Cells

2022

Jump to: 2021, 2020

18 pages, 3659 KiB

Open AccessArticle

Carbon Ion Irradiation Downregulates Notch Signaling in Glioma Cell Lines, Impacting Cell Migration and Spheroid Formation

by Vivek Kumar, Mohit Vashishta, Lin Kong, Jiade J. Lu, Xiaodong Wu, Bilikere S. Dwarakanath and Chandan Guha

Cells 2022, 11(21), 3354; https://doi.org/10.3390/cells11213354 - 24 Oct 2022

Cited by 3 | Viewed by 2181

Abstract

Photon-based radiotherapy upregulates Notch signaling in cancer, leading to the acquisition of the stem cell phenotype and induction of invasion/migration, which contributes to the development of resistance to therapy. However, the effect of carbon ion radiotherapy (CIRT) on Notch signaling in glioma and [...] Read more.

Photon-based radiotherapy upregulates Notch signaling in cancer, leading to the acquisition of the stem cell phenotype and induction of invasion/migration, which contributes to the development of resistance to therapy. However, the effect of carbon ion radiotherapy (CIRT) on Notch signaling in glioma and its impact on stemness and migration is not explored yet. Human glioma cell lines (LN229 and U251), stable Notch1 intracellular domain (N1ICD) overexpressing phenotype of LN229 cells, and Notch inhibitor resistant LN229 cells (LN229R) were irradiated with either photon (X-rays) or (carbon ion irradiation) CII, and expressions of Notch signaling components were accessed by RT-PCR, Western blotting, and enzymatic assays and flow cytometry. Spheroid forming ability, cell migration, and clonogenic assay were used to evaluate the effect of modulated Notch signaling by irradiation. Our results show that X-ray irradiation induced the expression of Notch signaling components such as Notch receptors, target genes, and ADAM17 activity, while CII reduced it in glioma cell lines. The differential modulation of ADAM17 activity by CII and X-rays affected the cell surface levels of NOTCH1 and NOTCH2 receptors, as they were reduced by X-ray irradiation but increased in response to CII. Functionally, CII reduced the spheroid formation and migration of glioma cells, possibly by downregulating the N1ICD, as stable overexpression of N1ICD rescued these inhibitory effects of CII. Moreover, LN229R that are less reliant on Notch signaling for their survival showed less response to CII. Therefore, downregulation of Notch signaling resulting in the suppression of stemness and impaired cell migration by CII seen here may reduce tumor regrowth and disease dissemination, in addition to the well-established cytotoxic effects. Full article

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18 pages, 767 KiB

Open AccessReview

MicroRNAs and Long Non-Coding RNAs in Adrenocortical Carcinoma

by Mario Detomas, Claudia Pivonello, Bianca Pellegrini, Laura-Sophie Landwehr, Silviu Sbiera, Rosario Pivonello, Cristina L. Ronchi, Annamaria Colao, Barbara Altieri and Maria Cristina De Martino

Cells 2022, 11(14), 2234; https://doi.org/10.3390/cells11142234 - 18 Jul 2022

Cited by 8 | Viewed by 2690

Abstract

Non-coding RNAs (ncRNAs) are a type of genetic material that do not encode proteins but regulate the gene expression at an epigenetic level, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The role played by ncRNAs in many physiological and pathological processes [...] Read more.

Non-coding RNAs (ncRNAs) are a type of genetic material that do not encode proteins but regulate the gene expression at an epigenetic level, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The role played by ncRNAs in many physiological and pathological processes has gained attention during the last few decades, as they might be useful in the diagnosis, treatment and management of several human disorders, including endocrine and oncological diseases. Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine cancer, still characterized by high mortality and morbidity due to both endocrine and oncological complications. Despite the rarity of this disease, recently, the role of ncRNA has been quite extensively evaluated in ACC. In order to better explore the role of the ncRNA in human ACC, this review summarizes the current knowledge on ncRNA dysregulation in ACC and its potential role in the diagnosis, treatment, and management of this tumor. Full article

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17 pages, 1976 KiB

Open AccessArticle

miR-126-3p and miR-21-5p as Hallmarks of Bio-Positive Ageing; Correlation Analysis and Machine Learning Prediction in Young to Ultra-Centenarian Sicilian Population

by Giulia Accardi, Filippa Bono, Giuseppe Cammarata, Anna Aiello, Maria Trinidad Herrero, Riccardo Alessandro, Giuseppa Augello, Ciriaco Carru, Paolo Colomba, Maria Assunta Costa, Immaculata De Vivo, Mattia Emanuela Ligotti, Alessia Lo Curto, Rosa Passantino, Simona Taverna, Carmela Zizzo, Giovanni Duro, Calogero Caruso and Giuseppina Candore

Cells 2022, 11(9), 1505; https://doi.org/10.3390/cells11091505 - 30 Apr 2022

Cited by 11 | Viewed by 2875

Abstract

Human ageing can be characterized by a profile of circulating microRNAs (miRNAs), which are potentially predictors of biological age. They can be used as a biomarker of risk for age-related inflammatory outcomes, and senescent endothelial cells (ECs) have emerged as a possible source [...] Read more.

Human ageing can be characterized by a profile of circulating microRNAs (miRNAs), which are potentially predictors of biological age. They can be used as a biomarker of risk for age-related inflammatory outcomes, and senescent endothelial cells (ECs) have emerged as a possible source of circulating miRNAs. In this paper, a panel of four circulating miRNAs including miR-146a-5p, miR-126-3p, miR-21-5p, and miR-181a-5p, involved in several pathways related to inflammation, and ECs senescence that seem to be characteristic of the healthy ageing phenotype. The circulating levels of these miRNAs were determined in 78 healthy subjects aged between 22 to 111 years. Contextually, extracellular miR-146a-5p, miR-126-3p, miR-21-5p, and miR-181a-5p levels were measured in human ECs in vitro model, undergoing senescence. We found that the levels of the four miRNAs, using ex vivo and in vitro models, progressively increase with age, apart from ultra-centenarians that showed levels comparable to those measured in young individuals. Our results contribute to the development of knowledge regarding the identification of miRNAs as biomarkers of successful and unsuccessful ageing. Indeed, they might have diagnostic/prognostic relevance for age-related diseases. Full article

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17 pages, 3038 KiB

Open AccessArticle

Effects of the Mutant TP53 Reactivator APR-246 on Therapeutic Sensitivity of Pancreatic Cancer Cells in the Presence and Absence of WT-TP53

by Stephen L. Abrams, Przemysław Duda, Shaw M. Akula, Linda S. Steelman, Matilde L. Follo, Lucio Cocco, Stefano Ratti, Alberto M. Martelli, Giuseppe Montalto, Maria Rita Emma, Melchiorre Cervello, Dariusz Rakus, Agnieszka Gizak and James A. McCubrey

Cells 2022, 11(5), 794; https://doi.org/10.3390/cells11050794 - 24 Feb 2022

Cited by 7 | Viewed by 3760

Abstract

The TP53 tumor suppressor is mutated in ~75% of pancreatic cancers. The mutant TP53 protein in pancreatic ductal adenocarcinomas (PDAC) promotes tumor growth and metastasis. Attempts have been made to develop molecules that restore at least some of the properties of wild-type (WT) [...] Read more.

The TP53 tumor suppressor is mutated in ~75% of pancreatic cancers. The mutant TP53 protein in pancreatic ductal adenocarcinomas (PDAC) promotes tumor growth and metastasis. Attempts have been made to develop molecules that restore at least some of the properties of wild-type (WT) TP53. APR-246 is one such molecule, and it is referred to as a mutant TP53 reactivator. To understand the potential of APR-246 to sensitize PDAC cells to chemotherapy, we introduced a vector encoding WT-TP53 into two PDAC cell lines, one lacking the expression of TP53 (PANC-28) and one with a gain-of-function (GOF) mutant TP53 (MIA-PaCa-2). APR-246 increased drug sensitivity in the cells containing either a WT or mutant TP53 protein with GOF activity, but not in cells that lacked TP53. The introduction of WT-T53 into PANC-28 cells increased their sensitivity to the TP53 reactivator, chemotherapeutic drugs, and signal transduction inhibitors. The addition of WT-TP53 to PDAC cells with GOF TP53 also increased their sensitivity to the drugs and therapeutics, indicating that APR-246 could function in cells with WT-TP53 and GOF TP53. These results highlight the importance of knowledge of the type of TP53 mutation that is present in cancer patients before the administration of drugs which function through the reactivation of TP53. Full article

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2021

Jump to: 2022, 2020

19 pages, 4781 KiB

Open AccessArticle

miR-140-5p Attenuates Hypoxia-Induced Breast Cancer Progression by Targeting Nrf2/HO-1 Axis in a Keap1-Independent Mechanism

by Megharani Mahajan and Sandhya Sitasawad

Cells 2022, 11(1), 12; https://doi.org/10.3390/cells11010012 - 22 Dec 2021

Cited by 21 | Viewed by 4221

Abstract

Hypoxia and oxidative stress significantly contribute to breast cancer (BC) progression. Although hypoxia-inducible factor 1α (Hif-1α) is considered a key effector of the cellular response to hypoxia, nuclear factor erythroid 2–related factor 2 (Nrf2), a master antioxidant transcription factor, is a crucial factor [...] Read more.

Hypoxia and oxidative stress significantly contribute to breast cancer (BC) progression. Although hypoxia-inducible factor 1α (Hif-1α) is considered a key effector of the cellular response to hypoxia, nuclear factor erythroid 2–related factor 2 (Nrf2), a master antioxidant transcription factor, is a crucial factor essential for Hif-1α-mediated hypoxic responses. Hence, targeting Nrf2 could provide new treatment strategies for cancer therapy. miRNAs are potential regulators of hypoxia-responsive genes. In a quest to identify novel hypoxia-regulated miRNAs involved in the regulation of Nrf2, we found that miR-140-5p significantly affects the expression of Nrf2 under hypoxia. In our study, miR-140-5p expression is downregulated in BC cells under hypoxic conditions. We have identified Nrf2 as a direct target of miR-140-5p, as confirmed by the luciferase assay. Knockdown of miR-140-5p under normoxic conditions significantly enhanced Nrf2/HO-1 signaling and tumor growth, angiogenesis, migration, and invasion in BC. In contrast, overexpression of miR-140-5p under hypoxic conditions revealed opposite results. Further silencing Nrf2 expression mimicked the miR-140-5p-induced anti-tumor effects. Consistent with the knockdown of miR-140-5p in vitro, mice injected with miR-140-5p-KD cells exhibited dramatically reduced miR-140-5p levels, increased Nrf2 levels, and increased tumor growth. In contrast, tumor growth is potently suppressed in mice injected with miR-140-5p-OE cells. Collectively, the above results demonstrate the importance of the Nrf2/HO-1 axis in cancer progression and, thus, targeting Nrf2 by miR-140-5p could be a better strategy for the treatment of Nrf2-driven breast cancer progression. Full article

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33 pages, 950 KiB

Open AccessReview

Role of MicroRNA in Inflammatory Bowel Disease: Clinical Evidence and the Development of Preclinical Animal Models

by Kanika Suri, Jason A. Bubier, Michael V. Wiles, Leonard D. Shultz, Mansoor M. Amiji and Vishnu Hosur

Cells 2021, 10(9), 2204; https://doi.org/10.3390/cells10092204 - 26 Aug 2021

Cited by 24 | Viewed by 5174

Abstract

The dysregulation of microRNA (miRNA) is implicated in cancer, inflammation, cardiovascular disorders, drug resistance, and aging. While most researchers study miRNA’s role as a biomarker, for example, to distinguish between various sub-forms or stages of a given disease of interest, research is also [...] Read more.

The dysregulation of microRNA (miRNA) is implicated in cancer, inflammation, cardiovascular disorders, drug resistance, and aging. While most researchers study miRNA’s role as a biomarker, for example, to distinguish between various sub-forms or stages of a given disease of interest, research is also ongoing to utilize these small nucleic acids as therapeutics. An example of a common pleiotropic disease that could benefit from miRNA-based therapeutics is inflammatory bowel disease (IBD), which is characterized by chronic inflammation of the small and large intestines. Due to complex interactions between multiple factors in the etiology of IBD, development of therapies that effectively maintain remission for this disease is a significant challenge. In this review, we discuss the role of dysregulated miRNA expression in the context of clinical ulcerative colitis (UC) and Crohn’s disease (CD)—the two main forms of IBD—and the various preclinical mouse models of IBD utilized to validate the therapeutic potential of targeting these miRNA. Additionally, we highlight advances in the development of genetically engineered animal models that recapitulate clinical miRNA expression and provide powerful preclinical models to assess the diagnostic and therapeutic promise of miRNA in IBD. Full article

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15 pages, 660 KiB

Open AccessFeature PaperReview

MicroRNAs Patterns as Potential Tools for Diagnostic and Prognostic Follow-Up in Cancer Survivorship

by Ilaria Conti, Carolina Simioni, Gabriele Varano, Cinzia Brenna, Eva Costanzi and Luca Maria Neri

Cells 2021, 10(8), 2069; https://doi.org/10.3390/cells10082069 - 12 Aug 2021

Cited by 9 | Viewed by 2790

Abstract

Advances in screening methods and pharmacological treatments are increasing the life expectancy of cancer patients. During recent decades, the community of long-term disease-free cancer survivors (LCS) has grown exponentially, raising the issues related to cancer follow-up. Cancer relapse and other cancer-related diseases, as [...] Read more.

Advances in screening methods and pharmacological treatments are increasing the life expectancy of cancer patients. During recent decades, the community of long-term disease-free cancer survivors (LCS) has grown exponentially, raising the issues related to cancer follow-up. Cancer relapse and other cancer-related diseases, as well as lifestyle, influence cancer survival. Recently, the regulatory role of microRNAs (miRNAs) in gene expression and their involvement in human diseases, including cancer, has been identified. Extracellular circulating miRNAs (ECmiRNAs) have been found in biological fluids and specific ECmiRNAs have been associated with cancer development and progression or with a therapy response. Here, we focus on the pivotal role of ECmiRNAs as biomarkers in cancer diagnosis and prognosis. Then, we discuss the relevance of ECmiRNAs expression in cancer survivors for the identification of specific ECmiRNAs profiles as potential tools to assess cancer outcome and to control LCS follow-up. Full article

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21 pages, 2959 KiB

Open AccessArticle

MiR-200c-3p Contrasts PD-L1 Induction by Combinatorial Therapies and Slows Proliferation of Epithelial Ovarian Cancer through Downregulation of β-Catenin and c-Myc

by Eleni Anastasiadou, Elena Messina, Tiziana Sanavia, Lucia Mundo, Federica Farinella, Stefano Lazzi, Francesca Megiorni, Simona Ceccarelli, Paola Pontecorvi, Francesco Marampon, Cira Rosaria Tiziana Di Gioia, Giorgia Perniola, Pierluigi Benedetti Panici, Lorenzo Leoncini, Pankaj Trivedi, Andrea Lenzi and Cinzia Marchese

Cells 2021, 10(3), 519; https://doi.org/10.3390/cells10030519 - 1 Mar 2021

Cited by 26 | Viewed by 3685

Abstract

Conventional/targeted chemotherapies and ionizing radiation (IR) are being used both as monotherapies and in combination for the treatment of epithelial ovarian cancer (EOC). Several studies show that these therapies might favor oncogenic signaling and impede anti-tumor responses. MiR-200c is considered a master regulator [...] Read more.

Conventional/targeted chemotherapies and ionizing radiation (IR) are being used both as monotherapies and in combination for the treatment of epithelial ovarian cancer (EOC). Several studies show that these therapies might favor oncogenic signaling and impede anti-tumor responses. MiR-200c is considered a master regulator of EOC-related oncogenes. In this study, we sought to investigate if chemotherapy and IR could influence the expression of miR-200c-3p and its target genes, like the immune checkpoint PD-L1 and other oncogenes in a cohort of EOC patients’ biopsies. Indeed, PD-L1 expression was induced, while miR-200c-3p was significantly reduced in these biopsies post-therapy. The effect of miR-200c-3p target genes was assessed in miR-200c transfected SKOV3 cells untreated and treated with olaparib and IR alone. Under all experimental conditions, miR-200c-3p concomitantly reduced PD-L1, c-Myc and β-catenin expression and sensitized ovarian cancer cells to olaparib and irradiation. In silico analyses further confirmed the anti-correlation between miR-200c-3p with c-Myc and β-catenin in 46 OC cell lines and showed that a higher miR-200c-3p expression associates with a less tumorigenic microenvironment. These findings provide new insights into how miR-200c-3p could be used to hold in check the adverse effects of conventional chemotherapy, targeted therapy and radiation therapy, and offer a novel therapeutic strategy for EOC. Full article

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16 pages, 2876 KiB

Open AccessArticle

Can Be miR-126-3p a Biomarker of Premature Aging? An Ex Vivo and In Vitro Study in Fabry Disease

by Alessia Lo Curto, Simona Taverna, Maria Assunta Costa, Rosa Passantino, Giuseppa Augello, Giorgia Adamo, Anna Aiello, Paolo Colomba, Carmela Zizzo, Marco Zora, Giulia Accardi, Giuseppina Candore, Daniele Francofonte, Tiziana Di Chiara, Riccardo Alessandro, Calogero Caruso, Giovanni Duro and Giuseppe Cammarata

Cells 2021, 10(2), 356; https://doi.org/10.3390/cells10020356 - 9 Feb 2021

Cited by 11 | Viewed by 3028

Abstract

Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by lysosomal accumulation of glycosphingolipids in a wide variety of cytotypes, including endothelial cells (ECs). FD patients experience a significantly reduced life expectancy compared to the general population; therefore, the association with a [...] Read more.

Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by lysosomal accumulation of glycosphingolipids in a wide variety of cytotypes, including endothelial cells (ECs). FD patients experience a significantly reduced life expectancy compared to the general population; therefore, the association with a premature aging process would be plausible. To assess this hypothesis, miR-126-3p, a senescence-associated microRNA (SA-miRNAs), was considered as an aging biomarker. The levels of miR-126-3p contained in small extracellular vesicles (sEVs), with about 130 nm of diameter, were measured in FD patients and healthy subjects divided into age classes, in vitro, in human umbilical vein endothelial cells (HUVECs) “young” and undergoing replicative senescence, through a quantitative polymerase chain reaction (qPCR) approach. We confirmed that, in vivo, circulating miR-126 levels physiologically increase with age. In vitro, miR-126 augments in HUVECs underwent replicative senescence. We observed that FD patients are characterized by higher miR-126-3p levels in sEVs, compared to age-matched healthy subjects. We also explored, in vitro, the effect on ECs of glycosphingolipids that are typically accumulated in FD patients. We observed that FD storage substances induced in HUVECs premature senescence and increased of miR-126-3p levels. This study reinforces the hypothesis that FD may aggravate the normal aging process. Full article

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2020

Jump to: 2022, 2021

20 pages, 696 KiB

Open AccessReview

Exploring the Roles of lncRNAs in GBM Pathophysiology and Their Therapeutic Potential

by Christian T. Stackhouse, G. Yancey Gillespie and Christopher D. Willey

Cells 2020, 9(11), 2369; https://doi.org/10.3390/cells9112369 - 28 Oct 2020

Cited by 43 | Viewed by 5537

Abstract

Glioblastoma (GBM) remains the most devastating primary central nervous system malignancy with a median survival of around 15 months. The past decades of research have not yielded significant advancements in the treatment of GBM. In that same time, a novel class of molecules, [...] Read more.

Glioblastoma (GBM) remains the most devastating primary central nervous system malignancy with a median survival of around 15 months. The past decades of research have not yielded significant advancements in the treatment of GBM. In that same time, a novel class of molecules, long non-coding RNAs (lncRNAs), has been found to play a multitude of roles in cancer and normal biology. The increased accessibility of next generation sequencing technologies and the advent of lncRNA-specific microarrays have facilitated the study of lncRNA etiology. Molecular and computational methods can be applied to predict lncRNA function. LncRNAs can serve as molecular decoys, scaffolds, super-enhancers, or repressors. These molecules can serve as phenotypic switches for GBM cells at the expression and/or epigenetic levels. LncRNAs can affect stemness/differentiation, proliferation, invasion, survival, DNA damage response, and chromatin dynamics. Aberrant expression of these transcripts may facilitate therapy resistance, leading to tumor recurrence. LncRNAs could serve as novel theragnostic or prognostic biomarkers in GBM and other cancers. RNA-based therapeutics may also be employed to target lncRNAs as a novel route of treatment for primary or recurrent GBM. In this review, we explore the roles of lncRNAs in GBM pathophysiology and posit their novel therapeutic potential for GBM. Full article

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27 pages, 1252 KiB

Open AccessReview

miRNAs in Health and Disease: A Focus on the Breast Cancer Metastatic Cascade towards the Brain

by Marta Sereno, Mafalda Videira, Imola Wilhelm, István A. Krizbai and Maria Alexandra Brito

Cells 2020, 9(8), 1790; https://doi.org/10.3390/cells9081790 - 28 Jul 2020

Cited by 17 | Viewed by 3713

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that mainly act by binding to target genes to regulate their expression. Due to the multitude of genes regulated by miRNAs they have been subject of extensive research in the past few years. This state-of-the-art review summarizes [...] Read more.

MicroRNAs (miRNAs) are small non-coding RNAs that mainly act by binding to target genes to regulate their expression. Due to the multitude of genes regulated by miRNAs they have been subject of extensive research in the past few years. This state-of-the-art review summarizes the current knowledge about miRNAs and illustrates their role as powerful regulators of physiological processes. Moreover, it highlights their aberrant expression in disease, including specific cancer types and the differential hosting-metastases preferences that influence several steps of tumorigenesis. Considering the incidence of breast cancer and that the metastatic disease is presently the major cause of death in women, emphasis is put in the role of miRNAs in breast cancer and in the regulation of the different steps of the metastatic cascade. Furthermore, we depict their involvement in the cascade of events underlying breast cancer brain metastasis formation and development. Collectively, this review shall contribute to a better understanding of the uniqueness of the biologic roles of miRNAs in these processes, to the awareness of miRNAs as new and reliable biomarkers and/or of therapeutic targets, which can change the landscape of a poor prognosis and low survival rates condition of advanced breast cancer patients. Full article

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20 pages, 7533 KiB

Open AccessArticle

Regorafenib Regulates AD Pathology, Neuroinflammation, and Dendritic Spinogenesis in Cells and a Mouse Model of AD

by Kyung-Min Han, Ri Jin Kang, Hyongjun Jeon, Hyun-ju Lee, Ji-Soo Lee, HyunHee Park, Seong Gak Jeon, Kyoungho Suk, Jinsoo Seo and Hyang-Sook Hoe

Cells 2020, 9(7), 1655; https://doi.org/10.3390/cells9071655 - 9 Jul 2020

Cited by 26 | Viewed by 4286

Abstract

The oral multi-target kinase inhibitor regorafenib, which targets the oncogenic receptor tyrosine kinase (RTK), is an effective therapeutic for patients with advanced gastrointestinal stromal tumors or metastatic colorectal cancer. However, whether regorafenib treatment has beneficial effects on neuroinflammation and Alzheimer’s disease (AD) pathology [...] Read more.

The oral multi-target kinase inhibitor regorafenib, which targets the oncogenic receptor tyrosine kinase (RTK), is an effective therapeutic for patients with advanced gastrointestinal stromal tumors or metastatic colorectal cancer. However, whether regorafenib treatment has beneficial effects on neuroinflammation and Alzheimer’s disease (AD) pathology has not been carefully addressed. Here, we report the regulatory function of regorafenib in neuroinflammatory responses and AD-related pathology in vitro and in vivo. Regorafenib affected AKT signaling to attenuate lipopolysaccharide (LPS)-mediated expression of proinflammatory cytokines in BV2 microglial cells and primary cultured microglia and astrocytes. In addition, regorafenib suppressed LPS-induced neuroinflammatory responses in LPS-injected wild-type mice. In 5x FAD mice (a mouse model of AD), regorafenib ameliorated AD pathology, as evidenced by increased dendritic spine density and decreased Aβ plaque levels, by modulating APP processing and APP processing-associated proteins. Furthermore, regorafenib-injected 5x FAD mice displayed significantly reduced tau phosphorylation at T212 and S214 (AT100) due to the downregulation of glycogen synthase kinase-3 beta (GSK3β) activity. Taken together, our results indicate that regorafenib has beneficial effects on neuroinflammation, AD pathology, and dendritic spine formation in vitro and in vivo. Full article

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21 pages, 764 KiB

Open AccessReview

Immuno-Surgical Management of Pancreatic Cancer with Analysis of Cancer Exosomes

by Yu Takeda, Shogo Kobayashi, Masatoshi Kitakaze, Daisaku Yamada, Hirofumi Akita, Ayumu Asai, Masamitsu Konno, Takahiro Arai, Toru Kitagawa, Ken Ofusa, Masami Yabumoto, Takaaki Hirotsu, Andrea Vecchione, Masateru Taniguchi, Yuichiro Doki, Hidetoshi Eguchi and Hideshi Ishii

Cells 2020, 9(7), 1645; https://doi.org/10.3390/cells9071645 - 9 Jul 2020

Cited by 8 | Viewed by 4411

Abstract

Exosomes (EXs), a type of extracellular vesicles secreted from various cells and especially cancer cells, mesenchymal cells, macrophages and other cells in the tumor microenvironment (TME), are involved in biologically malignant behaviors of cancers. Recent studies have revealed that EXs contain microRNAs on [...] Read more.

Exosomes (EXs), a type of extracellular vesicles secreted from various cells and especially cancer cells, mesenchymal cells, macrophages and other cells in the tumor microenvironment (TME), are involved in biologically malignant behaviors of cancers. Recent studies have revealed that EXs contain microRNAs on their inside and express proteins and glycolipids on their outsides, every component of which plays a role in the transmission of genetic and/or epigenetic information in cell-to-cell communications. It is also known that miRNAs are involved in the signal transduction. Thus, EXs may be useful for monitoring the TME of tumor tissues and the invasion and metastasis, processes that are associated with patient survival. Because several solid tumors secrete immune checkpoint proteins, including programmed cell death-ligand 1, the EX-mediated mechanisms are suggested to be potent targets for monitoring patients. Therefore, a companion therapeutic approach against cancer metastasis to distant organs is proposed when surgical removal of the primary tumor is performed. However, EXs and immune checkpoint mechanisms in pancreatic cancer are not fully understood, we provide an update on the recent advances in this field and evidence that EXs will be useful for maximizing patient benefit in precision medicine. Full article

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19 pages, 3548 KiB

Open AccessArticle

Mechanistic Models of Signaling Pathways Reveal the Drug Action Mechanisms behind Gender-Specific Gene Expression for Cancer Treatments

by Cankut Çubuk, Fatma E. Can, María Peña-Chilet and Joaquín Dopazo

Cells 2020, 9(7), 1579; https://doi.org/10.3390/cells9071579 - 29 Jun 2020

Cited by 6 | Viewed by 3257

Abstract

Despite the existence of differences in gene expression across numerous genes between males and females having been known for a long time, these have been mostly ignored in many studies, including drug development and its therapeutic use. In fact, the consequences of such [...] Read more.

Despite the existence of differences in gene expression across numerous genes between males and females having been known for a long time, these have been mostly ignored in many studies, including drug development and its therapeutic use. In fact, the consequences of such differences over the disease mechanisms or the drug action mechanisms are completely unknown. Here we applied mechanistic mathematical models of signaling activity to reveal the ultimate functional consequences that gender-specific gene expression activities have over cell functionality and fate. Moreover, we also used the mechanistic modeling framework to simulate the drug interventions and unravel how drug action mechanisms are affected by gender-specific differential gene expression. Interestingly, some cancers have many biological processes significantly affected by these gender-specific differences (e.g., bladder or head and neck carcinomas), while others (e.g., glioblastoma or rectum cancer) are almost insensitive to them. We found that many of these gender-specific differences affect cancer-specific pathways or in physiological signaling pathways, also involved in cancer origin and development. Finally, mechanistic models have the potential to be used for finding alternative therapeutic interventions on the pathways targeted by the drug, which lead to similar results compensating the downstream consequences of gender-specific differences in gene expression. Full article

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47 pages, 2181 KiB

Open AccessReview

Targeting the JAK/STAT Signaling Pathway Using Phytocompounds for Cancer Prevention and Therapy

by Sankhadip Bose, Sabyasachi Banerjee, Arijit Mondal, Utsab Chakraborty, Joshua Pumarol, Courtney R. Croley and Anupam Bishayee

Cells 2020, 9(6), 1451; https://doi.org/10.3390/cells9061451 - 11 Jun 2020

Cited by 127 | Viewed by 13038

Abstract

Cancer is a prevalent cause of mortality around the world. Aberrated activation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway promotes tumorigenesis. Natural agents, including phytochemicals, exhibit potent anticancer activities via various mechanisms. However, the therapeutic potency of phytoconstituents [...] Read more.

Cancer is a prevalent cause of mortality around the world. Aberrated activation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway promotes tumorigenesis. Natural agents, including phytochemicals, exhibit potent anticancer activities via various mechanisms. However, the therapeutic potency of phytoconstituents as inhibitors of JAK/STAT signaling against cancer has only come into focus in recent days. The current review highlights phytochemicals that can suppress the JAK/STAT pathway in order to impede cancer cell growth. Various databases, such as PubMed, ScienceDirect, Web of Science, SpringerLink, Scopus, and Google Scholar, were searched using relevant keywords. Once the authors were in agreement regarding the suitability of a study, a full-length form of the relevant article was obtained, and the information was gathered and cited. All the complete articles that were incorporated after the literature collection rejection criteria were applied were perused in-depth and material was extracted based on the importance, relevance, and advancement of the apprehending of the JAK/STAT pathway and their relation to phytochemicals. Based on the critical and comprehensive analysis of literature presented in this review, phytochemicals from diverse plant origins exert therapeutic and cancer preventive effects, at least in part, through regulation of the JAK/STAT pathway. Nevertheless, more preclinical and clinical research is necessary to completely comprehend the capability of modulating JAK/STAT signaling to achieve efficient cancer control and treatment. Full article

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13 pages, 6144 KiB

Open AccessArticle

Induction of the Endoplasmic-Reticulum-Stress Response: MicroRNA-34a Targeting of the IRE1α-Branch

by Lena Krammes, Martin Hart, Stefanie Rheinheimer, Caroline Diener, Jennifer Menegatti, Friedrich Grässer, Andreas Keller and Eckart Meese

Cells 2020, 9(6), 1442; https://doi.org/10.3390/cells9061442 - 10 Jun 2020

Cited by 15 | Viewed by 4731

Abstract

Neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and the unfolded protein response (UPR). Modulating the UPR is one of the major challenges to counteract the development [...] Read more.

Neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and the unfolded protein response (UPR). Modulating the UPR is one of the major challenges to counteract the development of neurodegenerative disorders and other diseases with affected UPR. Here, we show that miR-34a-5p directly targets the IRE1α branch of the UPR, including the genes BIP, IRE1α, and XBP1. Upon induction of ER stress in neuronal cells, miR-34a-5p overexpression impacts the resulting UPR via a significant reduction in IRE1α and XBP1s that in turn leads to decreased viability, increased cytotoxicity and caspase activity. The possibility to modify the UPR signaling pathway by a single miRNA that targets central genes of the IRE1α branch offers new perspectives for future therapeutic approaches against neurodegeneration. Full article

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Targeting Signal Transduction Pathways and Non-coding RNAs as Potential Therapy in Cancer and Aging

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