The regulation of the pleiotropic transcription factor, nuclear factor-κB (NF-κB) by miRNAs and proteins is extensively studied. More recently, the NF-κB signaling was also reported to be regulated ...by several long non-coding RNAs (lncRNAs) that constitute the major portion of the noncoding component of the human genome. The common NF-κB associated lncRNAs include NKILA, HOTAIR, MALAT1, ANRIL, Lethe, MIR31HG, and PACER. The lncRNA and NF-κB signaling crosstalk during cancer and other diseases such as cardiomyopathy, celiac disease, cerebral infarction, chronic kidney disease, diabetes mellitus, Kawasaki disease, pregnancy loss, and rheumatoid arthritis. Some NF-κB related lncRNAs can affect gene expression without modulating NF-κB signaling. Most of the lncRNAs with a potential to modulate NF-κB signaling are regulated by NF-κB itself suggesting a feedback regulation. The discovery of lncRNAs have provided a new type of regulation for the NF-κB signaling and thus could be explored for therapeutic interventions. The manner in which lncRNA and NF-κB crosstalk affects human pathophysiology is discussed in this review. The challenges associated with the therapeutic interventions of this crosstalk are also discussed.
Recent advances in exosome biology have uncovered a significant role of exosomes in cancer and make them a determining factor in intercellular communication. Exosomes are types of extracellular ...vesicles that are involved in the communication between cells by exchanging various signaling molecules between the surrounding cells. Among various signaling molecules, long non-coding RNAs (lncRNAs), a type of non-coding RNA having a size of more than 200 nt in length and lacking protein-coding potential, have emerged as crucial regulators of intercellular communication. Tumor-derived exosomes containing various lncRNAs, known as exosomal lncRNAs, reprogram the microenvironment by regulating numerous cellular functions, including the regulation of gene transcription that favors cancer growth and progression, thus significantly determining the biological effects of exosomes. In addition, deregulated expression of lncRNAs is found in various human cancers and serves as a diagnostic biomarker to predict cancer type. The present review discusses the role of exosomal lncRNAs in the crosstalk between tumor cells and the surrounding cells of the microenvironment. Furthermore, we also discuss the involvement of exosomal lncRNAs within the tumor microenvironment in favoring tumor growth, metabolic reprogramming of tumor cells, and tumor-supportive autophagy. Therefore, lncRNAs can be used as a therapeutic target in the treatment of various human cancers.
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lncRNAs are >200 nt long RNAs that are transcribed but not translated into proteins. Cells secrete lncRNAs into extracellular vesicles called exosomes to communicate with their microenvironment or distant cells. Cancer-related exosomal lncRNAs mediate tumor interaction with their microenvironment, which plays an important role in its reprogramming into a tumor-promoting microenvironment.
Recent advances in extracellular vesicle biology have uncovered a substantial role in maintaining cell homeostasis in health and disease conditions by mediating intercellular communication, thus ...catching the scientific community's attention worldwide. Extracellular microvesicles, some called exosomes, functionally transfer biomolecules such as proteins and non-coding RNAs from one cell to another, influencing the local environment's biology. Although numerous advancements have been made in treating cancer patients with immune therapy, controlling the disease remains a challenge in the clinic due to tumor-driven interference with the immune response and inability of immune cells to clear cancer cells from the body. The present review article discusses the recent findings and knowledge gaps related to the role of exosomes derived from tumors and the tumor microenvironment cells in tumor escape from immunosurveillance. Further, we highlight examples where exosomal non-coding RNAs influence immune cells' response within the tumor microenvironment and favor tumor growth and progression. Therefore, exosomes can be used as a therapeutic target for the treatment of human cancers.
How exosomic microRNAs (miRNAs) contribute to the development of drug resistance in the context of the tumor microenvironment has not been previously described in neuroblastoma (NBL).
Coculture ...experiments were performed to assess exosomic transfer of miR-21 from NBL cells to human monocytes and miR-155 from human monocytes to NBL cells. Luciferase reporter assays were performed to assess miR-155 targeting of TERF1 in NBL cells. Tumor growth was measured in NBL xenografts treated with Cisplatin and peritumoral exosomic miR-155 (n = 6 mice per group) CD163, miR-155, and TERF1 levels were assessed in 20 NBL primary tissues by Human Exon Arrays and quantitative real-time polymerase chain reaction. Student's t test was used to evaluate the differences between treatment groups. All statistical tests were two-sided.
miR-21 mean fold change (f.c.) was 12.08±0.30 (P < .001) in human monocytes treated with NBL derived exosomes for 48 hours, and miR-155 mean f.c. was 4.51±0.25 (P < .001) in NBL cells cocultured with human monocytes for 48 hours. TERF1 mean luciferase activity in miR-155 transfected NBL cells normalized to scrambled was 0.36 ± 0.05 (P <.001). Mean tumor volumes in Dotap-miR-155 compared with Dotap-scrambled were 322.80±120mm(3) and 76.00±39.3mm(3), P = .002 at day 24, respectively. Patients with high CD163 infiltrating NBLs had statistically significantly higher intratumoral levels of miR-155 (P = .04) and lower levels of TERF1 mRNA (P = .02).
These data indicate a unique role of exosomic miR-21 and miR-155 in the cross-talk between NBL cells and human monocytes in the resistance to chemotherapy, through a novel exosomic miR-21/TLR8-NF-кB/exosomic miR-155/TERF1 signaling pathway.
The long non-coding RNAs (lncRNAs) are the crucial regulators of human chronic diseases. Therefore, approaches such as antisense oligonucleotides, RNAi technology, and small molecule inhibitors have ...been used for the therapeutic targeting of lncRNAs. During the last decade, phytochemicals and nutraceuticals have been explored for their potential against lncRNAs. The common lncRNAs known to be modulated by phytochemicals include ROR, PVT1, HOTAIR, MALAT1, H19, MEG3, PCAT29, PANDAR, NEAT1, and GAS5. The phytochemicals such as curcumin, resveratrol, sulforaphane, berberine, EGCG, and gambogic acid have been examined against lncRNAs. In some cases, formulation of phytochemicals has also been used. The disease models where phytochemicals have been demonstrated to modulate lncRNAs expression include cancer, rheumatoid arthritis, osteoarthritis, and nonalcoholic fatty liver disease. The regulation of lncRNAs by phytochemicals can affect multi-steps of tumor development. When administered in combination with the conventional drugs, phytochemicals can also produce synergistic effects on lncRNAs leading to the sensitization of cancer cells. Phytochemicals target lncRNAs either directly or indirectly by affecting a wide variety of upstream molecules. However, the potential of phytochemicals against lncRNAs has been demonstrated mostly by preclinical studies in cancer models. How the modulation of lncRNAs by phytochemicals produce therapeutic effects on cancer and other chronic diseases is discussed in this review.
Neuroblastoma (NB) is the most common extracranial solid malignancy in children. Despite current aggressive treatment regimens, the prognosis for high‐risk NB patients remains poor, with the survival ...of less than 40%. Amplification/stabilization of MYCN oncogene, in NB is associated with a high risk of recurrence. Thus, there is an urgent need for novel therapeutics. The deregulated expression of microRNA (miR) is reported in NB; nonetheless, its effect on MYCN regulation is poorly understood. First, we identified that miR‐15a‐5p, miR‐15b‐5p, and miR‐16‐5p (hereafter miR‐15a, miR‐15b or miR‐16) were down‐regulated in patient‐derived xenografts (PDX) with high MYCN expression. MiR targeting sequences on MYCN mRNA were predicted using online databases such as TargetScan and miR database. The R2 database, containing 105 NB patients, showed an inverse correlation between MYCN mRNA and deleted in lymphocytic leukemia (DLEU) 2, a host gene of miR‐15. Moreover, overexpression of miR‐15a, miR‐15b or miR‐16 significantly reduced the levels of MYCN mRNA and N‐Myc protein. Conversely, inhibiting miR dramatically enhanced MYCN mRNA and N‐Myc protein levels, as well as increasing mRNA half‐life in NB cells. By performing immunoprecipitation assays of argonaute‐2 (Ago2), a core component of the RNA‐induced silencing complex, we showed that miR‐15a, miR‐15b and miR‐16 interact with MYCN mRNA. Luciferase reporter assays showed that miR‐15a, miR‐15b and miR‐16 bind with 3’UTR of MYCN mRNA, resulting in MYCN suppression. Moreover, induced expression of miR‐15a, miR‐15b and miR‐16 significantly reduced the proliferation, migration, and invasion of NB cells. Finally, transplanting miR‐15a‐, miR‐15b‐ and miR‐16‐expressing NB cells into NSG mice repressed tumor formation and MYCN expression. These data suggest that miR‐15a, miR‐15b and miR‐16 exert a tumor‐suppressive function in NB by targeting MYCN. Therefore, these miRs could be considered as potential targets for NB treatment.
A model summarizing how miR‐15a, miR‐15b, and miR‐16 suppress tumor progression in neuroblastoma by targeting MYCN. When miRs are overexpressed, argonaute‐2‐mediated interaction of miR with MYCN mRNA increases, followed by degradation of MYCN, leading to neuroblastoma regression.
The ubiquitin (Ub)–proteasome system plays a pivotal role in the regulation of p53 protein stability and activity. p53 is ubiquitinated and destabilized by MDM2 and several other Ub E3s, whereas it ...is deubiquitinated and stabilized by Ub‐specific protease (USP)7 and USP10. Here we show that the ovarian tumour domain‐containing Ub aldehyde‐binding protein 1 (Otub1) is a novel p53 regulator. Otub1 directly suppresses MDM2‐mediated p53 ubiquitination in cells and in vitro. Overexpression of Otub1 drastically stabilizes and activates p53, leading to apoptosis and marked inhibition of cell proliferation in a p53‐dependent manner. These effects are independent of its catalytic activity but require residue Asp88. Mutation of Asp88 to Ala (Otub1D88A) abolishes activity of Otub1 to suppress p53 ubiquitination. Further, wild‐type Otub1 and its catalytic mutant (Otub1C91S), but not Otub1D88A, bind to the MDM2 cognate E2, UbcH5, and suppress its Ub‐conjugating activity in vitro. Overexpression of Otub1D88A or ablation of endogenous Otub1 by siRNA markedly impaired p53 stabilization and activation in response to DNA damage. Together, these results reveal a novel function for Otub1 in regulating p53 stability and activity.
The deubiquitinating enzyme Otubain 1 regulates MDM2‐mediated p53 ubiquitination in a non‐catalytic manner, by binding and suppressing the activity of MDM2's cognate ubiquitin‐conjugating enzyme UbcH5.
Indiscriminate usage and mismanagement of chemicals in the agricultural and industrial sectors have contaminated different environmental compartments. Exposure to these persistent and hazardous ...pollutants like heavy metals, endocrine disruptors, aromatic hydrocarbons, and pesticides can result in various health adversities, including cancer. Chemical carcinogens follow a similar pattern of carcinogenesis, like oxidative stress, chromosomal aberration, DNA double-strand break, mismatch repair, and misregulation of oncogenic and/or tumor suppressors. Out of several cancer-associated endpoints, cellular metabolic homeostasis is the commonest to be deregulated upon chemical exposure. Chemical carcinogens hamper glycolytic reprogramming to fuel the malignant transformation of the cells and/or promote cancer progression. Several regulators like Akt, ERK, Ras, c-Myc, HIF-1α, and p53 regulate glycolysis in chemical-induced carcinogenesis. However, the deregulation of the anabolic biochemistry of glucose during chemical-induced carcinogenesis remains to be uncovered. This review comprehensively covers the environmental chemical-induced glycolytic shift during carcinogenesis and its mechanism. The focus is also to fill the major gaps associated with understanding the fairy tale between environmental carcinogens and metabolic reprogramming. Although evidence from studies regarding glycolytic reprogramming in chemical carcinogenesis provides valuable insights into cancer therapy, exposure to a mixture of toxicants and their mechanism of inducing carcinogenesis still needs to be studied.
Abstract Neuroblastoma (NB) is a highly aggressive pediatric cancer that originates from immature nerve cells, presenting significant treatment challenges due to therapy resistance. Despite intensive ...treatment, approximately 50% of high-risk NB cases exhibit therapy resistance or experience relapse, resulting in poor outcomes often associated with tumor immune evasion. B7-H3 is an immune checkpoint protein known to inhibit immune responses. MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation. Our study aims to explore the impact of miRNAs on B7-H3 regulation, the anti-tumor immune response, and tumorigenicity in NB. Analysis of NB patients and patient-derived xenograft tumors revealed a correlation between higher B7-H3 expression and poorer patient survival. Notably, deceased patients exhibited a depletion of miR-29 family members (miR-29a, miR-29b, and miR-29c), which displayed an inverse association with B7-H3 expression in NB patients. Overexpression and knockdown experiments demonstrated that these miRNAs degrade B7-H3 mRNA, resulting in enhanced NK cell activation and cytotoxicity. In vivo, experiments provided further evidence that miR-29 family members reduce tumorigenicity, macrophage infiltration, and microvessel density, promote infiltration and activation of NK cells, and induce tumor cell apoptosis. These findings offer a rationale for developing more effective combination treatments that leverage miRNAs to target B7-H3 in NB patients.
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