scholarly journals Evaluation of MicroRNAs Regulating Anoikis Pathways and Its Therapeutic Potential

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Sharan Malagobadan ◽  
Noor Hasima Nagoor
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Therapeutic Potential ◽  
Research Question ◽  
Therapeutic Strategies ◽  
Anoikis Resistance ◽  
The Past ◽  
Cancer Types ◽  
Novel Therapeutic Strategies ◽  
Survival Mechanisms

Dysregulation of microRNAs (miRNAs) has been implicated in almost every known survival mechanisms utilized by cancer cells. One of such mechanisms, anoikis resistance, plays a pivotal role in enabling metastasis by allowing cancer cells to circumvent cell death induced by lack of attachment. Understanding how miRNAs regulate the various anoikis pathways has become the research question of increasing number of studies published in the past years. Through these studies, a growing list of miRNAs has been identified to be important players in promoting either anoikis or resistance to anoikis. In this review, we will be focusing on these miRNAs and how the findings from those studies can contribute to novel therapeutic strategies against cancer progression. We will be examining miRNAs that have been found to promote anoikis sensitivity in numerous cancer types followed by miRNAs that inhibit anoikis. In addition, we will also be taking a look at major signaling pathways involved in the action of the each of these miRNAs to gain a better understanding on how miRNAs regulate anoikis.

scholarly journals Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 114
Author(s):  
Lisa Linck-Paulus ◽  
Claus Hellerbrand ◽  
Anja K. Bosserhoff ◽  
Peter Dietrich
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Therapeutic Targets ◽  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
The Future ◽  
Associated Proteins ◽  
Cancer Types ◽  
Novel Therapeutic Strategies

In this review, we summarize the current knowledge on miRNAs as therapeutic targets in two cancer types that were frequently described to be driven by miRNAs—melanoma and hepatocellular carcinoma (HCC). By focusing on common microRNAs and associated pathways in these—at first sight—dissimilar cancer types, we aim at revealing similar molecular mechanisms that are evolved in microRNA-biology to drive cancer progression. Thereby, we also want to outlay potential novel therapeutic strategies. After providing a brief introduction to general miRNA biology and basic information about HCC and melanoma, this review depicts prominent examples of potent oncomiRs and tumor-suppressor miRNAs, which have been proven to drive diverse cancer types including melanoma and HCC. To develop and apply miRNA-based therapeutics for cancer treatment in the future, it is essential to understand how miRNA dysregulation evolves during malignant transformation. Therefore, we highlight important aspects such as genetic alterations, miRNA editing and transcriptional regulation based on concrete examples. Furthermore, we expand our illustration by focusing on miRNA-associated proteins as well as other regulators of miRNAs which could also provide therapeutic targets. Finally, design and delivery strategies of miRNA-associated therapeutic agents as well as potential drawbacks are discussed to address the question of how miRNAs might contribute to cancer therapy in the future.

scholarly journals NUMB suppression by miR-9-5P enhances CD44+ prostate cancer stem cell growth and metastasis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xuan Wang ◽  
Jun Cai ◽  
Lei Zhao ◽  
Dejun Zhang ◽  
Guojie Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cells ◽  
Bioinformatics Analysis ◽  
Therapy Resistance ◽  
Therapeutic Strategies ◽  
Self Renewal ◽  
Tumor Relapse ◽  
The Past ◽  
Overwhelming Evidence ◽  
Novel Therapeutic Strategies

AbstractExperimental and clinical studies over the past two decades have provided overwhelming evidence that human cancers, including prostate cancer (PCa), harbor cancer stem cells (CSCs) that sustain tumor growth, drive tumor progression and mediate therapy resistance and tumor relapse. Recent studies have also implicated NUMB as a PCa suppressor and an inhibitor of PCa stem cells (PCSCs); however, exactly how NUMB functions in these contexts remains unclear. Here, by employing bioinformatics analysis and luciferase assays and by conducting rescue experiments, we first show that NUMB is directly targeted by microRNA-9-5p (miR-9-5p), an oncogenic miR associated with poor prognosis in many malignancies. We further show that miR-9-5p levels are inversely correlated with NUMB expression in CD44+ PCSCs. miR-9-5p reduced NUMB expression and inhibited numerous PCSC properties including proliferation, migration, invasion as well as self-renewal. Strikingly, overexpression of NUMB in CD44+ PCSCs overcame all of the above PCSC properties enforced by miR-9-5p. Taken together, our results suggest that inhibiting the expression of the oncomiR miR-9-5p and overexpressing NUMB may represent novel therapeutic strategies to target PCSCs and PCa metastasis.

scholarly journals Hypoxic tumor microenvironment: Implications for cancer therapy

2020 ◽  
Vol 245 (13) ◽  
pp. 1073-1086
Author(s):  
Sukanya Roy ◽  
Subhashree Kumaravel ◽  
Ankith Sharma ◽  
Camille L Duran ◽  
Kayla J Bayless ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Metabolic Regulation ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Tumor Vasculature ◽  
Therapeutic Strategies ◽  
Therapeutic Resistance ◽  
Low Oxygen ◽  
Cancer Types

Hypoxia or low oxygen concentration in tumor microenvironment has widespread effects ranging from altered angiogenesis and lymphangiogenesis, tumor metabolism, growth, and therapeutic resistance in different cancer types. A large number of these effects are mediated by the transcription factor hypoxia inducible factor 1⍺ (HIF-1⍺) which is activated by hypoxia. HIF1⍺ induces glycolytic genes and reduces mitochondrial respiration rate in hypoxic tumoral regions through modulation of various cells in tumor microenvironment like cancer-associated fibroblasts. Immune evasion driven by HIF-1⍺ further contributes to enhanced survival of cancer cells. By altering drug target expression, metabolic regulation, and oxygen consumption, hypoxia leads to enhanced growth and survival of cancer cells. Tumor cells in hypoxic conditions thus attain aggressive phenotypes and become resistant to chemo- and radio- therapies resulting in higher mortality. While a number of new therapeutic strategies have succeeded in targeting hypoxia, a significant improvement of these needs a more detailed understanding of the various effects and molecular mechanisms regulated by hypoxia and its effects on modulation of the tumor vasculature. This review focuses on the chief hypoxia-driven molecular mechanisms and their impact on therapeutic resistance in tumors that drive an aggressive phenotype. Impact statement Hypoxia contributes to tumor aggressiveness and promotes growth of many solid tumors that are often resistant to conventional therapies. In order to achieve successful therapeutic strategies targeting different cancer types, it is necessary to understand the molecular mechanisms and signaling pathways that are induced by hypoxia. Aberrant tumor vasculature and alterations in cellular metabolism and drug resistance due to hypoxia further confound this problem. This review focuses on the implications of hypoxia in an inflammatory TME and its impact on the signaling and metabolic pathways regulating growth and progression of cancer, along with changes in lymphangiogenic and angiogenic mechanisms. Finally, the overarching role of hypoxia in mediating therapeutic resistance in cancers is discussed.

scholarly journals The Role of TGF-β in Bone Metastases

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1643
Author(s):  
Trupti Trivedi ◽  
Gabriel M. Pagnotti ◽  
Theresa A. Guise ◽  
Khalid S. Mohammad
Keyword(s):  
Growth Factors ◽  
Bone Metastases ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Biologically Active ◽  
Immune Checkpoints ◽  
Vicious Cycle ◽  
Mesenchymal Transition

Complications associated with advanced cancer are a major clinical challenge and, if associated with bone metastases, worsen the prognosis and compromise the survival of the patients. Breast and prostate cancer cells exhibit a high propensity to metastasize to bone. The bone microenvironment is unique, providing fertile soil for cancer cell propagation, while mineralized bone matrices store potent growth factors and cytokines. Biologically active transforming growth factor β (TGF-β), one of the most abundant growth factors, is released following tumor-induced osteoclastic bone resorption. TGF-β promotes tumor cell secretion of factors that accelerate bone loss and fuel tumor cells to colonize. Thus, TGF-β is critical for driving the feed-forward vicious cycle of tumor growth in bone. Further, TGF-β promotes epithelial-mesenchymal transition (EMT), increasing cell invasiveness, angiogenesis, and metastatic progression. Emerging evidence shows TGF-β suppresses immune responses, enabling opportunistic cancer cells to escape immune checkpoints and promote bone metastases. Blocking TGF-β signaling pathways could disrupt the vicious cycle, revert EMT, and enhance immune response. However, TGF-β’s dual role as both tumor suppressor and enhancer presents a significant challenge in developing therapeutics that target TGF-β signaling. This review presents TGF-β’s role in cancer progression and bone metastases, while highlighting current perspectives on the therapeutic potential of targeting TGF-β pathways.

scholarly journals Characterizing Intercellular Communication of Pan-Cancer Reveals SPP1+ Tumor-Associated Macrophage Expanded in Hypoxia and Promoting Cancer Malignancy Through Single-Cell RNA-Seq Data

2021 ◽  
Vol 9 ◽  
Author(s):  
Jinfen Wei ◽  
Zixi Chen ◽  
Meiling Hu ◽  
Ziqing He ◽  
Dawei Jiang ◽  
...  
Keyword(s):  
Single Cell ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Single Cells ◽  
Matrix Remodeling ◽  
Rna Seq ◽  
Mesenchymal Transition ◽  
Tumor Associated Macrophage ◽  
Cancer Types

Hypoxia is a characteristic of tumor microenvironment (TME) and is a major contributor to tumor progression. Yet, subtype identification of tumor-associated non-malignant cells at single-cell resolution and how they influence cancer progression under hypoxia TME remain largely unexplored. Here, we used RNA-seq data of 424,194 single cells from 108 patients to identify the subtypes of cancer cells, stromal cells, and immune cells; to evaluate their hypoxia score; and also to uncover potential interaction signals between these cells in vivo across six cancer types. We identified SPP1+ tumor-associated macrophage (TAM) subpopulation potentially enhanced epithelial–mesenchymal transition (EMT) by interaction with cancer cells through paracrine pattern. We prioritized SPP1 as a TAM-secreted factor to act on cancer cells and found a significant enhanced migration phenotype and invasion ability in A549 lung cancer cells induced by recombinant protein SPP1. Besides, prognostic analysis indicated that a higher expression of SPP1 was found to be related to worse clinical outcome in six cancer types. SPP1 expression was higher in hypoxia-high macrophages based on single-cell data, which was further validated by an in vitro experiment that SPP1 was upregulated in macrophages under hypoxia-cultured compared with normoxic conditions. Additionally, a differential analysis demonstrated that hypoxia potentially influences extracellular matrix remodeling, glycolysis, and interleukin-10 signal activation in various cancer types. Our work illuminates the clearer underlying mechanism in the intricate interaction between different cell subtypes within hypoxia TME and proposes the guidelines for the development of therapeutic targets specifically for patients with high proportion of SPP1+ TAMs in hypoxic lesions.

scholarly journals MBNL1 alternative splicing isoforms play opposing roles in cancer

2018 ◽  
Vol 1 (5) ◽  
pp. e201800157 ◽  
Author(s):  
Tommaso Tabaglio ◽  
Diana HP Low ◽  
Winnie Koon Lay Teo ◽  
Pierre Alexis Goy ◽  
Piotr Cywoniuk ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Gene Function ◽  
Dominant Negative ◽  
Individual Gene ◽  
Cancer Types ◽  
Splicing Isoforms ◽  
Isoform Switching ◽  
And Migration

The extent of and the oncogenic role played by alternative splicing (AS) in cancer are well documented. Nonetheless, only few studies have attempted to dissect individual gene function at an isoform level. Here, we focus on the AS of splicing factors during prostate cancer progression, as these factors are known to undergo extensive AS and have the potential to affect hundreds of downstream genes. We identified exon 7 (ex7) in the MBNL1 (Muscleblind-like 1) transcript as being the most differentially included exon in cancer, both in cell lines and in patients' samples. In contrast, MBNL1 overall expression was down-regulated, consistently with its described role as a tumor suppressor. This observation holds true in the majority of cancer types analyzed. We first identified components associated to the U2 splicing complex (SF3B1, SF3A1, and PHF5A) as required for efficient ex7 inclusion and we confirmed that this exon is fundamental for MBNL1 protein homodimerization. We next used splice-switching antisense oligonucleotides (AONs) or siRNAs to compare the effect of MBNL1 splicing isoform switching with knockdown. We report that whereas the absence of MBNL1 is tolerated in cancer cells, the expression of isoforms lacking ex7 (MBNL1 Δex7) induces DNA damage and inhibits cell viability and migration, acting as dominant negative proteins. Our data demonstrate the importance of studying gene function at the level of alternative spliced isoforms and support our conclusion that MBNL1 Δex7 proteins are antisurvival factors with a defined tumor suppressive role that cancer cells tend to down-regulate in favor of MBNL +ex7 isoforms.

Nanophytomedicine Based Novel Therapeutic Strategies in Liver Cancer

2020 ◽  
Vol 20 (22) ◽  
pp. 1999-2024
Author(s):  
Sachin Kumar ◽  
Faizana Fayaz ◽  
Faheem Hyder Pottoo ◽  
Sakshi Bajaj ◽  
Satish Manchanda ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Therapeutic Response ◽  
Water Solubility ◽  
Therapeutic Potential ◽  
Therapeutic Strategies ◽  
Resistance Development ◽  
Local Ablation ◽  
Novel Drugs ◽  
Targeted Agent ◽  
Novel Therapeutic Strategies

Liver cancer is the fifth (6.3% of all cancers i.e., 548,000 cases/year) and ninth (2.8% of all cancers i.e., 244,000 cases/year) most prevalent cancer worldwide in men and women, respectively. Although multiple choices of therapies are offered for Hepatocellular Carcinoma (HCC) like liver resection or transplant, radiofrequency ablation, transarterial chemoembolization, radioembolization, and systemic targeted agent, by the time of diagnosis, most of the cases of HCC are in an advanced stage, which renders therapies like liver transplant or resection and local ablation impractical; and targeted therapy has its shortcomings like general toxicity, imprecise selectivity, several adversative reactions, and resistance development. Therefore, novel drugs with specificity and selectivity are needed to provide the potential therapeutic response. Various researches have shown the potential of phytomedicines in liver cancer by modulating cell growth, invasion, metastasis, and apoptosis. However, their therapeutic potential is held up by their unfavorable properties like stability, poor water solubility, low absorption, and quick metabolism. Nonetheless, the advancement of nanotechnology-based innovative nanocarrier formulations has improved the phytomedicines’ profile to be used in the treatment of liver cancer. Nanocarriers not only improve the solubility and stability of phytomedicines but also extend their residence in plasma and accomplish specificity. In this review, we summarize the advancements introduced by nanotechnology in the treatment of liver cancer. In particular, we discuss quite a few applications of nanophytomedicines like curcumin, quercetin, epigallocatechin-3-gallate, berberine, apigenin, triptolide, and resveratrol in liver cancer treatment.

scholarly journals miR-125b Suppresses Proliferation and Invasion by Targeting MCL1 in Gastric Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Shihua Wu ◽  
Feng Liu ◽  
Liming Xie ◽  
Yaling Peng ◽  
Xiaoyuan Lv ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Clinical Stage ◽  
Gastric Cancer Cells ◽  
Gastric Cancer Progression

Understanding the molecular mechanisms underlying gastric cancer progression contributes to the development of novel targeted therapies. In this study, we found that the expression levels of miR-125b were strongly downregulated in gastric cancer and associated with clinical stage and the presence of lymph node metastases. Additionally, miR-125b could independently predict OS and DFS in gastric cancer. We further found that upregulation of miR-125b inhibited the proliferation and metastasis of gastric cancer cells in vitro and in vivo. miR-125b elicits these responses by directly targeting MCL1 (myeloid cell leukemia 1), which results in a marked reduction in MCL1 expression. Transfection of miR-125b sensitizes gastric cancer cells to 5-FU-induced apoptosis. By understanding the function and molecular mechanisms of miR-125b in gastric cancer, we may learn that miR-125b has the therapeutic potential to suppress gastric cancer progression and increase drug sensitivity to gastric cancer.

scholarly journals LncRNAs: New Players in Apoptosis Control

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Marianna Nicoletta Rossi ◽  
Fabrizio Antonangeli
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Noncoding Rnas ◽  
New Class ◽  
Physiological Processes ◽  
Specific Cancer ◽  
Cancer Types ◽  
Major Attention ◽  
Apoptotic Pathways ◽  
Polyadenylated Rnas

The discovery that the mammalian genome is largely transcribed and that almost half of the polyadenylated RNAs is composed of noncoding RNAs has attracted the attention of the scientific community. Growing amount of data suggests that long noncoding RNAs (lncRNAs) are a new class of regulators involved not only in physiological processes, such as imprinting and differentiation, but also in cancer progression and neurodegeneration. Apoptosis is a well regulated type of programmed cell death necessary for correct organ development and tissue homeostasis. Indeed, cancer cells often show an inhibition of the apoptotic pathways and it is now emerging that overexpression or downregulation of different lncRNAs in specific types of tumors sensitize cancer cells to apoptotic stimuli. In this review we summarize the latest studies on lncRNAs and apoptosis with major attention to those performed in cancer cells and in healthy cells upon differentiation. We discuss the new perspectives of using lncRNAs as targets of anticancer drugs. Finally, considering that lncRNA levels have been reported to have a correlation with specific cancer types, we argue the possibility of using lncRNAs as tumor biomarkers.

scholarly journals Meiosis and Kinetochore genes are used by cancer cells as genome destabilizers and transformation catalysts

2019 ◽  
Author(s):  
Roshina Thapa ◽  
Swetha Vasudevan ◽  
Mimi Abo-Ayoub Ashqar ◽  
Eli Reich ◽  
Nataly Kravchenko-Balasha ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Genome Instability ◽  
Chromosome Instability ◽  
Information Theoretic ◽  
Cancer Types ◽  
Altered Gene ◽  
The Relationship ◽  
Hct116 Cells

AbstractCancer cells have an altered transcriptome which contributes to their altered behaviors compared to normal cells. Indeed, many tumors express high levels of genes participating in meiosis or kinetochore biology, but the role of this high expression has not been fully elucidated. In this study we explore the relationship between this overexpression and genome instability and transformation capabilities of cancer cells. For this, we obtained expression data from 5 different cancer types which were analyzed using computational information-theoretic analysis. We were able to show that highly expressed meiotic/kinetochore genes were enriched in the altered gene expression subnetworks characterizing unstable cancer types with high chromosome instability (CIN). However, altered subnetworks found in the cancers with low CIN did not include meiotic and kinetochore genes. Representative gene candidates, found by the analysis to be correlated with a CIN phenotype, were further explored by transfecting genomically-stable (HCT116) and unstable (MCF7) cancer cell lines with vectors overexpressing those genes. This overexpression resulted in an increase in the numbers of abnormal cell divisions and defective spindle formations and in increased transformation properties in stable cancer HCT116 cells. Interestingly, the same properties were less affected by the overexpressed genes in the unstable MCF7 cancer cells. Our results indicate that overexpression of both meiosis and kinetochore genes is capable of driving genomic instability and cancer progression.

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