Yosuke Inomata  Jae-Won Oh  Kohei Taniguchi  Nobuhiko Sugito  Nao Kawaguchi  Fumitoshi Hirokawa  Sang-Woong Lee  Yukihiro Akao  Shinji Takai  Kwang-Pyo Kim  Kazuhisa Uchiyama 《International journal of molecular sciences》2022,23(9)

Non-alcoholic steatohepatitis (NASH) has pathological characteristics similar to those of alcoholic hepatitis, despite the absence of a drinking history. The greatest threat associated with NASH is its progression to cirrhosis and hepatocellular carcinoma. The pathophysiology of NASH is not fully understood to date. In this study, we investigated the pathophysiology of NASH from the perspective of glycolysis and the Warburg effect, with a particular focus on microRNA regulation in liver-specific macrophages, also known as Kupffer cells. We established NASH rat and mouse models and evaluated various parameters including the liver-to-body weight ratio, blood indexes, and histopathology. A quantitative phosphoproteomic analysis of the NASH rat model livers revealed the activation of glycolysis. Western blotting and immunohistochemistry results indicated that the expression of pyruvate kinase muscle 2 (PKM2), a rate-limiting enzyme of glycolysis, was upregulated in the liver tissues of both NASH models. Moreover, increases in PKM2 and p-PKM2 were observed in the early phase of NASH. These observations were partially induced by the downregulation of microRNA122-5p (miR-122-5p) and occurred particularly in the Kupffer cells. Our results suggest that the activation of glycolysis in Kupffer cells during NASH was partially induced by the upregulation of PKM2 via miR-122-5p suppression.  相似文献   

    

Nam Cong-Nhat Huynh  Tze-Ta Huang  Chi Thi-Kim Nguyen  Fang-Kuei Lin 《International journal of molecular sciences》2022,23(12)

Cancer-associated fibroblasts (CAFs) and partial epithelial–mesenchymal transition (p-EMT) tumor cells are closed together and contribute to the tumor progression of oral squamous cell carcinoma (OSCC). In the present study, we deeply analyzed and integrated OSCC single-cell RNA sequencing datasets to define OSCC CAFs and p-EMT subpopulations. We highlighted the cell–cell interaction network of CAFs and p-EMT tumor cells and suggested biomarkers for the diagnosis and prognosis of OSCC during the metastasis condition. The analysis discovered four subtypes of CAFs: one p-EMT tumor cell population, and cycling tumor cells as well as TNFSF12-TNFRSF25/TNFRSF12A interactions between CAFs and p-EMT tumor cells during tumor metastasis. This suggests the prediction of therapeutically targetable checkpoint receptor–ligand interactions between CAFs and p-EMT tumor cells in OSCC regarding the metastasis status.  相似文献   

    

Ramona Erber  Steffen Spoerl  Andreas Mamilos  Rosemarie Krupar  Arndt Hartmann  Matthias Ruebner  Juergen Taxis  Mareike Wittenberg  Torsten E. Reichert  Gerrit Spanier  Silvia Spoerl 《International journal of molecular sciences》2022,23(1)

Oral cancer often presents with aggressive behavior and a high risk of recurrence and metastasis. For oral squamous cell carcinoma (OSCC), which is the most frequent histological subtype, therapy strategies include surgery, radiation therapy, chemotherapy, immune checkpoint inhibitors, and EGFR inhibitors. Recently, a Trop-2 antibody-drug conjugate (ADC) has been approved in the United States of America for the treatment of advanced triple-negative breast cancer. However, this ADC has also been tested in other solid tumors including head & neck squamous cell carcinoma. The prognostic impact of Trop-2 has already been reported for several cancers. We studied the prognostic influence of Trop-2 protein expression on OSCC patients’ survival. The cohort comprised n = 229 OSCC patients with available archived tumor tissue and corresponding non-neoplastic oral mucosa tissue. Using immunohistochemistry, we investigated Trop-2 expression in both the central and peripheral regions of each tumor and in corresponding non-neoplastic oral mucosa. In patients suffering from OSCC with combined high central and low peripheral Trop-2 expression, five-year overall survival (OS) was 41.2%, whereas 55.6% of OSCC patients who presented lower central and/or higher peripheral tumoral Trop-2 expression were alive after five years (p = 0.075). In multivariate Cox regression, the expression pattern of high central tumoral and lower peripheral Trop-2 expression was significantly correlated with impaired OS (HR = 1.802, 95%-CI: 1.134–2.864; p = 0.013) and recurrence-free survival (RFS) (HR = 1.633, 95%-CI: 1.042–2.560; p = 0.033), respectively, when adjusting for co-variables. Hence, Trop-2 may serve as an independent prognostic biomarker in OSCC. In subsequent studies, the pathophysiological meaning of downregulated Trop-2 expression in the OSCC periphery has to be analyzed.  相似文献   

    

Ildik Krencz  Enik&#x; Vetlnyi  Titanilla Dank  Gbor Pet&#x;vri  Dorottya Moldvai  Dniel Sztankovics  Regina Raffay  Katalin Mszros  Endre Sebestyn  Gyula Vgs&#x;  Judit Ppay  Anna Sebestyn 《International journal of molecular sciences》2022,23(18)

Metabolic characteristics of kidney cancers have mainly been obtained from the most frequent clear cell renal cell carcinoma (CCRCC) studies. Moreover, the bioenergetic perturbances that affect metabolic adaptation possibilities of papillary renal cell carcinoma (PRCC) have not yet been detailed. Therefore, our study aimed to analyze the in situ metabolic features of PRCC vs. CCRCC tissues and compared the metabolic characteristics of PRCC, CCRCC, and normal tubular epithelial cell lines. The protein and mRNA expressions of the molecular elements in mammalian target of rapamycin (mTOR) and additional metabolic pathways were analyzed in human PRCC cases compared to CCRCC. The metabolic protein expression pattern, metabolite content, mTOR, and metabolic inhibitor sensitivity of renal carcinoma cell lines were also studied and compared with tubular epithelial cells, as “normal” control. We observed higher protein expressions of the “alternative bioenergetic pathway” elements, in correlation with the possible higher glutamine and acetate consumption in PRCC cells instead of higher glycolytic and mTOR activity in CCRCCs. Increased expression of certain metabolic pathway markers correlates with the detected differences in metabolite ratios, as well. The lower lactate/pyruvate, lactate/malate, and higher pyruvate/citrate intracellular metabolite ratios in PRCC compared to CCRCC cell lines suggest that ACHN (PRCC) have lower Warburg glycolytic capacity, less pronounced pyruvate to lactate producing activity and shifted OXPHOS phenotype. However, both studied renal carcinoma cell lines showed higher mTOR activity than tubular epithelial cells cultured in vitro, the metabolite ratio, the enzyme expression profiles, and the higher mitochondrial content also suggest increased importance of mitochondrial functions, including mitochondrial OXPHOS in PRCCs. Additionally, PRCC cells showed significant mTOR inhibitor sensitivity and the used metabolic inhibitors increased the effect of rapamycin in combined treatments. Our study revealed in situ metabolic differences in mTOR and metabolic protein expression patterns of human PRCC and CCRCC tissues as well as in cell lines. These underline the importance in the development of specific new treatment strategies, new mTOR inhibitors, and other anti-metabolic drug combinations in PRCC therapy.  相似文献   

    

Patrik Palacka  Anna Gvozdjkov  Zuzana Rausov  Jarmila Kucharsk  Jn Slopovský  Jana Obertov  Daniel Furka  Samuel Furka  Keshav K. Singh  Zuzana Sumbalov 《International journal of molecular sciences》2022,23(1)

Mitochondrial bioenergetics reprogramming is an essential response of cells to stress. Platelets, an accessible source of mitochondria, have a crucial role in cancer development; however, the platelet mitochondrial function has not been studied in urothelial carcinoma (UC) patients. A total of 15 patients with UC and 15 healthy controls were included in the study. Parameters of platelet mitochondrial respiration were evaluated using the high-resolution respirometry method, and the selected antioxidant levels were determined by HPLC. In addition, oxidative stress was evaluated by the thiobarbituric acid reactive substances (TBARS) concentration in plasma. We demonstrated deficient platelet mitochondrial respiratory chain functions, oxidative phosphorylation (OXPHOS), and electron transfer (ET) capacity with complex I (CI)-linked substrates, and reduced the endogenous platelet coenzyme Q₁₀ (CoQ₁₀) concentration in UC patients. The activity of citrate synthase was decreased in UC patients vs. controls (p = 0.0191). γ-tocopherol, α-tocopherol in platelets, and β-carotene in plasma were significantly lower in UC patients (p = 0.0019; p = 0.02; p = 0.0387, respectively), whereas the plasma concentration of TBARS was increased (p = 0.0022) vs. controls. The changes in platelet mitochondrial bioenergetics are consistent with cell metabolism reprogramming in UC patients. We suppose that increased oxidative stress, decreased OXPHOS, and a reduced platelet endogenous CoQ₁₀ level can contribute to the reprogramming of platelet mitochondrial OXPHOS toward the activation of glycolysis. The impaired mitochondrial function can contribute to increased oxidative stress by triggering the reverse electron transport from the CoQ₁₀ cycle (Q-junction) to CI.  相似文献   

    

Niklas Harland  Florian B. Maurer  Tanja Abruzzese  Cornelia Bock  Ivonne A. Montes-Mojarro  Falko Fend  Wilhelm K. Aicher  Arnulf Stenzl  Bastian Amend 《International journal of molecular sciences》2022,23(9)

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Alexander Michael Grandits  Sophie Bromberger  Gerwin Heller  Barbara Andrea Reinoehl  Erwin Tomasich  Klaudia Schossleitner  Anna Sophie Berghoff  Thorsten Fuereder  Rotraud Wieser 《International journal of molecular sciences》2022,23(3)

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Samuel Swearson  Aseel O. Rataan  Steven Eliason  Brad A. Amendt  Yousef Zakharia  Aliasger K. Salem  Thai Ho  Youcef M. Rustum 《International journal of molecular sciences》2022,23(10)

This study was carried out to quantitate the expression levels of microRNA-17, -19a, -34a, -155, and -210 (miRs) expressed in nine clear cell renal cell carcinoma (ccRCC) and one chromophobe renal cell carcinoma cell line with and without sarcomatoid differentiation, and in six primary kidney tumors with matching normal kidney tissues. The data in the five non-sarcomatoid ccRCC cell lines—RC2, CAKI-1, 786-0, RCC4, and RCC4/VHL—and in the four ccRCC with sarcomatoid differentiation—RCJ41T1, RCJ41T2, RCJ41M, and UOK-127—indicated that miR-17 and -19a were expressed at lower levels relative to miR-34a, -155, and -210. Compared with RPTEC normal epithelial cells, miR-34a, miR-155, and miR-210 were expressed at higher levels, independent of the sarcomatoid differentiation status and hypoxia-inducible factors 1α and 2α (HIFs) isoform expression. In the one chromophobe renal cell carcinoma cell line, namely, UOK-276 with sarcomatoid differentiation, and expressing tumor suppressor gene TP53, miR-34a, which is a tumor suppressor gene, was expressed at higher levels than miR-210, -155, -17, and -19a. The pilot results generated in six tumor biopsies with matching normal kidney tissues indicated that while the expression of miR-17 and -19a were similar to the normal tissue expression profile, miR-210, -155, -and 34a were expressed at a higher level. To confirm that differences in the expression levels of the five miRs in the six tumor biopsies were statistically significant, the acquisition of a larger sample size is required. Data previously generated in ccRCC cell lines demonstrating that miR-210, miR-155, and HIFs are druggable targets using a defined dose and schedule of selenium-containing molecules support the concept that simultaneous and concurrent downregulation of miR-210, miR-155, and HIFs, which regulate target genes associated with increased tumor angiogenesis and drug resistance, may offer the potential for the development of a novel mechanism-based strategy for the treatment of patients with advanced ccRCC.  相似文献   

    

Yi-Chung Lin  Bor-Sen Chen 《International journal of molecular sciences》2022,23(18)

In this study, we provide a systems biology method to investigate the carcinogenic mechanism of oral squamous cell carcinoma (OSCC) in order to identify some important biomarkers as drug targets. Further, a systematic drug discovery method with a deep neural network (DNN)-based drug–target interaction (DTI) model and drug design specifications is proposed to design a potential multiple-molecule drug for the medical treatment of OSCC before clinical trials. First, we use big database mining to construct the candidate genome-wide genetic and epigenetic network (GWGEN) including a protein–protein interaction network (PPIN) and a gene regulatory network (GRN) for OSCC and non-OSCC. In the next step, real GWGENs are identified for OSCC and non-OSCC by system identification and system order detection methods based on the OSCC and non-OSCC microarray data, respectively. Then, the principal network projection (PNP) method was used to extract core GWGENs of OSCC and non-OSCC from real GWGENs of OSCC and non-OSCC, respectively. Afterward, core signaling pathways were constructed through the annotation of KEGG pathways, and then the carcinogenic mechanism of OSCC was investigated by comparing the core signal pathways and their downstream abnormal cellular functions of OSCC and non-OSCC. Consequently, HES1, TCF, NF-κB and SP1 are identified as significant biomarkers of OSCC. In order to discover multiple molecular drugs for these significant biomarkers (drug targets) of the carcinogenic mechanism of OSCC, we trained a DNN-based drug–target interaction (DTI) model by DTI databases to predict candidate drugs for these significant biomarkers. Finally, drug design specifications such as adequate drug regulation ability, low toxicity and high sensitivity are employed to filter out the appropriate molecular drugs metformin, gefitinib and gallic-acid to combine as a potential multiple-molecule drug for the therapeutic treatment of OSCC.  相似文献   

    

Ioana Rusu  Radu Pirlog  Paul Chiroi  Andreea Nutu  Vlad Radu Puia  Alin Cornel Fetti  Daniel Radu Rusu  Ioana Berindan-Neagoe  Nadim Al Hajjar 《International journal of molecular sciences》2022,23(20)

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide. Meanwhile, liver cancer represents the sixth most common malignancy, with hepatocellular carcinoma (HCC) as the primary, most prevalent subtype. Due to the rising incidence of metabolic disorders, NAFLD has become one of the main contributing factors to HCC development. However, although NAFLD might account for about a fourth of HCC cases, there is currently a significant gap in HCC surveillance protocols regarding noncirrhotic NAFLD patients, so the majority of NAFLD-related HCC cases were diagnosed in late stages when survival chances are minimal. However, in the past decade, the focus in cancer genomics has shifted towards the noncoding part of the genome, especially on the microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which have proved to be involved in the regulation of several malignant processes. This review aims to summarize the current knowledge regarding some of the main dysregulated, noncoding RNAs (ncRNAs) and their implications for NAFLD and HCC development. A central focus of the review is on miRNA and lncRNAs that can influence the progression of NAFLD towards HCC and how they can be used as potential screening tools and future therapeutic targets.  相似文献