlation between CPZ expression and overall survival (OS) and disease-free survival (DFS) time in GC [9]. We analyzed CPZ expression in different types of cancer and the correlation of CPZ expression with the abundance of immune infiltrates, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells, via gene modules using TIMER Database. Results: The present study identified that CPZ was overexpressed in multiple types of human cancer, including Gastric cancer. We found that overexpression of CPZ correlates to the poor prognosis of patients with STAD. Furthermore, our analyses show that immune infiltration levels and diverse immune marker sets are correlated with levels of CPZ expression in STAD. Bioinformatics analysis revealed that CPZ was involved in regulating multiple pathways, including PI3K-Akt signaling pathway, cGMP-PKG signaling pathway, Rap1 signaling pathway, TGF-beta signaling pathway, regulation of cell adhesion, extracellular matrix organization, collagen fibril organization, collagen catabolic process. Conclusion: This study for the first time provides useful information to understand the potential roles of CPZ in tumor immunology and validate it to be a potential biomarker for GC.

scholarly journals Inhibition of CCL7 derived from Mo-MDSCs prevents metastatic progression from latency in colorectal cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Xiaoli Ren ◽  
Jianbiao Xiao ◽  
Wanning Zhang ◽  
Feifei Wang ◽  
Yongrong Yan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Suppressor Cells ◽  
Metastatic Progression ◽  
Ht29 Cells ◽  
Metastatic Cells ◽  
Long Time ◽  
Mice Liver ◽  
Short Time ◽  
Related Proteins

AbstractIn colorectal cancer (CRC), overt metastases often appear after years of latency. But the signals that cause micro-metastatic cells to remain indolent, thereby enabling them to survive for extended periods of time, are unclear. Immunofluorescence and co-immunoprecipitation assays were used to explore the co-localization of CCL7 and CCR2. Immunohistochemical (IHC) assays were employed to detect the characters of metastatic HT29 cells in mice liver. Flow cytometry assays were performed to detect the immune cells. Bruberin vivo MS FX Pro Imager was used to observe the liver metastasis of CRC in mice. Quantitative real-time PCR (qRT-PCR) and western blot were employed to detect the expressions of related proteins. Trace RNA sequencing was employed to identify differentially expressed genes in MDSCs from liver micro-M and macro-M of CRC in mice. Here, we firstly constructed the vitro dormant cell models and metastatic dormant animal models of colorectal cancer. Then we found that myeloid-derived suppressor cells (MDSCs) were increased significantly from liver micro-metastases to macro-metastases of CRC in mice. Moreover, monocytic MDSCs (Mo-MDSC) significantly promoted the dormant activation of micro-metastatic cells compared to polymorphonuclear MDSCs (PMN-MDSC). Mechanistically, CCL7 secreted by Mo-MDSCs bound with membrane protein CCR2 of micro-metastatic cells and then stimulated the JAK/STAT3 pathway to activate the dormant cells. Low-dose administration of CCL7 and MDSCs inhibitors in vivo could significantly maintain the CRC metastatic cells dormant status for a long time to reduce metastasis or recurrence after radical operation. Clinically, the level of CCL7 in blood was positively related to the number of Mo-MDSCs in CCR patients, and highly linked with the short-time recurrence and distant metastasis. CCL7 secreted by Mo-MDSCs plays an important role in initiating the outgrowth of metastatic latent CRC cells. Inhibition of CCL7 might provide a potential therapeutic strategy for the prevention of metastasis recurrence.

Phase I Study of Fludarabine Plus Cyclophosphamide in Patients With Previously Untreated Low-Grade Lymphoma: Results and and Long-Term Follow-Up—A Report From the Eastern Cooperative Oncology Group

2000 ◽  
Vol 18 (5) ◽  
pp. 987-987 ◽  
Author(s):  
Howard S. Hochster ◽  
Martin M. Oken ◽  
Jane N. Winter ◽  
Leo I. Gordon ◽  
Bruce G. Raphael ◽  
...  
Keyword(s):  
Phase Ii ◽  
Bone Marrow Involvement ◽  
Survival Rates ◽  
Eastern Cooperative Oncology Group ◽  
Disease Free Survival ◽  
Low Grade ◽  
Survival Times ◽  
Free Survival ◽  
Disease Free

PURPOSE: To determine the toxicity and recommended phase II doses of the combination of fludarabine plus cyclophosphamide in chemotherapy-naive patients with low-grade lymphoma. PATIENTS AND METHODS: Previously untreated patients with low-grade lymphoma were entered onto dosing cohorts of four patients each. The cyclophosphamide dose, given on day 1, was increased from 600 to 1,000 mg/m2. Fludarabine 20 mg/m2 was administered on days 1 through 5. The first eight patients were treated every 21 days; later patients were treated every 28 days. Prophylactic antibiotics were required. RESULTS: Prolonged cytopenia and pulmonary toxicity each occurred in three of eight patients treated every 3 weeks. The 19 patients treated every 28 days, who were given granulocyte colony-stimulating factor as indicated, did not have undue nonhematologic toxicity. Dose-limiting toxicity was hematologic. At the recommended phase II/III dose (cyclophosphamide 1,000 mg/m2), grade 4 neutropenia was observed in 17% of all cycles and 31% of first cycles. Grade 3 or 4 thrombocytopenia was seen in only 1% of all cycles. The median number of cycles per patient was six (range, two to 11) for all patients enrolled. The response rate was 100% of 27 patients entered; 89% achieved a complete and 11% a partial response. Nineteen of 22 patients with bone marrow involvement had clearing of the marrow. Median duration of follow-up was more than 5 years; median overall and disease-free survival times have not been reached. Kaplan-Meier estimated 5-year overall survival and disease-free survival rates were 66% and 53%, respectively. CONCLUSION: The recommended dosing for this combination in patients with previously untreated low-grade lymphoma is cyclophosphamide 1,000 mg/m2 day 1 and fludarabine 20 mg/m2 days 1 through 5. The regimen has a high level of activity, with prolonged complete remissions providing 5-year overall and disease-free survival rates as high as those reported for other therapeutic approaches in untreated patients.

Clinical significance of kallikrein-related peptidase 7 (KLK7) in colorectal cancer

2009 ◽  
Vol 101 (04) ◽  
pp. 741-747 ◽  
Author(s):  
Konstantina Mathioudaki ◽  
Panagiotis Prezas ◽  
Dimitra Alexopoulou ◽  
Eleftherios Diamandis ◽  
Dimitris Xynopoulos ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Stratum Corneum ◽  
Human Tissue ◽  
Serine Proteases ◽  
Human Cancer ◽  
Disease Free Survival ◽  
Normal Colonic Mucosa ◽  
Tissue Kallikrein ◽  
Human Cancer Cell Lines

SummaryHuman tissue kallikrein-related peptidases are a family of 15 secreted serine proteases, located at chromosome 19q13.4. Most of them have been reported to be potential biomarkers for several carcinomas and other diseases. Human tissue kallikrein-related peptidase 7 (KLK7) has been purified from human stratum corneum and resembles a chymotryptic endopeptidase originally called stratum corneum chymotryptic enzyme (SCCE). In this study, we examined for the first time, the prognostic value of KLK7 mRNA expression, using a semi-quantitative RT-PCR method, in 105 colorectal cancer tissues for 54 of which, paired normal colonic mucosa were available. Furthermore, we analysed the expression of KLK7 in 10 adenomas, in 18 biopsies of inflamed colon mucosa, as well as in 22 human cancer cell lines of various origin, four of them being of colon. A defined number of colon cancer samples were also examined by immunohisto-chemistry. KLK7 expression was higher in cancerous than in normal tissues. Less differentiated tumors of more advanced stage showed higher KLK7 expression. Follow-up analysis revealed that KLK7 was significantly associated with shorter overall survival (OS) and disease-free survival (DFS). In addition, selected colon cancer samples highly expressing KLK7 gene, showed intense immunohistochemical staining for KLK7, enhancing RTPCR results. Present data suggest that KLK7 gene is up-regulated in colon cancer and its expression predicts poor prognosis for colon cancer patients.

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