Histology and histopathology Vol.36,nº10 (2021)

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Open Access
Mitochondrial support and local translation of mitochondrial proteins in synaptic plasticity and function
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Liang, YongTian
Complex neural and brain functions are executed through structural and functional alterations of synapses and neurons. Neuronal compartmentalization requires neurons to allocate mitochondria and proteins in a spatiotemporal manner to allow their plasticity, function and homeostasis. Importantly, mitochondria are known to interact with and modulate synaptic activities through their ATP supply, calcium buffering and signaling abilities. Over the years, mitochondrial support and local translation (including mitochondrial proteins) at neuronal sub-compartments and their synaptic specializations have been considered critical for maintaining synaptic plasticity and function. Recently, evidence has shown that late endosomes can serve as sites for local translation of mRNAs crucial for mitochondrial integrity and mitochondrial compartments can fuel plasticity-induced local translation. Indeed, failed mitochondrial homeostasis and subsequent synaptic dysfunction are often intricately linked in the malfunction of the central nervous system in synaptic aging and diseases. In this review, I will discuss the critical role of local translation (including mitochondrial proteins) in dendrites, axons and synapses on neuronal/synaptic plasticity and function.
Open Access
High FITM2 expression promotes cell migration ability of hepatocellular carcinoma by regulating the formation of caveolae and indicates poor patient survival
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Chen, Yan; Ji, Li-juan; Wang, Yan; Guo, Xiang-Feng
Background. Hepatocellular carcinoma (HCC) is among the most malignant tumors with high recurrence and low 5-year survival rate. Lipid metabolism is essential in tumor metastasis, although how altered lipid metabolism promotes HCC progression has not been well elucidated. Fat Storage Inducing Transmembrane Protein 2 (FITM2) is a gene involved in lipid homeostasis and cytoskeletal organization; however, its role in regulating tumor biological behavior has not been evaluated. Methods. In this study, immunohistochemistry was performed to evaluate the expression of FITM2 in HCC. Univariate and multivariate analysis was performed to identify the prognostic factors. RNA interference wound healing and transwell experiments were performed to analyze the biological role of FITM2. Western blot analysis was performed to investigate the potential downstream signaling. Results. The results revealed that FITM2 was highly expressed in the intratumoral tissues of HCC. Expression of intratumoral FITM2 was associated with microvascular invasion. FITM2 is an independent risk factor of HCC disease-free survival and overall survival. In vitro studies revealed that knockdown of FITM2 significantly inhibited the migration ability of HCC cells. FITM2 promotes HCC cell migration by regulating the expression of caveolin-1 and promoting the formation of caveolae. These results indicate that high intratumoral expression of FITM2 is associated with poor HCC prognosis, which may be applied to develop a new adjuvant therapy
Open Access
Prognostic significance of E-cadherin, β-catenin and cyclin D1 in oral squamous cell carcinoma: a tissue microarray study
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Al-Rawi, Natheer; Al Ani, Muwaffaq; Quadri, Asif; Hamdoon, Zaid; Awwad, Aktham; Al Kawas, Sausan; Al Nuaim, Ahmed
Objective. To study the prognostic significance of E-cadherin, β-catenin, and cyclin D1 expression in oral squamous cell carcinoma. Subjects and Methods. The study included 65 subjects with histologically confirmed squamous cell carcinoma. TMA blocks were prepared for immunohistochemical quantification of the expression of the three markers using IHC profiler and Immune ratio plugin of Image J. Results. E-cadherin expression was significantly correlated with histological grades and the metastasis status (p<0.05), whereas β-catenin expression was significantly correlated with smoking and tumor recurrence (P<0.05). Cyclin D1 expression was significantly correlated with depth of invasion and tumor recurrence. (p<0.05). Advanced tumor stage and depth of tumor invasion increases the risk of recurrence or death by 2.5 times (OR=2.53 and 0.84 respectively). Conclusion. High expression of β-catenin and cyclin D1 are significantly correlated with tumor recurrence and old age. Depth of invasion, low histological grade and old age were a significant predictor for the risk of having tumor recurrence and cancer related death.
Open Access
Immunohistological score of transcription factor 21 had a positive correlation with its urinary excretion and proteinuria in immunoglobulin a nephropathy
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Takahashi-Kobayashi, Mayumi; Usui, Joichi; Yaguchi, Misa; Yamazaki, Satoshi; Kawamura, Tetsuya; Kaneko, Shuzo; Seshan, Surya V; Yamagata, Kunihiro
Transcription factor 21 (TCF21) contributes to mammalian nephrogenesis, and especially to glomerular maturation. Our previous study suggested its influence on glomerular injury, showing that TCF21 expression in podocytes had a positive correlation with the urinary protein value and also with the urinary TCF21 concentration. We now focus on its influence on the clinical course of immunoglobulin A nephropathy (IgAN), as patients with IgAN constitute the largest population of individuals with primary chronic glomerulonephritis in the world. Twenty cases of IgAN were divided into two groups according to the immunohistological score (IHS) of glomerular TCF21 expression: group IHS1 (n=7) and group IHS2+3 (n=13). Sixteen of the 20 cases were followed up for 2 years. Group IHS2+3 had heavier urinary protein (p=0.03) and a greater urinary TCF21 level (p<0.001) compared to group IHS1 at baseline. None of the other factors including hematuria, estimated glomerular filtration rate (eGFR), or the Oxford classification showed a statistically significant difference between these two groups. At the 2-year follow-up, even though the rate of remission in urinary protein, hematuria and the eGFR decline were not statistically correlated to IHS, the IHS2+3 group had a slight tendency toward a steeper eGFR decline compared to IHS1 (p=0.31). The present study suggested that the higher IHS of TCF21 corresponded to heavier proteinuria and a higher urinary TCF21 level in IgAN. This could be the first step in determining the TCF21 value for predicting the prognosis for IgAN.
Open Access
D-2-hydroxyglutarate dehydrogenase in breast carcinoma as a potent prognostic marker associated with proliferation
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Hayashi, Chiaki; Takagi, Kiyoshi; Sato, Ai; Yamaguchi, Mio; Minemura, Hiroyuki; Miki, Yasuhiro; Harada-Shoji, Narumi; Miyashita, Minoru; Sasano, Hironobu; Suzuki, Takashi
Background. D-2-hydroxyglutarate dehydrogenase (D2HGDH) catalyzes D-2-hydroxyglutarate to α-ketoglutarate and is involved in the regulation of cellular energy and biosynthetic intermediates. Previously, D2HGDH was reported to decrease 2-hydroxyglutarate level in breast carcinoma cells, but no other report has examined D2HGDH in breast carcinoma, and its significance remains unknown. Methods. We first immunolocalized D2HGDH in 224 invasive breast carcinomas and evaluated its clinicopathological significance. We next examined associations between gene expression of D2HGDH and α-ketoglutarate-dependent dioxygenases in 23 breast carcinoma tissues using the gene expression profile data. Finally, we examined the effects of D2HGDH on the proliferation in three breast carcinoma cells. Results. D2HGDH immunoreactivity was detected in 49% of invasive breast carcinomas, and the immunohistochemical D2HGDH status was positively associated with histological grade, HER2 and Ki-67, while it was inversely associated with estrogen receptor. Moreover, it was significantly associated with worse prognosis of the breast cancer patients, and it turned out to be an independent prognostic factor for both the disease-free and breast cancer-specific survival in these patients. Gene expression profile data revealed that D2HGDH expression was positively associated with the expression of 6 α-ketoglutarate-dependent dioxygenases (KDM3A, PLOD1, EGLN2, ALKBH1, ASPH and ALKBH7). Consequent in vitro experiments demonstrated that D2HGDH overexpression significantly increased the cell proliferation activity of MCF-7, T47D and MDA-MB-231 cells. Conclusion. These results suggest that D2HGDH plays an important role in the growth of breast carcinoma, possibly through regulating functions of αketoglutarate-dependent dioxygenases, and that D2HGDH status is a potent worse prognostic factor in breast cancer patients
Open Access
The pathologic diagnosis of mantle cell lymphoma
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Li, Shaoying; Xu, Jie; You, James
Mantle cell lymphoma (MCL) is a mature Bcell non-Hodgkin lymphoma usually characterized by t(11;14) (q13;q32), or CCND1 translocation and Cyclin D1 over expression. A very small subset of MCL may lack the t(11;14) (q13;q32) translocation and Cyclin D1 over expression, but show alternative translocations involving CCND2 and CCND3, and over expression of SOX11. In general, MCL has been considered a very aggressive and incurable lymphoma and patients with MCL usually have a poor prognosis. However, indolent variants, including in situ mantle cell neoplasm and the recently recognized leukemic non-nodal MCL do exist. In recent years, genome-wide molecular genetic studies have revealed a characteristic MCL genetic profile. This review will focus on the pathologic diagnosis of MCL using the traditional morphological and immunophenotypic strategies combined with cytogenetic characteristics and recently identified molecular profile. Morphological subtypes, immunophenotypic variants, recently recognized indolent variants, as well as MCL risk stratification will also be discussed.
Open Access
Long non-coding RNA-KCNQ1OT1 mediates miR-423-5p/microfibril-associated protein 2 axis in colon adenocarcinoma
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Yin, Xunhai; Jiang, Amín; Ma, Zhibin; Lu, Xi; Li, Dongyue; Chen, Yingying
Backgrounds. Long non-coding RNAs (lncRNAs) function as competing endogenous RNAs (ceRNAs) that contribute to carcinogenesis. Herein, we plan to explore whether lncRNA KCNQ1OT1 modulated miR-423-5p/microfibril-associated protein 2 (MFAP2) signaling axis is implicated in the progression of human colon adenocarcinoma. Material and methods. Clinical specimens were collected for histologic examination and gene expression analysis. In vitro experimental measurements, including CCK8, transwell and TUNEL staining, were performed to evaluate cell proliferation, migration and apoptosis. Results. up-regulation of KCNQ1OT1 and MFAP2 and down-regulation of miR-423-5p in COAD tissues were substantiated by The Cancer Genome Atlas (TCGA) database and our clinical specimens. In vitro experimental measurements exhibited that knockdown of KCNQ1OT1 facilitated miR-423-5p expression and inhibited MFAP2 expression, simultaneously. Transfection of si-KCNQ1OT1, miR-423-5p mimics or si-MFAP2 had the ability to repress malignant phenotypes of COAD cells. Intriguingly, overexpression of MFAP2 restrained si-KCNQ1OT1- or miR-423-5p mimics-induced the inhibition of cell proliferation and migration and elevation of the apoptotic proportion of COAD cells. Conclusions. KCNQ1OT1 serves as a molecular sponge of miR-423-5p to accelerate the expression of MFAP2 that may be involved in the development of COAD. Our findings present a novel signaling axis KCNQ1OT1/miR-423-5p/MFAP2, which provides a theoretical basis and therapeutic target for the treatment of COAD.
Open Access
The hypertrophic chondrocyte: To be or not to be
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Hallett, Shawn A.; Ono, Wanida; Ono, Noriaki
Hypertrophic chondrocytes are the master regulators of endochondral ossification; however, their ultimate cell fates cells remain largely elusive due to their transient nature. Historically, hypertrophic chondrocytes have been considered as the terminal state of growth plate chondrocytes, which are destined to meet their inevitable demise at the primary spongiosa. Chondrocyte hypertrophy is accompanied by increased organelle synthesis and rapid intracellular water uptake, which serve as the major drivers of longitudinal bone growth. This process is delicately regulated by major signaling pathways and their target genes, including growth hormone (GH), insulin growth factor-1 (IGF-1), indian hedgehog (Ihh), parathyroid hormone-related protein (PTHrP), bone morphogenetic proteins (BMPs), sex determining region Y-box 9 (Sox9), runt-related transcription factors (Runx) and fibroblast growth factor receptors (FGFRs). Hypertrophic chondrocytes orchestrate endochondral ossification by regulating osteogenic-angiogenic and osteogenic-osteoclastic coupling through the production of vascular endothelial growth factor (VEGF), receptor activator of nuclear factor kappa-B ligand (RANKL) and matrix metallopeptidases-9/13 (MMP-9/13). Hypertrophic chondrocytes also indirectly regulate resorption of the cartilaginous extracellular matrix, by controlling formation of a special subtype of osteoclasts termed "chondroclasts". Notably, hypertrophic chondrocytes may possess innate potential for plasticity, reentering the cell cycle and differentiating into osteoblasts and other types of mesenchymal cells in the marrow space. We may be able to harness this unique plasticity for therapeutic purposes, for a variety of skeletal abnormalities and injuries. In this review, we discuss the morphological and molecular properties of hypertrophic chondrocytes, which carry out important functions during skeletal growth and regeneration.
Open Access
LncRNA ADAMTS9-AS1 knockdown restricts cell proliferation and EMT in non-small cell lung cancer
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Li, Zhongwen; Yue, Guojun; Zhang, Tingyou; Wu, Jinzhi; Tian, Xin
A recent bioinformatics analysis identified long non‐coding RNA antisense 1 ADAMTS9-AS1 as an independent prognostic marker in several tumors, including prostate cancer and bladder cancer. Nevertheless, the prognostic value and functional role of ADAMTS9-AS1 in non-small cell lung cancer (NSCLC) remain elusive. Here, we first found that the expression of ADAMTS9-AS1 was significantly upregulated in NSCLC tissues compared with adjacent normal tissues using quantitative real time PCR analysis. Clinically, we observed that ADAMTS9-AS1 expression was associated with TNM stage, lymph node metastasis and poor prognosis in NSCLC patients. By performing lossof-function assay in A549 and 95D cells, our in vitro experiments further showed that knockdown of ADAMTS9-AS1 remarkedly suppressed cell proliferation, caused cell cycle G0/G1 arrest and apoptosis, and inhibited cell migration and invasion in NSCLC cells using CCK-8, colony formation, flow cytometry and transwell assays. Moreover, we found that ADAMTS9-AS1 knockdown downregulated the expression of CDK4, N-cadherin, Vimentin, but upregulated the expression of Bad and E-cadherin. In summary, our results revealed that ADAMTS9-AS1 may serve as a potential therapeutic target for the treatment of patients with NSCLC

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