Histology and histopathology Vol.38, nº6 (2023)
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- PublicationOpen AccessCircular RNA circLRCH3 promotes oxaliplatin resistance in gastric cancer through the modulation of the miR-383-5p/FGF7 axis(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Xiang, Chengcheng; Li, Rong; Qiu, Huizhu; Zuo, Erdong; Zhang, Yuan; Shan, Li; Cheng, XuBackground. Gastric cancer (GC) is a common malignant tumor of the digestive system. Circular RNAs (circRNAs) play a vital role in tumorigenesis and chemoresistance. The current study aimed to explore the possible role and mechanism of circRNA leucine rich repeats and calponin homology domain containing 3 (circLRCH3) in GC chemoresistance. Methods. The levels of circLRCH3, microRNA-3835p (miR-383-5p) and fibroblast growth factor 7 (FGF7) were determined by quantitative real-time PCR or Western blot. Cell Counting Kit-8 (CCK-8) assay was utilized to evaluate cell survival rate and proliferation ability. Colony formation, transwell and flow cytometry assays were used to assess cell proliferation, migration, invasion and apoptosis. The expression of multidrug resistance proteins was detected by Western blot. The binding relationship between miR-383-5p and circLRCH3/FGF7 was verified by dual-luciferase reporter assay or RNA immunoprecipitation assay. Xenograft assay was conducted to analyze the role of circLRCH3 in OXA resistance in vivo. Results. CircLRCH3 and FGF7 levels were upregulated, while miR-383-5p level was reduced in OXAresistant GC tissues and cells. Depletion of circLRCH3 attenuated the resistance of OXA-resistant cells to OXA. CircLRCH3 silence reduced OXA resistance by regulating miR-383-5p. Besides, miR-383-5p elevated OXA sensitivity of GC cells by repressing FGF7. Moreover, the deletion of circLRCH3 increased OXA sensitivity in vivo. Conclusions. Knockdown of circLRCH3 alleviated OXA resistance of GC by modulating the miR-3835p/FGF7 axis, which provided a promising therapeutic target for GC chemoresistance.
- PublicationOpen AccessTropomyosin 2 exerts anti-tumor effects in lung adenocarcinoma and is a novel prognostic biomarker(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Duan, Peng; Cui, Jing; Li, Hongyan; Yuan, LeiBackground. Tropomyosin 2 (TPM2), a member of the actin filament binding protein family, plays distinct roles in the progression of different cancer types. Until now, there has been no study reporting TPM2 expression nor its function in lung adenocarcinoma (LUAD). Methods. In the present study, we examined the expression profile of TPM2 by immunohistochemistry (IHC). The clinical significance of TPM2 was assessed by univariate and multivariate analyses. Function of TPM2 in LUAD was evaluated by knockdown and overexpression strategies in three LUAD cell lines, followed by proliferation and invasion assays. Xenografts were conducted in nude mice to further validate the tumor-related role of TPM2. Results. Our results showed that TPM2 was downregulated in LUAD specimens and the low expression of TPM2 was associated with poor outcomes of LUAD patients. Overexpressing TPM2 inhibited cell proliferation and invasion of LUAD cell lines, while silencing TPM2 exerted the opposite effects. The effects of TPM2 in LUAD were further confirmed by xenograft assays. Conclusions. Our results indicated that TPM2 exerted an anti-oncogenic role in LUAD via inhibiting tumor progression, thus providing a novel dire
- PublicationOpen AccessLncRNA UBE2R2-AS1, as prognostic marker, promotes cell proliferation and EMT in prostate cancer(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Wang, Feng; Zhao, Miao; Jiang, Yuehong; Xia, Silong; Sun, Dapeng; Zhou, Dahong; Dong, ZipuBackground. Long noncoding RNA ubiquitin-conjugating enzyme E2 R2 antisense RNA 1 (UBE2R2-AS1) has been recently reported to participate in the progression of tumors, including glioma and liver cancer. However, the roles of UBE2R2-AS1 in prostate cancer (PC) remained poorly understood. Methods. The expression of UBE2R2-AS1 was determined in tumor tissues and paired adjacent tissues from PC patients using quantitative reverse transcription PCR analysis. Correlation between UBE2R2-AS1 expression and clinicopathological parameters and overall survival were investigated by Chi-square test and Kaplan-Meier method analysis. The in vitro experiments, including CCK-8 assay, colony formation, flow cytometry and transwell assay were performed to investigate the functional role of UBE2R2-AS1 knockdown or overexpression on PC cell lines (PC-3 and DU145). Related protein expression levels were measured by western blot analysis. Results. Our data showed that UBE2R2-AS1 expression was significantly upregulated in PC tissues compared with that in adjacent tissues. The high levels of UBE2R2-AS1 were associated with high Gleason score, advanced clinical T stage, lymph node metastasis and poor prognosis. Knockdown of UBE2R2-AS1 suppressed cell proliferation, migration and invasion, induced cell cycle G0/G1 arrest and apoptosis in PC cells, along with decreased expression of PCNA, CDK4, Cyclin D1, Bcl-2, N-cadherin and Vimentin, and increased E-cadherin expression. Overexpression of UBE12R2-AS1 obtained the opposite results in PC cells. Conclusions. Our findings suggest that UBE2R2- AS1 might be a potential diagnostic and/or therapeutic target in PC.
- PublicationOpen AccessChemokine CCL14 affected the clinical outcome and correlated with immune infiltrates in thyroid carcinoma(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Zhang, Mi mi; Zhao, Yan dong; Li, Qiang; He, Yue junBackground. As an important member of the chemokines, CCL14 plays a vital role in cancer progression. However, the role of CCL14 in THCA has not been investigated. This study aimed to reveal the clinical significance of CCL14 in THCA. Material and Methods. This study evaluated the expression and prognostic value of CCL14 in THCA. Also, the correlation between CCL14 and immune infiltrates was assessed. Enrichment analysis was finally performed to predict CCL14-associated pathways involved in THCA. Results. The mRNA and protein expressions of CCL14 in THCA tissues were down-regulated compared with normal tissues. CCL14 high expression predicted favorable DFI and PFI but did not influence the DSS and OS. Further, CCL14 showed a good prediction performance on the PFI of patients. Enrichment analysis found that CCL14 was negatively correlated with migration-related pathways such as Notch signaling, ECM-receptor interaction, and cell adhesion molecules. Further, we found that CCL14 was negatively related to immune infiltrates and their gene markers. A negative relationship was also observed between CCL14 and immune checkpoint genes. These results implied the potential effect of CCL14 on the immune response and immune therapy in THCA. Conclusions. CCL14 high expression prolonged the DFI and PFI of THCA patients. It was negatively correlated with the migration-related pathways, suggesting that CCL14 might participate in the recurrence of THCA. Further, CCL14 was also shown to be important in immune response and immune therapy in THCA.
- PublicationOpen AccessExperimental models for ageing research(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Toniolo, Luana; Sirago, Giuseppe; Giacomello, EmilianaAgeing is a biological process caused by the malfunctioning of multiple cellular mechanisms, ascribable to nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These ageing pillars have three common traits: (i) they appear during normal ageing; (ii) their experimental intensification accelerates ageing; and (iii) their experimental reduction delays ageing. The evidence that the elderly are more prone to develop pathologies such as cancer, diabetes and degenerative diseases, together with data showing that the elderly population is steadily increasing, has stimulated an important effort to find specific countermeasures to physiological ageing. Unfortunately, the investigation of ageing processes and the search for countermeasures in humans is very difficult. Therefore, researchers must rely on a wide range of experimental models that span from unicellular to more complex organisms. Unfortunately, experimental models are not devoid of pitfalls, flaws or obstacles that can have an impact in ageing research. In the present review we describe the most exploited experimental models in the field, such as in vitro, animal and human models, highlighting the characteristics that justify their application in the laboratory routine, and translation to human research.
- PublicationOpen AccessCircRNA hsa_circ_0075048 promotes the malignant progression of non-small cell lung cancer by upregulating HMGB2 expression via targeting miR-1225-5p(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Zhang, Jijiong; Mao, JinjuanBackground. Non-small cell lung cancer (NSCLC) is one of the most common forms of lung cancer. Circular RNAs (circRNAs) have been recognized that can be used as novel molecular markers for cancer therapy. Here, we attempted to identify the role of hsa_circRNA_0075048 (circ_0075048) in NSCLC. Methods. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to analyze the levels of hsa_circ_0075048, miR-1225-5p and high mobility group box-2 (HMGB2). Cell proliferation was detected by Cell Counting Kit 8 (CCK8) and 5-Ethynyl-2’- deoxyuridine (EdU) assays. Flow cytometry was used to detect apoptosis. Transwell assay was used to assess cell migration and invasion. Sphere formation ability was tested by cell pellet test. The protein expression levels were detected by western blot and immunohistochemistry. Dual-luciferase reporter assay, RNA-pull down and RNA immunoprecipitation (RIP) assays were used to verify the targeting relationships between miR1225-5p and circ_0075048 or HMGB2. Mice tumor models were constructed to ascertain the effects of circ_0075048 on tumor growth in vivo. Results. Circ_0075048 was increased in NSCLC tissues and cells. NSCLC cell proliferation, migration, invasion and sphere formation ability were decreased by circ_0075048 knockdown, and cell apoptosis was induced. Downregulation of miR-1225-5p recuperated the effects of circ_0075048 knockdown on NSCLC progression. The effects of miR-1225-5p on cell proliferation, apoptosis, migration, invasion and sphere formation were attenuated by HMGB2 overexpression. Conclusion. This study indicated that circ_0075048 played an oncogenic role in the development of NSCLC by regulating miR-1225-5p and HMGB2. The data provide more possibilities for the treatment of NSCLC.
- PublicationOpen AccessSalivary gland bioengineering - yesterday, today, tomorrow!(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Iyer, Janaki; Pillai, Sangeeth; Munguia Lopez, Jose G.; Zhang, Yuli; Mielkozorova, Mariia; Tran, Simon D.Salivary glands are specialized structures developed as an extensively compact, arborized design through classical embryogenesis, accompanied by a cascade of events channelized by numerous growth factors and genetic regulatory pathways. Salivary secretions maintain oral homeostasis and, when diminished in certain conditions, present as xerostomia or salivary hypofunction, adversely impacting the patient’s quality of life. The current available treatments primarily aim at tackling the immediate symptoms providing temporary relief to the patient. Despite scientific efforts to develop permanent and effective solutions to restore salivation, a significant permanent treatment is yet to be established. Tissue engineering has proven as a promising remedial tool in several diseases, as well as in xerostomia, and aims to restore partial loss of organ function. Recapitulating the physiological cellular microenvironment to in vitro culture conditions is constantly evolving. Replicating the dynamic multicellular interactions, genetic pathways, and cytomorphogenic forces, as displayed during salivary gland development have experienced considerable barriers. Through this review, we endeavour to provide an outlook on the evolution of in vitro salivary gland research, highlighting the key bioengineering advances and the challenges faced with the current therapeutic strategies for salivary hypofunction, with an insight into our team’s scientific contributions.
- PublicationOpen AccessEarliest histopathological changes in COVID-19 pneumonia with comprehensive gene expression analyses: A case series study(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Okudela, Koji; Hayashi, Hiroyuki; Yoshimura, Yukihiro; Sasaki, Hiroaki; Miyata, Nobuyuki; Iwashita, Hiromichi; Kataoka, Toshiaki; Matsumura, Mai; Mitsui, Hideaki; Hatayama, Yasuyoshi; Yamashiro, Tsuneo; Ryo, Akihide; Tachikawa, NatsuoAims. In COVID-19 pneumonia, early detection and appropriate treatment are essential to prevent severe exacerbation. Therefore, it is important to understand the initiating events of COVID-19 pneumonia. However, at present, the literature about early stage disease has been very limited. Here, we investigated the earliest histopathological changes and gene expression profiles associated with COVID-19 pneumonia. Methods and Results. We carefully examined 25 autopsied cases with different clinical courses. Dilation of capillaries and edematous thickening of the alveolar septa were found even in areas that macroscopically looked almost normal. Pneumocytes, histocytes/ macrophages, and vascular endothelial cells were immunohistochemically positive for tissue factor, which is an important early responder to tissue injuries. Comprehensive gene expression analyses revealed that those lesions presented differential profiles compared to those of control lungs and were associated with a significant upregulation of the lysosomal pathway. Conclusions. Alveolar capillary dilation and edematous thickening may be the earliest histopathological change detected in COVID-19 pneumonia. Intensive investigations of such lesions may lead to an understanding of the initiating event of not only COVID-19 pneumonia but also of general diffuse alveolar damage.
- PublicationOpen AccessMiR-195-5p suppresses gastric adenocarcinoma cell progression via targeting OTX1(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Hu, Sizhe; Zhou, Huanting; Zhao, Xiaokang; Qian, Feng; Jin, CancanGastric adenocarcinoma (GAC) caused by malignant transformation of gastric adenocytes is a malignancy with high incidence. MiR-195-5p modulates a variety of cancers. One of its target genes, orthodenticle homeobox 1 (OTX1), is believed to be a key modulator of tumor progression. We aim to analyze the mechanism of miR-195-5p and OTX1 in GAC. MiR195-5p and OTX1 mRNA levels in GAC cells were tested via qRT-PCR. OTX1 protein and EMT-related protein levels were examined through western blot. Several cell functional assays were designed to measure changes in cell malignant behaviors. Dual luciferase assay verified the targeting relation of miR-195-5p and OTX1. These experimental results showed significantly low miR-195-5p expression and significantly high OTX1 expression in GAC cells. Enforced miR-195-5p level repressed cell malignant progression and accelerated cell apoptosis in GAC. Increased OTX1 weakened the above-mentioned effect caused by overexpressing miR-195-5p. Thus, miR-195-5p restrained migration, proliferation, invasion and epithelial-mesenchymal transition process of GAC cells, and promoted cell apoptosis through regulating OTX1. A new insight is provided for searching for biomarkers or therapeutic targets of GAC.
- PublicationOpen AccessCirc_0079530 stimulates THBS2 to promote the malignant progression of non-small cell lung cancer by sponging miR-584-5p(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2023) Fang, Kun; Deng, Yibin; Yang, Ping; Zhang, Yurong; Luo, Dan; Wang, Fang; Cai, Zhilong; Liu, YangBackground. Circ_0079530 has been confirmed to be a novel potential oncogene in non-small cell lung cancer (NSCLC). This study aims to explore the role and mechanism of circ_0079530 in NSCLC progression. Methods. Levels of circ_0079530, microRNA (miR)-584-5p, thrombospondin-2 (THBS2), PCNA, Bax, E-cadherin, and ki67 were detected by quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry. The proliferation of NSCLC cells was measured using cell counting kit 8 (CCK8) assay, colony formation assay, and EdU staining. Cell apoptosis and motility were respectively detected by flow cytometry and transwell assays. Interaction between miR-584-5p and circ_0079530 or THBS2 was predicted by bioinformatics analysis and confirmed via luciferase reporter assay and RNA immunoprecipitation (RIP) assay. A xenograft tumor model was used to analyze the role of circ_0079530 in tumor growth in vivo. Results. Circ_0079530 was highly expressed in NSCLC tissues and cell lines. Circ_0079530 overexpression facilitated proliferation, migration, and invasion whereas it restrained the apoptosis of NSCLC cells. Circ_0079530 silence showed the opposite effects on the above malignant biological behaviors. Mechanistic analysis showed that circ_0079530 functioned as a sponge of miR-584-5p to relieve the suppressive action of miR-584-5p on its target THBS2. Additionally, circ_0079530 knockdown impeded the growth of xenografts in vivo. Conclusion. Circ_0079530 promoted NSCLC progression by regulating the miR-584-5p/THBS2 axis, providing a possible circRNA-targeted therapy for NSCLC.