Search Results (43)

Lung cancer treatment and detection can be improved by the identification of new biomarkers. Novel approaches in investigating circular RNAs (circRNAs) as biomarkers have yielded promising results. A circRNA molecule circHIPK3 was found to be widely expressed in non-small-cell lung cancer (NSCLC) cells, where it plays a crucial role in lung cancer tumorigenesis. CircHIPK3 promotes lung cancer progression by sponging oncosuppressive miRNAs such as miR-124, miR-381-3p, miR-149, and miR-107, which results in increased cell proliferation, migration, and resistance to therapies. Inhibiting circHIPK3 has been demonstrated to suppress tumour growth and induce apoptosis, which suggests its potential use in the development of new lung cancer treatment strategies targeting circHIPK3-related pathways. As a biomarker, circHIPK3 shows promise for early detection and monitoring of lung cancer. CircHIPK3 increased expression levels in lung cancer cells, and its potential link to metastasis risk highlights its clinical relevance. Given the promising preliminary findings, more clinical trials are needed to validate circHIPK3 efficacy as a biomarker. Moreover, future research should determine if the mechanisms discovered in NSCLC apply to small cell lung cancer (SCLC) to investigate circHIPK3-targeted therapies for SCLC. Full article

Colon cancer, one of the most common and fatal cancers worldwide, is characterized by stepwise accumulation of specific genetic alterations in tumor suppressor genes or oncogenes, leading to tumor growth and metastasis. HIPK2 (homeodomain-interacting protein kinase 2) is a serine/threonine protein kinase and a “bona fide” oncosuppressor protein. Its activation inhibits tumor growth mainly by promoting apoptosis, while its inactivation increases tumorigenicity and resistance to therapies of many different cancer types, including colon cancer. HIPK2 interacts with many molecular pathways by means of its kinase activity or transcriptional co-repressor function modulating cell growth and apoptosis, invasion, angiogenesis, inflammation and hypoxia. HIPK2 has been shown to participate in several molecular pathways involved in colon cancer including p53, Wnt/β-catenin and the newly identified nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2). HIPK2 also plays a role in tumor–host interaction in the tumor microenvironment (TME) by inducing angiogenesis and cancer-associated fibroblast (CAF) differentiation. The aim of this review is to assess the role of HIPK2 in colon cancer and the underlying molecular pathways for a better understanding of its involvement in colon cancer carcinogenesis and response to therapies, which will likely pave the way for novel colon cancer therapies. Full article

The rainbow trout (Oncorhynchus mykiss) is the most important produced species in freshwater within the European Union, usually reared in intensive farming systems. This species is highly susceptible to viral hemorrhagic septicemia (VHS), a severe systemic disease widespread globally throughout the world. Viral hemorrhagic septicemia virus (VHSV) is the etiological agent and, recently, three classes of VHSV virulence (high, moderate, and low) have been proposed based on the mortality rates, which are strictly dependent on the viral strain. The molecular mechanisms that regulate VHSV virulence and the stimulated gene responses in the host during infection are not completely unveiled. While some preliminary transcriptomic studies have been reported in other fish species, to date there are no publications on rainbow trout. Herein, we report the first time-course RNA sequencing analysis on rainbow trout juveniles experimentally infected with high and low VHSV pathogenic Italian strains. Transcriptome analysis was performed on head kidney samples collected at different time points (1, 2, and 5 days post infection). A large set of notable genes were found to be differentially expressed (DEGs) in all the challenged groups (e.s. trim63a, acod1, cox-2, skia, hipk1, cx35.4, ins, mtnr1a, tlr3, tlr7, mda5, lgp2). Moreover, the number of DEGs progressively increased especially during time with a greater amount found in the group infected with the high VHSV virulent strain. The gene ontology (GO) enrichment analysis highlighted that functions related to inflammation were modulated in rainbow trout during the first days of VHSV infection, regardless of the pathogenicity of the strain. While some functions showed slight differences in enrichments between the two infected groups, others appeared more exclusively modulated in the group challenged with the highly pathogenic strain. Full article

The formation and function of membrane-less organelles (MLOs) is one of the main driving forces in the molecular life of the cell. These processes are based on the separation of biopolymers into phases regulated by multiple specific and nonspecific inter- and intramolecular interactions. Among the realm of MLOs, a special place is taken by the promyelocytic leukemia nuclear bodies (PML-NBs or PML bodies), which are the intranuclear compartments involved in the regulation of cellular metabolism, transcription, the maintenance of genome stability, responses to viral infection, apoptosis, and tumor suppression. According to the accepted models, specific interactions, such as SUMO/SIM, the formation of disulfide bonds, etc., play a decisive role in the biogenesis of PML bodies. In this work, a number of bioinformatics approaches were used to study proteins found in the proteome of PML bodies for their tendency for spontaneous liquid–liquid phase separation (LLPS), which is usually caused by weak nonspecific interactions. A total of 205 proteins found in PML bodies have been identified. It has been suggested that UBC9, P53, HIPK2, and SUMO1 can be considered as the scaffold proteins of PML bodies. It was shown that more than half of the proteins in the analyzed proteome are capable of spontaneous LLPS, with 85% of the analyzed proteins being intrinsically disordered proteins (IDPs) and the remaining 15% being proteins with intrinsically disordered protein regions (IDPRs). About 44% of all proteins analyzed in this study contain SUMO binding sites and can potentially be SUMOylated. These data suggest that weak nonspecific interactions play a significantly larger role in the formation and biogenesis of PML bodies than previously expected. Full article

While metal-based complexes are deeply investigated as anticancer chemotherapeutic drugs, fewer studies are devoted to their anti-invasive activity. Herein, two copper (Cu)(II) tropolone derivatives, [Cu(Trop)Cl] and [Cu(Trop)Sac], both containing the N,N-chelated 4,4′-bishydroxymethyl-2,2′-bipyridne ligand, were evaluated for their anticancer and anti-invasive properties. RKO (RKO-ctr) colon cancer cells and their derivatives undergoing stable small interference (si) RNA for HIPK2 protein (RKO-siHIPK2) with acquisition of pro-invasive capacity were used. The results demonstrate that while [Cu(Trop)Sac] did not show cytotoxic activity, [Cu(Trop)Cl] induced cell death in both RKO-ctr and RKO-siHIPK2 cells, indicating that structural changes on substituting the coordinated chloride ligand with saccharine (Sac) could be a key factor in suppressing mechanisms of cellular death. On the other hand, both [Cu(Trop)Sac] and [Cu(Trop)Cl] complexes counteracted RKO-siHIPK2 cell migration in the wound healing assay. The synergic effect exerted by the concomitant presence of both tropolone and saccharin ligands in [Cu(Trop)Sac] was also supported by its significant inhibition of RKO-siHIPK2 cell migration compared to the free Sac ligand. These data suggest that the two Cu(II) tropolone derivatives are also interesting candidates to be further tested in in vivo models as an anti-invasive tumor strategy. Full article

Circular RNAs (circRNAs) are single-stranded RNA molecules often circularized by backsplicing. Growing evidence implicates circRNAs in the underlying mechanisms of various diseases, such as Alzheimer’s and Parkinson’s disease (PD)—the first and second most prevalent neurodegenerative disorders. In this sense, circSNCA, circHIPK2, circHIPK3, and circSLC8A1 are circRNAs that have been related to the neurodegenerative process of PD. Gain-of-function and loss-of-function studies on circRNAs have shed light on their roles in the pathobiology of various diseases. Gain-of-function approaches typically employ viral or non-viral vectors that hyperexpress RNA sequences capable of circularizing to form the specific circRNA under investigation. In contrast, loss-of-function studies utilize CRISPR/Cas systems, antisense oligonucleotides (ASOs), or RNAi techniques to knock down the target circRNA. The role of aberrantly expressed circRNAs in brain pathology has raised a critical question: could circRNAs serve as viable targets for neuroprotective treatments? Translating any oligonucleotide-based therapy, including those targeting circRNAs, involves developing adequate brain delivery systems, minimizing off-target effects, and addressing the high costs of treatment. Nonetheless, RNAi-based FDA-approved drugs have entered the market, and circRNAs have attracted significant attention and investment from major pharmaceutical companies. Spanning from bench to bedside, circRNAs present a vast opportunity in biotechnology for oligonucleotide-based therapies designed to slow or even halt the progression of neurodegenerative diseases. Full article

Indigenous pig populations in Hainan Province live in tropical climate conditions and a relatively closed geographical environment, which has contributed to the formation of some excellent characteristics, such as heat tolerance, strong disease resistance and excellent meat quality. Over the past few decades, the number of these pig populations has decreased sharply, largely due to a decrease in growth rate and poor lean meat percentage. For effective conservation of these genetic resources (such as heat tolerance, meat quality and disease resistance), the whole-genome sequencing data of 78 individuals from 3 native Chinese pig populations, including Wuzhishan (WZS), Tunchang (TC) and Dingan (DA), were obtained using a 150 bp paired-end platform, and 25 individuals from two foreign breeds, including Landrace (LR) and Large White (LW), were downloaded from a public database. A total of 28,384,282 SNPs were identified, of which 27,134,233 SNPs were identified in native Chinese pig populations. Both genetic diversity statistics and linkage disequilibrium (LD) analysis indicated that indigenous pig populations displayed high genetic diversity. The result of population structure implied the uniqueness of each native Chinese pig population. The selection signatures were detected between indigenous pig populations and foreign breeds by using the population differentiation index (F_ST) method. A total of 359 candidate genes were identified, and some genes may affect characteristics such as immunity (IL-2, IL-21 and ZFYVE16), adaptability (APBA1), reproduction (FGF2, RNF17, ADAD1 and HIPK4), meat quality (ABCA1, ADIG, TLE4 and IRX5), and heat tolerance (VPS13A, HSPA4). Overall, the findings of this study will provide some valuable insights for the future breeding, conservation and utilization of these three Chinese indigenous pig populations. Full article

Altered expression of circular RNAs (circRNAs) has previously been investigated in breast cancer. However, little is known about the effects of drugs on their regulation and relationship with the cognate linear transcript (linRNA). We analyzed the dysregulation of both 12 cancer-related circRNAs and their linRNAs in two breast cancer cell lines undergoing various treatments. We selected 14 well-known anticancer agents affecting different cellular pathways and examined their impact. Upon drug exposure circRNA/linRNA expression ratios increased, as a result of the downregulation of linRNA and upregulation of circRNA within the same gene. In this study, we highlighted the relevance of identifying the drug-regulated circ/linRNAs according to their oncogenic or anticancer role. Interestingly, VRK1 and MAN1A2 were increased by several drugs in both cell lines. However, they display opposite effects, circ/linVRK1 favors apoptosis whereas circ/linMAN1A2 stimulates cell migration, and only XL765 did not alter the ratio of other dangerous circ/linRNAs in MCF-7. In MDA-MB-231 cells, AMG511 and GSK1070916 decreased circGFRA1, as a good response to drugs. Furthermore, some circRNAs might be associated with specific mutated pathways, such as the PI3K/AKT in MCF-7 cells with circ/linHIPK3 correlating to cancer progression and drug-resistance, or NHEJ DNA repair pathway in TP-53 mutated MDA-MB-231 cells. Full article

HIPK2 is an evolutionary conserved protein kinase which modulates many molecular pathways involved in cellular functions such as apoptosis, DNA damage response, protein stability, and protein transcription. HIPK2 plays a key role in the cancer cell response to cytotoxic drugs as its deregulation impairs drug-induced cancer cell death. HIPK2 has also been involved in regulating fibrosis, angiogenesis, and neurological diseases. Recently, hyperglycemia was found to positively and/or negatively regulate HIPK2 activity, affecting not only cancer cell response to chemotherapy but also the progression of some diabetes complications. The present review will discuss how HIPK2 may be influenced by the high glucose (HG) metabolic condition and the consequences of such regulation in medical conditions. Full article

Lysosomotropic agent chloroquine was shown to sensitize non-stem glioblastoma cells to radiation in vitro with p53-dependent apoptosis implicated as one of the underlying mechanisms. The in vivo outcomes of chloroquine or its effects on glioblastoma stem cells have not been previously addressed. This study undertakes a combinatorial approach encompassing in vitro, in vivo and in silico investigations to address the relationship between chloroquine-mediated radiosensitization and p53 status in glioblastoma stem cells. Our findings reveal that chloroquine elicits antagonistic impacts on signaling pathways involved in the regulation of cell fate via both transcription-dependent and transcription-independent mechanisms. Evidence is provided that transcriptional impacts of chloroquine are primarily determined by p53 with chloroquine-mediated activation of pro-survival mevalonate and p21-DREAM pathways being the dominant response in the background of wild type p53. Non-transcriptional effects of chloroquine are conserved and converge on key cell fate regulators ATM, HIPK2 and AKT in glioblastoma stem cells irrespective of their p53 status. Our findings indicate that pro-survival responses elicited by chloroquine predominate in the context of wild type p53 and are diminished in cells with transcriptionally impaired p53. We conclude that p53 is an important determinant of the balance between pro-survival and pro-death impacts of chloroquine and propose that p53 functional status should be taken into consideration when evaluating the efficacy of glioblastoma radiosensitization by chloroquine. Full article

There are several studies on the deregulated gene expression profiles in kidney cancer, with varying results depending on the tumor histology and other parameters. None of these, however, have identified the networks that the co-deregulated genes (co-DEGs), across different studies, create. Here, we reanalyzed 10 Gene Expression Omnibus (GEO) studies to detect and annotate co-deregulated signatures across different subtypes of kidney cancer or in single-gene perturbation experiments in kidney cancer cells and/or tissue. Using a systems biology approach, we aimed to decipher the networks they form along with their upstream regulators. Differential expression and upstream regulators, including transcription factors [MYC proto-oncogene (MYC), CCAAT enhancer binding protein delta (CEBPD), RELA proto-oncogene, NF-kB subunit (RELA), zinc finger MIZ-type containing 1 (ZMIZ1), negative elongation factor complex member E (NELFE) and Kruppel-like factor 4 (KLF4)] and protein kinases [Casein kinase 2 alpha 1 (CSNK2A1), mitogen-activated protein kinases 1 (MAPK1) and 14 (MAPK14), Sirtuin 1 (SIRT1), Cyclin dependent kinases 1 (CDK1) and 4 (CDK4), Homeodomain interacting protein kinase 2 (HIPK2) and Extracellular signal-regulated kinases 1 and 2 (ERK1/2)], were computed using the Characteristic Direction, as well as GEO2Enrichr and X2K, respectively, and further subjected to GO and KEGG pathways enrichment analyses. Furthermore, using CMap, DrugMatrix and the LINCS L1000 chemical perturbation databases, we highlight putative repurposing drugs, including Etoposide, Haloperidol, BW-B70C, Triamterene, Chlorphenesin, BRD-K79459005 and β-Estradiol 3-benzoate, among others, that may reverse the expression of the identified co-DEGs in kidney cancers. Of these, the cytotoxic effects of Etoposide, Catecholamine, Cyclosporin A, BW-B70C and Lasalocid sodium were validated in vitro. Overall, we identified critical co-DEGs across different subtypes in kidney cancer, and our results provide an innovative framework for their potential use in the future. Full article

Angiogenesis is the formation of new blood capillaries taking place from preexisting functional vessels, a process that allows cells to cope with shortage of nutrients and low oxygen availability. Angiogenesis may be activated in several pathological diseases, from tumor growth and metastases formation to ischemic and inflammatory diseases. New insights into the mechanisms that regulate angiogenesis have been discovered in the last years, leading to the discovery of new therapeutic opportunities. However, in the case of cancer, their success may be limited by the occurrence of drug resistance, meaning that the road to optimize such treatments is still long. Homeodomain-interacting protein kinase 2 (HIPK2), a multifaceted protein that regulates different molecular pathways, is involved in the negative regulation of cancer growth, and may be considered a “bona fide” oncosuppressor molecule. In this review, we will discuss the emerging link between HIPK2 and angiogenesis and how the control of angiogenesis by HIPK2 impinges in the pathogenesis of several diseases, including cancer. Full article

GRTH/DDX25 is a testis-specific DEAD-box family of RNA helicase, which plays an essential role in spermatogenesis and male fertility. There are two forms of GRTH, a 56 kDa non-phosphorylated form and a 61 kDa phosphorylated form (pGRTH). GRTH-KO and GRTH Knock-In (KI) mice with R242H mutation (lack pGRTH) are sterile with a spermatogenic arrest at step 8 of spermiogenesis due to failure of round spermatids (RS) to elongate. We performed mRNA-seq and miRNA-seq analysis on RS of WT, KI, and KO to identify crucial microRNAs (miRNAs) and mRNAs during RS development by establishing a miRNA–mRNA network. We identified increased levels of miRNAs such as miR146, miR122a, miR26a, miR27a, miR150, miR196a, and miR328 that are relevant to spermatogenesis. mRNA–miRNA target analysis on these DE-miRNAs and DE-mRNAs revealed miRNA target genes involved in ubiquitination process (Ube2k, Rnf138, Spata3), RS differentiation, and chromatin remodeling/compaction (Tnp1/2, Prm1/2/3, Tssk3/6), reversible protein phosphorylation (Pim1, Hipk1, Csnk1g2, Prkcq, Ppp2r5a), and acrosome stability (Pdzd8). Post-transcriptional and translational regulation of some of these germ-cell-specific mRNAs by miRNA-regulated translation arrest and/or decay may lead to spermatogenic arrest in KO and KI mice. Our studies demonstrate the importance of pGRTH in the chromatin compaction and remodeling process, which mediates the differentiation of RS into elongated spermatids through miRNA–mRNA interactions. Full article

Fibrosis is an unmet medical problem due to a lack of evident biomarkers to help develop efficient targeted therapies. Fibrosis can affect almost every organ and eventually induce organ failure. Homeodomain-interacting protein kinase 2 (HIPK2) is a protein kinase that controls several molecular pathways involved in cell death and development and it has been extensively studied, mainly in the cancer biology field. Recently, a role for HIPK2 has been highlighted in tissue fibrosis. Thus, HIPK2 regulates several pro-fibrotic pathways such as Wnt/β-catenin, TGF-β and Notch involved in renal, pulmonary, liver and cardiac fibrosis. These findings suggest a wider role for HIPK2 in tissue physiopathology and highlight HIPK2 as a promising target for therapeutic purposes in fibrosis. Here, we will summarize the recent studies showing the involvement of HIPK2 as a novel regulator of fibrosis. Full article

Exosome-based therapy is emerging as a promising strategy to promote bone regeneration due to exosomal bioactive cargos, among which circular RNA (circRNA) has recently been recognized as the key effector. The role of exosomal circRNA derived from bone marrow mesenchymal stem cells (BMSCs) has not been well-defined. The present study aimed to clarify the regulatory function and molecular mechanism of BMSC-derived exosomal circRNA in osteogenesis. Exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) were isolated and identified. BMSC-Exos’ pro-osteogenic effect on MC3T3-E1 cells was validated by alkaline phosphatase (ALP) activity and Alizarin Red staining. Through bioinformatic analysis and molecular experiments, circHIPK3 was selected and verified as the key circRNA of BMSC-Exos to promote osteoblast differentiation of MC3T3-E1 cells. Mechanistically, circHIPK3 acted as an miR-29a-5p sponge and functioned in mitophagy via targeting miR-29a-5p and PINK1. Additionally, we showed that the mitophagy level of MC3T3-E1 cells were mediated by BMSC-Exos, which promoted the osteogenic differentiation. Collectively, our results revealed an important role for BMSC-derived exosomal circHIPK3 in osteogenesis. These findings provide a potentially effective therapeutic strategy for bone regeneration. Full article