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

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.

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Expression of Glucose Metabolism-Related Proteins in Adrenal Neoplasms

Pathobiology ◽

10.1159/000518208 ◽

2021 ◽

pp. 1-10

Author(s):

Eun Kyung Kim ◽

Hye Min Kim ◽

Ja Seung Koo

Keyword(s):

Prognostic Factors ◽

Glucose Metabolism ◽

Expression Patterns ◽

Univariate Analysis ◽

Hexokinase Ii ◽

Expression Levels ◽

Adrenal Cortical Adenoma ◽

Adrenal Neoplasms ◽

Cox Analysis ◽

Related Proteins

Purpose: The aim of this study was to investigate the expression patterns of glucose metabolism-related proteins and their clinicopathologic implications in adrenal cortical neoplasms (ACN) and pheochromocytoma (PCC). Methods: Immunohistochemical staining was performed to evaluate glucose metabolism-related proteins (GLUT1, CAIX, hexokinase II, G6PDH, PHGDH, and SHMT1) in 132 ACN cases (115 adrenal cortical adenoma [ACA] and 17 adrenal cortical carcinoma [ACC]) and 189 PCC cases. Results: Expression levels of GLUT1 in tumor cells ([T]; p < 0.001), GLUT1 in stromal cells ([S]; p < 0.001), G6PDH (p < 0.001), and SHMT1 (p = 0.002) were higher in ACN than in PCC. GLUT1 (T; p = 0.045) and PHGDH (p = 0.043) levels were higher in ACC than in ACA. In a univariate analysis of ACN, GLUT1 (T; p = 0.017), CAIX (S; p = 0.003), and PHGDH (p = 0.009) levels were correlated with a shorter overall survival (OS). GLUT1 (T; p = 0.001) and PHGDH (p < 0.001) were related to a shorter OS in PCC. GLUT1 (T) positivity (p = 0.043) in ACN predicted a poor OS in a multivariate Cox analysis. In PCC, high GAPP score (p = 0.026), GLUT1 (T; p = 0.002), and PHGDH (p < 0.001) were independent prognostic factors for poor OS. Conclusions: The adrenal gland tumors ACN and PCC had different expression patterns of glucose metabolism-related proteins (GLUT1, G6PDH, and SHMT1), with higher expression levels in ACN than in PCC. GLUT1 and PHGDH were significant prognostic factors in these adrenal neoplasms.

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

Frontiers in Oncology ◽

10.3389/fonc.2020.589849 ◽

2020 ◽

Vol 10 ◽

Cited By ~ 1

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.

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CONGENITAL CONCURRENCE OF ADRENAL CORTICAL TUMOR, GANGLIONEUROMA, AND TOXOPLASMOSIS

PEDIATRICS ◽

10.1542/peds.51.4.705 ◽

1973 ◽

Vol 51 (4) ◽

pp. 705-709

Author(s):

Juan J. Gershanik ◽

Miles Elmore ◽

Abner H. Levkoff

Keyword(s):

Adrenal Gland ◽

Abdominal Mass ◽

Postmortem Examination ◽

Adrenal Cortical Tumor

A neonate with hypertension, hyperglycemia, glycosuria, and an abdominal mass had, at postmortem examination, an adrenal cortical tumor, multiple microscopic ganglioneuromas of the contralateral adrenal gland, and toxoplasmosis. The possibility of a common linkage among these three entities is discussed.

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Ammonium ion transport by the AMT/Rh homologue LeAMT1;1

Biochemical Journal ◽

10.1042/bj20060051 ◽

2006 ◽

Vol 396 (3) ◽

pp. 431-437 ◽

Cited By ~ 56

Author(s):

Maria Mayer ◽

Marek Dynowski ◽

Uwe Ludewig

Keyword(s):

Structural Data ◽

Homology Model ◽

Ammonium Transporter ◽

Ammonium Ion ◽

Molecular Architecture ◽

Gas Channel ◽

Domains Of Life ◽

Single Positive ◽

Key Residues ◽

Related Proteins

AMT (ammonium transporter)/Rh (Rhesus) ammonium transporters/channels are identified in all domains of life and fulfil contrasting functions related either to ammonium acquisition or excretion. Based on functional and crystallographic high-resolution structural data, it was recently proposed that the bacterial AmtB (ammonium transporter B) is a gas channel for NH3 [Khademi, O'Connell, III, Remis, Robles-Colmenares, Miercke and Stroud (2004) Science 305, 1587–1594; Zheng, Kostrewa, Berneche, Winkler and Li (2004) Proc. Natl. Acad. Sci. U.S.A. 101, 17090–17095]. Key residues, proposed to be crucial for NH3 conduction, and the hydrophobic, but obstructed, pore were conserved in a homology model of LeAMT1;1 from tomato. Transport by LeAMT1;1 was affected by mutations of residues that were predicted to constitute the aromatic recruitment site for NH4+ at the external pore entrance. Despite the structural similarities, LeAMT1;1 was shown to transport only the ion; each transported 14C-methylammonium molecule carried a single positive elementary charge. Similarly, NH4+ (or H+/NH3) was transported, but NH3 conduction was excluded. It is concluded that related proteins and a similar molecular architecture can apparently support contrasting transport mechanisms.

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The prognostic relevance of 14-3-3 expression in cancers: a meta-analysis

Journal of the Pakistan Medical Association ◽

10.47391/jpma.03-402 ◽

2021 ◽

pp. 1-9

Author(s):

Caihong Li ◽

Honglan Zhu ◽

Changlu Liu ◽

Ya Liu ◽

Ting Huang ◽

...

Keyword(s):

Cancer Patients ◽

Meta Analysis ◽

Disease Free Survival ◽

Size Analysis ◽

Tumor Type ◽

Cancer Specific Survival ◽

Free Survival ◽

Hazard Ratios ◽

Prognostic Importance ◽

Patient Prognosis

AbstractObjective: A number of recent clinical studies have identified a relationship between elevated expressions of 14-3-3 and poorer patient prognosis in the context of several cancers. The present meta-analysis was therefore conducted to gain an enhanced understanding of the prognostic importance of 14-3-3 levels in cancer patients. Methods: Two reviewers independently systematically reviewed the Web of Science, Embase, and PubMed databases to identify published, suitable studies through October 2019. The correlation between the level of 14-3-3 and cancer patient survival were assessed based upon pooled HR (hazard ratios) and 95% CI (confidence intervals) derived from chosen studies. Results: In total we were able to identify 22 eligible studies that had enrolled 2676 patients in the present meta-analysis. Assessment of these studies revealed that elevated 14-3-3 level correlated significantly with poorer OS (overall survival) (HR : 1.93, 95% CI : 1.42-2.61) in cancer patients. This was true even when studies were analyzed in subgroups according to tumor type, sample size, analysis type, and method of HR determination. With respect to disease-free survival (DFS), the pooled HR for cancer patients expressing high levels of 14-3-3 was 1.89 (95% CI: 1.56-2.30). Patients with elevated 14-3-3 expression also exhibited reduced CSS (cancer-specific survival) (HR: 3.47, 95% CI: 2.12-5.69).Conclusions: The outcomes indicate that higher level of 14-3-3 correlates with poorer patient prognosis in a range of cancer types.Keywords: Meta-analysis, Prognosis, 14-3-3 Proteins C Continuous...

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Abstract 10246: Hydroxychloroquine Pretreatment Reduces Myocardial Ischemia-Reperfusion Injury: Role of Cardiac Extracellular-Signal-Regulated Kinase 5 and Autophagy

Circulation ◽

10.1161/circ.132.suppl_3.10246 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Feiyan Yang ◽

Chang Yin ◽

Lei Xi ◽

Rakesh C Kukreja

Keyword(s):

Infarct Size ◽

Ischemia Reperfusion Injury ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Beclin 1 ◽

Myocardial Infarct Size ◽

Western Blots ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Related Proteins

Background: Hydroxychloroquine (HCQ) is an antimalarial drug, which is also widely used to treat chronic rheumatologic diseases. Since HCQ was reported to inhibit cell autophagy and to activate extracellular-signal-regulated kinase 5 (ERK5) in vascular endothelial cells, we designed the current study to determine the effects of HCQ on cardiac ischemia-reperfusion (I-R) injury and post-I-R expression of ERK5 and autophagy marker proteins. Methods: Adult C57BL/6J mice of both genders were pretreated with HCQ (50 mg/kg, i.p.) 1 hour prior to isolation of the hearts, which were subjected to 30 min of no-flow global ischemia followed by 60 min of reperfusion in Langendorff mode. Ventricular function was continuously assessed and myocardial infarct size was determined at the end of I-R. Heart samples were collected following normoxic perfusion (no-ischemic controls), I-R, or I-R with HCQ for assessing ERK5 and autophagy-related proteins with Western blots. Results: HCQ pretreatment reduced infarct size significantly in the female hearts (P<0.05) as compared with the male hearts (Fig. A). Post-I-R cardiac function was better in HCQ-treated males (Fig. B). I-R resulted in a robust increase in total ERK5 (Fig. C) and phosphorylated ERK5 (Thr218/Tyr220) in both genders, which was abolished in HCQ-treated groups. Conversely, either I-R or HCQ did not affect the post-I-R cardiac expression of autophagy-related proteins (e.g., Atg5, Beclin-1, LC3II/LC3I ratio), except Beclin-1 phosphorylation was inhibited in HCQ-treated male hearts, but not females (Fig. D). Conclusions: Acute HCQ pretreatment affords cardioprotection against I-R injury in both genders. Interestingly, cardioprotective effects of HCQ are associated with a strong inhibitory effect on the induction of ERK5 following I-R in the heart, indicating a novel molecular mechanism underlying the HCQ-induced cardioprotection. However, the cardioprotective dose of HCQ has no major impact on cardiac autophagy.

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Multi-omics reveals a relationship between endometrial amino acid metabolism and autophagy in women with recurrent miscarriage

Biology of Reproduction ◽

10.1093/biolre/ioab101 ◽

2021 ◽

Author(s):

Ling Hong ◽

Yuan chang Zhu ◽

Su Liu ◽

Tonghua Wu ◽

Yuye Li ◽

...

Keyword(s):

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Recurrent Miscarriage ◽

Normal Pregnancy ◽

Beclin 1 ◽

Endometrial Stromal Cells ◽

Associated Proteins ◽

Glutamine Deprivation ◽

Related Proteins

Abstract Deterioration of the endometrial environment is an essential cause of recurrent miscarriage (RM). However, current studies in terms of endometrial amino acid metabolic characterization and autophagy are still inadequate. This study aimed to assess differences in the endometrial amino acid metabolism and autophagy between normal pregnant and RM women to reveal the association between amino acid metabolism, autophagy, and the endometrial microenvironment. We tried to (1) identify the alternation in metabolite profiles in the RM endometrium; (2) investigate the expression of autophagy-related proteins in RM; (3) elucidate the association between amino acid metabolism and autophagy in RM. Our results showed that glutamine metabolites were upregulated while glutamate metabolites were downregulated in the endometrium of RM women. The levels of autophagy-associated proteins, including LC3B, ATG12, and Beclin-1, were significantly higher in the endometrium of RM women. Hemostasis, autophagy and IFNα signaling were the top three differentially activated signaling pathways between women with RM and normal pregnancy. Interestingly, we also found that the expression of AMPK and GCN2 was significantly up-regulated in the endometrium of women with RM, and the same expression trend was also observed in the human endometrial stromal cells cultured in glutamine deprivation medium. Furthermore, inhibition of AMPK decreased the level of GCN2, indicating a positive correlation between GCN2 and AMPK. The expression of GCN2 was consistent with the expression of ATG12 and beclin-1; however, it was opposite to that of p62. Exposure to glutamine deprivation increased the level of LC3B, GCN2, ATG12 and beclin-1. Altogether, these findings suggested significant crosstalk between amino acid metabolism and autophagy. In summary, our data suggested that aberrant crosstalk between amino acid metabolism and autophagy may contribute to the impaired endometrial microenvironment of RM. Our study may provide new insight into the diagnosis of recurrent miscarriage due to endometrial factors.

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All-Trans-Retinoid Acid (ATRA) Induced Upregulation of Autophagy Related Proteins (LC3–1, II and Beclin 1) in Acute Promyelocytic Leukemia

International Journal of Pharmacology ◽

10.3923/ijp.2014.315.321 ◽

2014 ◽

Vol 10 (6) ◽

pp. 315-321 ◽

Cited By ~ 1

Author(s):

Amany H. Mansour ◽

Rokia Anwer ◽

Ahmad Darwish ◽

Abdulrahman Fahmi Alshaik ◽

Mohamed Mabed

Keyword(s):

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Beclin 1 ◽

Related Proteins ◽

Retinoid Acid

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Beclin 1, LC3, and p62 expression in paraquat-induced pulmonary fibrosis

Human & Experimental Toxicology ◽

10.1177/0960327119842633 ◽

2019 ◽

Vol 38 (7) ◽

pp. 794-802 ◽

Cited By ~ 4

Author(s):

G Xu ◽

X Wang ◽

H Yu ◽

C Wang ◽

Y Liu ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Light Chain ◽

Lung Fibrosis ◽

Beclin 1 ◽

Related Protein ◽

Protein Expressions ◽

Hematoxylin And Eosin ◽

Hematoxylin And Eosin Staining ◽

Related Proteins

Paraquat (PQ) is a highly toxic herbicide to humans. Pulmonary fibrosis is one of the most typical features of PQ poisoning, which develops from several days to weeks after ingestion. However, the mechanism of fibrosis is still unclear. In this study, we aimed to determine expressions of autophagy-related markers Beclin 1, microtubule-associated protein light chain 3 (LC3), and p62 in PQ-poisoned lungs and to explore the role of autophagy in pulmonary fibrosis induced by PQ. We detected markers of lung fibrosis and expressions of autophagy-related protein in the specimens from eight fatal cases of PQ poisoning by hematoxylin and eosin staining, Masson’s trichrome staining, and immunohistochemistry. Based on the staining results of lung fibrosis, these cases were divided into two groups, fibrosis and non-fibrosis groups. The correlation between autophagy protein expressions and pulmonary fibrosis was examined. The results demonstrated that the autophagy-related proteins were significantly expressed in fibrosis group compared with the non-fibrosis group. There was a significantly positive correlation between these protein expressions and severity of lung fibrosis. In conclusion, autophagy dysfunction may be involved in lung fibrogenesis caused by PQ poisoning. This may be a promising clue for understanding the molecular mechanism underlying PQ-induced lung fibrosis and provide evidence for treating fibrosis by regulating the level of autophagy.

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Dengue Nonstructural Protein 1 Maintains Autophagy through Retarding Caspase-Mediated Cleavage of Beclin-1

International Journal of Molecular Sciences ◽

10.3390/ijms21249702 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9702

Author(s):

Zi-Yi Lu ◽

Miao-Huei Cheng ◽

Chia-Yi Yu ◽

Yee-Shin Lin ◽

Trai-Ming Yeh ◽

...

Keyword(s):

Cell Apoptosis ◽

Nonstructural Protein ◽

Antiviral Drug ◽

Cellular Responses ◽

Denv Infection ◽

Beclin 1 ◽

Protein Inhibition ◽

Nonstructural Protein 1 ◽

Significant Public Health ◽

Related Proteins

Dengue virus (DENV) infection is a significant public health threat in tropical and subtropical regions; however, there is no specific antiviral drug. Accumulated studies have revealed that DENV infection induces several cellular responses, including autophagy and apoptosis. The crosstalk between autophagy and apoptosis is associated with the interactions among components of these two pathways, such as apoptotic caspase-mediated cleavage of autophagy-related proteins. Here, we show that DENV-induced autophagy inhibits early cell apoptosis and hence enhances DENV replication. Later, the apoptotic activities are elevated to suppress autophagy through cleavage of Beclin-1, an essential autophagy-related protein. Inhibition of cleavage of Beclin-1 by a pan-caspase inhibitor, Z-VAD, increases both autophagy and viral replication. Regarding the mechanism, we further found that DENV nonstructural protein 1 (NS1) is able to interact with Beclin-1 during DENV infection. The interaction between Beclin-1 and NS1 attenuates Beclin-1 cleavage and facilitates autophagy to prevent cell apoptosis. Our study suggests a novel mechanism whereby NS1 preserves Beclin-1 for maintaining autophagy to antagonize early cell apoptosis; however, elevated caspases trigger apoptosis by degrading Beclin-1 in the late stage of infection. These findings suggest implications for anti-DENV drug design.

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