Histology and histopathology Vol.35, nº9 (2020)

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Open Access
Expression and prognostic significance of YAP, TAZ, TEAD4 and p73 in human laryngeal cancer
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Tsinias, Georgios; Nikou, Sofia; Mastronikolis, Nicholas; Bravou, Vasiliki; Papadaki, Helen
Objectives. The Hippo signaling pathway plays a critical role in organ size control and tissue homeostasis and its perturbation is associated with tumorigenesis. YAP (Yes associated protein) and TAZ (transcriptional co-activator with PDZ- binding motif) are the major nuclear effectors of the Hippo pathway interacting with TEADs (TEA domain) and p73 transcriptional factors to regulate gene expression. Altered expression of the above proteins promotes tumor initiation, progression and metastasis in a variety of cancer types. This study addresses their expression and prognostic significance in human laryngeal carcinoma. Methods. Protein expression of YAP, TAZ, TEAD4 and p73 was examined by immunohistochemistry in 121 human laryngeal squamous cell carcinomas. Correlations with clinicopathological data and survival were evaluated. Results. All proteins were overexpressed in human laryngeal carcinomas compared to non-neoplastic adjacent epithelium. High expression of YAP, TAZ, TEAD4 and p73 correlated significantly with high grade, advanced stage, supraglottic location of tumor, nodal metastases and recurrence. Furthermore, high expression of all proteins was significantly associated with poor overall and disease- free survival. p73 expression proved to be an independent predictive factor of survival and YAP expression proved to be an independent predictive factor of disease recurrence. Conclusions. Deregulation of the expression of the Hippo pathway proteins is implicated in human laryngeal carcinogenesis and YAP and p73 have prognostic significance in the outcome of the disease
Open Access
Knockdown of ADAMDEC1 inhibits the progression of glioma in vitro
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Liu, Xueliang; Huang, Hao; Li, Xuehan; Zheng, Xiaomei; Zhou, Chong; Xue, Bin; He, Jimin; Zhang, Ye; Liu, Liang
Background. Glioma is one of the most lethal malignant tumors all over the world. The prognosis of patients with high-grade glioma remains very poor. Therefore, it is urgent to find a novel strategy for the treatment of glioma. It has been reported that ADAMDEC1 could regulate the progression of multiple diseases, including cancers. However, the role of ADAMDEC1 during the tumorigenesis of glioma remains largely unknown. Methods, Gene expression of ADAMDEC1 in glioma tissues or in cells was detected by qRT-PCR. Western blot was performed to measure the protein expressions of p53, active caspase3, active caspase9, CDK2 and Cyclin A in glioma cells. Cell proliferation was detected by CCK-8 assay. Cell apoptosis or cycle was tested by flow cytometry. Transwell was used to test the invasion of glioma cells. Results. The expression of ADAMDEC1 in glioma tissues or cells was significantly upregulated. In addition, downregulation of ADAMDEC1 notably inhibited the proliferation and induced apoptosis of glioma cells through upregulation of active caspase 3 and active caspase 9. Besides, silencing of ADAMDEC1 obviously induced G1 arrest in glioma cells via modulation of cell cycle-related proteins. Finally, knockdown of ADAMDEC1 significantly inhibited the migration and invasion of glioma cells. In contrast, overexpression of ADAMDEC1 promoted cell proliferation, migration and invasion of glioma cells. Conclusion. Downregulation of ADAMDEC1 could significantly inhibit the tumorigenesis of glioma in vitro, which may serve as a novel target for the treatment of glioma
Open Access
Angiopoietin-1 is associated with a decreased risk of lymph node metastasis in early stage cervical cancer
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Cai, E.; Yang, Dongyun; Zhang, Yifan; Cai, Jing; Sun, Si; Yang, Ping; Huang, Yuhui; Han, Qing; Xiong, Zhoufang; Wang, Shaohai
Objectives. Lymph node metastasis (LNM) is an important determinant of prognosis in patients with cervical cancer. Members of the angiopoietin family have been demonstrated to regulate tumor-associated angiogenesis and lymphangiogenesis. This study aimed to investigate the expression levels of angiopoietin-1 (ANG1) and angiopoietin-2 (ANG2) in clinically early stage of cervical cancer along with their correlations with LNM. Methods. In total, 124 human cervical cancer cases classified into stage IA-IIB in accordance with the International Federation of Gynecology and Obstetrics (FIGO) 2009 staging criteria were included. ANG1 and ANG2 expression levels in the tumor sections were assessed by immunohistochemistry (IHC). Univariate and multivariate logistic regression models, including age at diagnosis, FIGO stage, tumor size, pathological type, histological grading, depth of stromal invasion, lymph-vascular space invasion (LVSI) and the expression status of ANG1 and ANG2, were used to evaluate the odds ratios (ORs) for LNM. Results. ANG1 and ANG2 were positively expressed in 75 (60.5%) and 89 (71.8%) cervical cancers respectively, with predominant staining in the cytoplasm. ANG1 expression was significantly decreased in tumors with LNM, while no correlation was observed between ANG2 expression and LNM. More importantly, the multivariate logistic regression analysis demonstrated that high ANG1 expression was an independent protective factor of LNM (OR 0.107, 95% confidential interval [CI] 0.020~0.567), while LVSI was an independent risk factor of LNM (OR 34.313, 95% CI 5.914~199.092). Conclusion. ANG1 is associated with a significantly decreased risk of LNM in early stage cervical cancer. The predictive value and role of ANG1 in LNM needs to be further investigated in future studies.
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Follicle-stimulating hormone promotes nerve growth factor and vascular endothelial growth factor expression in epithelial ovarian cells
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Garrido, Maritza P.; Bruneau, Nicole; Vega, Margarita; Selman, Alberto; Tapia, Julio C.; Romero, Carmen
Ovarian cancer is the first cause of death for gynecological malignances in developed countries and around 80% correspond to Epithelial Ovarian Cancer (EOC). Overexpression of Nerve Growth Factor (NGF) and its high affinity receptor TRKA are involved in EOC progression, modulating several oncogenic processes such as angiogenesis by the increase of Vascular Endothelial Growth Factor (VEGF). FSH receptors (FSH-R) are present in EOC, but their changes and contribution during EOC progression are still not thoroughly known. The aims of this study were to evaluate the abundance of FSH receptors during EOC differentiation and to determine whether FSH modulates oncoproteins such as NGF and VEGF in ovarian cells. FSH-R expression in EOC tissues and cell lines (A2780, poorly differentiated EOC cells and HOSE, non-tumoral ovarian surface epithelial cells) were measured by RT- PCR and laser capture of epithelial cells from EOC samples by qPCR. FSH-R protein levels were evaluated by immunohisto/cytochemistry. Additionally, ovarian explants and ovarian cell lines were stimulated with FSH and/or FSH-R inhibitor to assess NGF and VEGF mRNA and protein levels. The results showed that FSH-R levels decreased during loss of EOC cell differentiation, nevertheless these receptors are still present in poorly differentiated EOC. FSH increased NGF expression in ovarian cells, which was prevented using a FSH-R inhibitor. Similarly, in ovarian cancer explants, FSH increased NGF and VEGF mRNA, as well as NGF protein levels. These results suggest that FSH would display a key role not only in initial stages of EOC, but also in late stages of this disease, by modulation of NGF and VEGF levels in EOC cells
Open Access
Long non-coding RNA SNHG7 promotes malignant melanoma progression through negative modulation of miR-9
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Wang, Wendi; Liu, Guangjing; Liu, Man; Li, Xiaobing
Long non-coding small nucleolar RNA host gene 7 (lncRNA SNHG7) was verified to act as an onco- gene in human cancers. Nevertheless, the role of SNHG7 in malignant melanoma remains elusive. The present study showed an increase of SNHG7 expression in malignant melanoma tissues and cell lines. Besides, SNHG7 knockdown inhibited proliferation and migration in malignant melanoma cells. Bioinformatics analysis demonstrated that SNHG7 functions as a molecular sponge for miR-9 in biological behavior of melanoma cells. And miR-9 could inhibit the expression of PI3KR3 by binding with the 3’ -UTR. Furthermore, PI3KR3, pAKT, cyclin D1 and Girdin expression was down-regulated after SNHG7 knockdown by siRNA. In addition, SNHG7 knockdown decreased xenograft growth in vivo. Taken together, this research demonstrated that SNHG7 was an oncogene in malignant melanoma, providing a novel insight for the pathogenesis and new potential therapeutic target for malignant melanoma.
Open Access
Analysis of wt1a reporter line expression levels during proepicardium formation in the zebrafish
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Andrés Delgado, Laura; Galardi Castilla, María; Mercader, Nadia; Santamaría, Luis
The epicardium is the outer mesothelial layer of the heart. It covers the myocardium and plays important roles in both heart development and regeneration. It is derived from the proepicardium (PE), groups of cells that emerges at early developmental stages from the dorsal pericardial layer (DP) close to the atrio-ventricular canal and the venous pole of the heart- tube. In zebrafish, PE cells extrude apically into the pericardial cavity as a consequence of DP tissue constriction, a process that is dependent on Bmp pathway signaling. Expression of the transcription factor Wilms tumor-1, Wt1, which is a leader of important morphogenetic events such as apoptosis regulation or epithelial-mesenchymal cell transition, is also necessary during PE formation. In this study, we used the zebrafish model to compare intensity level of the wt1a reporter line epi:GFP in PE and its original tissue, the DP. We found that GFP is present at higher intensity level in the PE tissue, and differentially wt1 expression at pericardial tissues could be involved in the PE formation process. Our results reveal that bmp2b overexpression leads to enhanced GFP level both in DP and in PE tissues
Open Access
Phosphorylated TDP-43 localizes to chronic cerebral infarctions in human brains
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Umahara, Takahiko; Uchihara, Toshiki; Hirao, Kentaro; Shimizu, Soichiro; Hanyu, Haruo
The transactivation response DNA-binding protein of 43 kDa (TDP-43) is a nuclear protein pivotal in RNA processing. Because phosphorylated TDP43 (pTDP-43) has been identified as a component of the ubiquitin-positive and tau-negative inclusions observed in the brains of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) patients, it is considered to play a major role in neurodegenerative processes. We previously reported that pTDP-43 is located in macrophages of atherosclerotic lesions of human carotid and major cerebral arteries. We hence hypothesized that pTDP-43 might be localized in the macrophages of other human brain lesions. Therefore, we investigated the immunolocalization of pTDP-43 in human brains with chronic cerebral infarction. Furthermore, we investigated the colocalization of pTDP-43 and the 14-3-3 eta isoform and found that pTDP-43 was localized in many macrophages located in chronic cerebral infarctions, in 6 out of the 15 human brains analyzed. pTDP-43 colocalized with the 14-3-3 eta isoform in these lesions. This is the first demonstration of pTDP-43 immunolocalization in chronic cerebral infarctions in human brains. We believe that our findings may be useful towards further understanding the pathophysiological roles of TDP-43 in various neurological disorders.
Open Access
PSMA expression on neovasculature of solid tumors
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Wiele, Christophe Van de; Sathekge, Mike; Spiegeleer, Bart de; Jonghe, Pieter Jan De; Debruyne, Philip R.; Borms, Marleen; Beels, Laurence; Maes, Alex
The use of prostate specific membrane antigen (PSMA) binding agents, labelled with diagnostic and therapeutic radio-isotopes is opening the potential for a new era of personalized management of prostate carcinoma. A wide variety of immuno- histochemistry studies have shown PSMA also to be upregulated on the endothelial cells of the neovasculature of a wide variety of other solid tumors where it may facilitate endothelial cell sprouting and invasion through its regulation of lytic proteases that have the ability to cleave the extracellular matrix. Similar to the introduction of PSMA-targeting theranostics in prostate carcinoma, overexpression of PSMA on newly formed tumor vessels may serve as a target for imaging and subsequent treatment of cancer through the use of agents that are capable of blocking PSMA in its function or through PSMA-mediated delivery of chemotherapeutics or radiation agents. In this review, the available data on PSMA expression on tumor neovasculature in human solid tumors assessed by using immunohistochemistry are discussed
Open Access
Comparative analysis of the expression profiles of genes related to the Gadd45α signaling pathway in four kinds of liver diseases
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Yang, Xianguang; Chen, Xuelin; Xia, Cong; Li, Shuaihong; Zhu, Lin; Xu, Cunshuan
Gadd45α (growth arrest and DNA damage inducible alpha) is a member of a group of genes whose transcript levels are increased following stressful conditions that lead to growth arrest and treatment with agents that lead to DNA damage. Gadd45α is upregulated in liver cirrhosis (LC), hepatic cancer (HC), acute liver failure (AHF) and non-alcoholic fatty liver disease(NAFLD). Here, we investigated the essential differences in the Gadd45α signaling pathway in these diseases at the transcriptional level. The results showed that 44, 46, 71 and 27 genes significant changes in these diseases, and the H-cluster showed that the expression of the Gadd45α signaling-related genes was significantly different in the four liver diseases. DAVID functional analysis showed that the Gadd45α signaling pathway- related genes were mainly involved in cell adhesion and migration, cell proliferation, apoptosis, stress and inflammatory responses, etc. Ingenuity pathway analysis (IPA) software was used to predict the functions of the Gadd45α signaling-related genes, and the results indicated that there were significant changes in cell differentiation, DNA damage repair, autophagy, apoptosis and necrosis. Gadd45α signaling pathway is involved in four kinds of liver disease and regulates a variety of activities via P38 MAPK, NF-κB, mTOR/STAT3, P21, PCNA, PI3K/Akt and other signaling pathways. Modulation of Gadd45α may be exploited to prevent the progression of liver disease, and to identify specific treatments for different stages of liver disease. In summary, the Gadd45α signaling pathway is involved in four kinds of liver disease and regulates a variety of physiological activities through various signaling pathways.
Open Access
Treatment and new progress of neonatal hypoxic-ischemic brain damage
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Yang, Lijun; Zhao, Hehua; Cui, Hong
Neonatal hypoxic ischemia (HI) results in different extents of brain damage, and immature brain tissue is particularly sensitive to the stimulation of HI. Hypoxic-ischemic brain damage (HIBD) is a common and serious nervous system disease in neonates, for both full-term infants and preterm infants, and is one of the main causes of neonatal death. The surviving infants are often associated with cerebral palsy, mental retardation, and other sequelae, which severely affect quality of life. For term infants, hypoxia and ischemia mainly affect gray matter, whereas in preterm infants, the white matter. However, up to now, inadequate standards and specific measures that can be used to treat hypoxic-ischemic brain injury are available. Recently, in addition to supportive therapy and symptomatic treatment, research on the treatment of hypoxic-ischemic brain injury has focused on the following aspects: hypothermia therapy, stem cell therapy, neuroprotective agents, ibuprofen, and combination therapy. In this review, we will summarize the treatment of HIBD and make suggestions for the future treatment direction
Open Access
Silence of FOXD2-AS1 inhibited the proliferation and invasion of esophagus cells by regulating miR-145-5p/CDK6 axis
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Shi, Woda; Gao, Zhengya; Song, Jianxiang; Wang, Wencai
This study aimed to investigate the function of long non-coding RNA FOXD2 adjacent opposite strand RNA 1 (lncRNA FOXD2-AS1) during the progression of esophagus cancer (EC) and explore its underlying molecular mechanisms. The level of FOXD2-AS1 in EC tissues and paracancerous tissues was detected by using RT-qPCR; ROC curve was used to evaluate the diagnostic value of FOXD2-AS1 for EC. In addition, CCK8 assay and immunofluorescence staining assay were used to detect the proliferation of Eca-109 and TE-1 cells. To investigate the function of FOXD2- AS1 on cell apoptosis and cell cycle, flow cytometry was performed. To detect the invasion ability of EC cells, transwell invasion assay was performed. Starbase3.0 and Targetscan were used to predict the target genes of FOXD2-AS1 and miR-145-5p, and protein expressions were detected with western blot. We found FOXD2-AS1 was significantly upregulated in EC tissues compared with adjacent normal tissues, which was positively correlated with clinicopathological parameters of patients with EC. Downregulation of FOXD2-AS1 inhibited the proliferation and invasion by inducing apoptosis of EC cells. Moreover, FOXD2-AS1 may regulate the expression of CDK6 by targeting miR- 145-3p. Meanwhile, silencing of FOXD2-AS1 caused G1 phase arrest of EC cells by reducing the expression of CDK6. In conclusion, silening FOXD2-AS1 significantly inhibited the proliferation and invasion of EC cells by regulating the miR-145-5p/CDK6 axis. Therefore, FOXD2-AS1 might be used as diagnostic biomarker and therapeutic target for EC
Open Access
Solid phase-based cross-matching for solid organ transplantation: Currently out-of-stock but urgently required for improved allograft outcome
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Schlaf, Gerald; Bau, Daniela; Horstmann, Nathalie; Sawers, Gary; Altermann, Wolfgang
Transplant recipients who have undergone sensitizing events, such as pregnancy, blood transfusion or previous transplants, frequently develop antibodies directed against the highly polymorphous human leukocyte antigen (HLA)-molecules. These pre-formed, donor-specific antibodies (DSA) present a high risk of causing organ failure or even complete loss of the grafted organ as a consequence of antibody-mediated, hyper-acute or acute allograft rejection. In order to detect DSA, the so-called functional complement- dependent lymphocytotoxicity assay (CDC-XM) was established about 50 years ago. Although effective in improving the outcome of solid organ allo-grafting, for the last ten years this assay has been controversially discussed due to its low sensitivity and especially because of its high susceptibility to various artificial factors, which generally do not yield reliable results. As a consequence, novel immunochemical test systems have been developed using ELISA- or bead-based solid phase assays as replacements for the traditional CDC- based assays. Because these assays are independent of single or vital cells, which are frequently not available, they have provided an additional and alternative diagnostic approach compared with the traditional CDC-based and flow-cytometric analyses. Unfortunately, however, the AMS-ELISA (Antibody Monitoring System), which was the first system to become commercially available, was recently discontinued by the manufacturer after seven years of successful use. Alternative procedures, such as the AbCross-ELISA, had to be either considerably modified, or did not yield reliable results, as in the case of the Luminex-based assay termed DSA. We draw the conclusion that due to the unique features and fields of application reviewed here, the implementation of solid phase cross-matching still represents an urgent requirement for any HLA-laboratory’s routine tasks
Open Access
Histone deacetylase 6 inhibitor ACY1215 ameliorates mitochondrial dynamic and function injury in hepatocytes by activating AMPK signaling pathway in acute liver failure mice
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Chen, Qian; Wang, Yao; Jiao, Fangzhou; Shi, Chunxia; Pei, Maohua; Wang, Luwen; Gong, Zuojiong
Acute liver failure (ALF) is often accompanied by dynamic and functional disorders of mitochondria in hepatocytes. The histone deacetylase 6 inhibitor Rocilinostat (ACY1215) has a hepatoprotective effect. However, its protective effect on mitochondria of hepatocytes and its related mechanisms in ALF remain unknown. The purpose of the present study was to elucidate the protective effect of ACY1215 on mitochondrial of hepatocytes in ALF by regulating AMPK signaling pathway. LPS and D-Gal were used to induce ALF model in C57BL/6 mice. D-Gal and TNF-α were applied in L02 cells as model group. ACY1215 was administered to the mice or culture cells before the model' s establishment as ACY1215 group. The normal group in mice and L02 cells was not given any drug intervention. ACY1215 improves liver histological and functional changes in ALF model mice. Compared with normal group, the expression of p-AMPK and p-ACC proteins was decreased in model group. ACY1215 activated the AMPK signaling pathway with an increase of p-AMPK and p-ACC proteins level in model group. ACY1215 treatment decreased levels of mitochondrial fission proteins DRP1 and FIS1, and enhanced levels of mitochondrial fusion proteins MFN1, MFN2 and OPA1 in models. MtDNA copies in model group was decreased compared with normal group, but ACY1215 elevated the mtDNA copies in models. Mitochondrial respiratory electron transfer chain Complex I-III and citrate synthase (CS) activities in model group were decreased compared with normal group, but ACY1215 treatment enhanced these activities in model group. ACY1215 protects against dynamic disorders and dysfunction of mitochondria in hepatocytes in ALF by activating AMPK signaling pathway.
Open Access
Merkel cells of human oral mucosa express the pluripotent stem cell transcription factor Sox2
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) García Caballero, Lucía; Caneiro, Javier; Gándara, Marina; González Ortega, Noel; Cepeda Emiliani, Alfonso; Gude, Francisco; Collado, Manuel; Gallego, Rosalía
Merkel cells are neuroendocrine cells associated to a neural sensitive ending and localized primarily in the epidermis, although they are also found in oral mucosa. Sox2 or SRY-box2 is a key transcription factor important in the maintenance of embryonic neural crest stem cell pluripotency. Sox2 has been described in Merkel cells of skin and in Merkel cell carcinomas, but not specifically in oral Merkel cells. The aims of the present study were to analyze the density of Merkel cells in human oral mucosa and to study the expression of Sox2 in these cells. For these purposes, immuno- histochemical analyses for Sox2 and CK20 (the best marker for Merkel cells) were automatically performed on sections of normal human oral mucosa. Double immunofluorescence for Sox2 and CK20 was also performed. To analyze the density of Merkel cells, CK20 positive cells were counted in each sample and the length of the epithelial apical edge was measured (cells/mm). Merkel cells, demonstrated by CK20 immunoreactivity, were found in 95% of oral mucosa specimens studied (n=21). Mean density of Merkel cells in oral mucosa was 1.71±2.34 cells/mm. Sox2 immunoreactivity was found in the nuclei of scattered cells located at the basal layer. Serial sections immunostained for Sox2 and CK20 showed that Sox2- positive cells of oral mucosa coexpressed CK20, confirming that they were Merkel cells. Immuno- fluorescence for Sox2 and CK20 showed colocalization of both markers, demonstrating that virtually all oral Merkel cells expressed Sox2. This transcription factor could play a role in Merkel cell maturation and maintenance.

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