Emerging cell cycle related non-coding RNA biomarkers from saliva and blood for oral squamous cell carcinoma.

The unnotified or undifferentiable early stages of oral squamous cell carcinoma (OSCC) progression are the prime reasons for late-stage detection and poor survival outcomes of oral cancer. This review summarizes the prior research and recent advancements on the influence of dysregulated non-coding RNA (ncRNA) on cell cycle and their employability as diagnostic and prognostic biomarkers of oral cancer. The literature search was performed using the following keywords: 'serum/saliva non-coding RNAs' and 'serum/saliva non-coding RNAs and cell cycle', 'serum/saliva dysregulated ncRNAs and cell cycle', 'Cdk/CKI and ncRNAs', 'tissue ncRNAs' concerning 'oral cancer''. The compiled data focuses mainly on the diagnostic and prognostic significance of MicroRNAs (miRNAs), Circular RNAs (circRNAs), and Long noncoding RNAs (lncRNAs) on oral cancer and all other cancers as well as subject-relevant articles published in languages other than English are beyond the scope of this review and excluded from the study. Moreover, articles focusing on DNA, protein, and metabolite markers are eliminated from the study. While there exist various potential biomolecules such as DNA, RNA, proteins, metabolites, and specific antigens representing predictive biomarkers in body fluids for oral cancer, this review completely focuses on non-coding RNAs restricted to saliva and blood, picking out a few of the reliable ones amongst the recent investigations based on the sophisticated techniques, cohort, and sensitivity as well as specificity, i.e., salivary miR-1307-5p, miR-3928, hsa_circ_0001874 and ENST00000412740, NR_131012, ENST00000588803, NR_038323, miR-21 in circulation. Thus, further studies are required to clinically confirm the usage of these non-invasive biomarkers in oral cancer.

Combinatorial approaches of nanotherapeutics for inflammatory pathway targeted therapy of prostate cancer.

Prostate cancer (PC) is the most prevalent male urogenital cancer worldwide. PC patients presenting an advanced or metastatic cancer succumb to the disease, even after therapeutic interventions including radiotherapy, surgery, androgen deprivation therapy (ADT), and chemotherapy. One of the hallmarks of PC is evading immune surveillance and chronic inflammation, which is a major challenge towards designing effective therapeutic formulations against PC. Chronic inflammation in PC is often characterized by tumor microenvironment alterations, epithelial-mesenchymal transition and extracellular matrix modifications. The inflammatory events are modulated by reactive nitrogen and oxygen species, inflammatory cytokines and chemokines. Major signaling pathways in PC includes androgen receptor, PI3K and NF-κB pathways and targeting these inter-linked pathways poses a major therapeutic challenge. Notably, many conventional treatments are clinically unsuccessful, due to lack of targetability and poor bioavailability of the therapeutics, untoward toxicity and multidrug resistance. The past decade witnessed an advancement of nanotechnology as an excellent therapeutic paradigm for PC therapy. Modern nanovectorization strategies such as stimuli-responsive and active PC targeting carriers offer controlled release patterns and superior anti-cancer effects. The current review initially describes the classification, inflammatory triggers and major inflammatory pathways of PC, various PC treatment strategies and their limitations. Subsequently, recent advancement in combinatorial nanotherapeutic approaches, which target PC inflammatory pathways, and the mechanism of action are discussed. Besides, the current clinical status and prospects of PC homing nanovectorization, and major challenges to be addressed towards the advancement PC therapy are also addressed.

Cdk2 catalytic activity is essential for meiotic cell division in vivo.

Cyclin-dependent kinases (Cdks) control the eukaryotic cell cycle by phosphorylating serine and threonine residues in key regulatory proteins, but some Cdk family members may exert kinase-independent functions that cannot easily be assessed using gene knockout approaches. While Cdk2-deficient mice display near-normal mitotic cell proliferation due to the compensatory activities of Cdk1 and Cdk4, they are unable to undergo meiotic generation of gametes and are consequently sterile. To investigate whether Cdk2 regulates meiosis via protein phosphorylation or by alternative kinase-independent mechanisms, we generated two different knockin mouse strains in which Cdk2 point mutations ablated enzyme activity without altering protein expression levels. Mice homozygous for the mutations Cdk2(D145N/D145N) or Cdk2(T160A/T160A) expressed only 'kinase-dead' variants of Cdk2 under the control of the endogenous promoter, and despite exhibiting normal expression of cell cycle regulatory proteins and complexes, both mutations rendered mice sterile. Mouse cells that expressed only 'kinase-dead' variants of Cdk2 displayed normal mitotic cell cycle progression and proliferation both in vitro and in vivo, indicating that loss of Cdk2 kinase activity exerted little effect on this mode of cell division. In contrast, the reproductive organs of Cdk2 mutant mice exhibited abnormal morphology and impaired function associated with defective meiotic cell division and inability to produce gametes. Cdk2 mutant animals were therefore comparable to gene knockout mice, which completely lack the Cdk2 protein. Together, our data indicate that the essential meiotic functions of Cdk2 depend on its kinase activity, without which the generation of haploid cells is disrupted, resulting in sterility of otherwise healthy animals.

Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration.

Cyclin-dependent kinase 1 (Cdk1) is an archetypical kinase and a central regulator that drives cells through G2 phase and mitosis. Knockouts of Cdk2, Cdk3, Cdk4, or Cdk6 have resulted in viable mice, but the in vivo functions of Cdk1 have not been fully explored in mammals. Here we have generated a conditional-knockout mouse model to study the functions of Cdk1 in vivo. Ablation of Cdk1 leads to arrest of embryonic development around the blastocyst stage. Interestingly, liver-specific deletion of Cdk1 is well tolerated, and liver regeneration after partial hepatectomy is not impaired, indicating that regeneration can be driven by cell growth without cell division. The loss of Cdk1 does not affect S phase progression but results in DNA re-replication because of an increase in Cdk2/cyclin A2 activity. Unlike other Cdks, loss of Cdk1 in the liver confers complete resistance against tumorigenesis induced by activated Ras and silencing of p53.

Circulating metabolite biomarkers: a game changer in the human prostate cancer diagnosis.

PURPOSE: Prostate cancer (PCa) is the second most commonly diagnosed cancer in men in Western and Asian countries. Serum prostate-specific antigen (PSA) test has been the routine diagnostic method despite the tremendous research in diagnostic markers for early detection of PCa. A shift towards a promising and potential biomarker for PCa detection is through metabolomic profiling of biofluids, particularly the blood and urine samples. Finding reliable, routinely usable circulating metabolite biomarkers may not be a distant reality. METHODS: We performed a PubMed-based literature search of metabolite biomarkers in blood and urine for the early detection of prostate cancer. The timeline of these searches was limited between 2007 and 2022 and the following keywords were used: 'metabolomics', 'liquid biopsy', 'circulating metabolites', 'serum metabolite', 'plasma metabolite', and 'urine metabolite' with respect to 'prostate cancer'. We focussed only on diagnosis-based studies with only the subject-relevant articles published in the English language and excluded all of the other irrelevant publications that included prostate tissue biomarkers and cell line biomarkers. RESULTS: We have consolidated all the blood and urine-based potential metabolite candidates in individual as well as panels, including lipid classes, fatty acids, amino acids, and volatile organic compounds which may become useful for PCa diagnosis. CONCLUSION: All these metabolome findings unveil the impact of different dimensions of PCa development, giving a promising strategy to diagnose the disease since suspected individuals can be subjected to repeated and largescale blood and urine testing.

Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinoma.

Studies of prostate cancer pathogenesis and development of new therapies have been hampered by a lack of appropriate mouse models. We have generated PSA-Cre-ER(T2) mice that express the tamoxifen-dependent Cre-ER(T2) recombinase selectively in prostatic epithelium, thus allowing us to target floxed genes selectively in epithelial cells of fully differentiated prostate of adult mice and to modulate the number of genetically altered cells. Our present mouse model, in which prostate carcinogenesis is initiated through Cre-ER(T2)-mediated somatic biallelic ablation of the tumor suppressor gene PTEN after puberty, closely mimics the course of human cancer formation. Indeed, mutant mice developed prostate epithelium hyperplasia within 4 weeks after PTEN ablation and prostatic intraepithelial neoplasia (PIN) in all lobes within 2-3 months, with the highest incidence in the dorsolateral lobe, which is considered to be the most similar to the peripheral zone of the human prostate, in which adenocarcinoma is preferentially localized. Eight to 10 months after PTEN ablation some PINs of the dorsolateral lobe had progressed to adenocarcinoma, but no distant metastases were found up to 20 months after PTEN ablation, indicating that progression to metastasis requires an additional mutation or mutations. Interestingly, monoallelic Cre-ER(T2)-mediated PTEN ablation in epithelial cells of adult prostate also generated focal hyperplasia and PINs, but exclusively in the dorsolateral lobe, and in much lower number and after a longer latency. However, no progression to adenocarcinoma was observed. Because PTEN expression was undetectable in epithelial cells from these PINs, loss of PTEN function appears to act as a permissive event for uncontrolled cell proliferation.

Repertoires of MicroRNA-30 family as gate-keepers in lung cancer.

Lung cancer is a prominent global health issue responsible for the highest fraction of cancer-related mortality. The disease burden has incited the investigation of associated molecular pathways, to explore better therapeutic possibilities. MicroRNAs are extensively studied in recent years for their pivotal role in the regulation of several tumorigenic pathways. MicroRNA-30 (miR-30) family is primarily investigated in case of non-small cell lung cancer (NSCLC) and has been found to play the role of a tumour suppressor. There are six members of miR-30 family: miR-30a, miR-30b, miR-30c-1, miR-30c-2, miR-30d and miR-30e. They regulate several imperative signalling pathways like p53, PI3K/AKT, resulting in the modulation of key carcinogenic events involving cell proliferation, apoptosis, metastasis, epithelial-mesenchymal transition, and drug resistance. Their altered levels are documented in NSCLC tissue and blood samples. They are suggested as biomarkers of disease progression and therapeutic outcomes in lung cancer. They possess immense therapeutic potential in the treatment of lung cancer and combat the emerging problem of drug resistance by modulating prime regulatory axes. However, there are many limitations in the existing studies, and additional research is required for the comprehensive understanding of pathways so that the tumour suppressive potential of miR-30 can be translated into clinical benefits. In this review, we present a deeper understanding of the regulatory role and clinical significance of miR-30 and have emphasized the emerging roles in lung cancer.

CDK2 regulates the NRF1/Ehmt1 axis during meiotic prophase I.

Meiosis generates four genetically distinct haploid gametes over the course of two reductional cell divisions. Meiotic divisions are characterized by the coordinated deposition and removal of various epigenetic marks. Here we propose that nuclear respiratory factor 1 (NRF1) regulates transcription of euchromatic histone methyltransferase 1 (EHMT1) to ensure normal patterns of H3K9 methylation during meiotic prophase I. We demonstrate that cyclin-dependent kinase (CDK2) can bind to the promoters of a number of genes in male germ cells including that of Ehmt1 through interaction with the NRF1 transcription factor. Our data indicate that CDK2-mediated phosphorylation of NRF1 can occur at two distinct serine residues and negatively regulates NRF1 DNA binding activity in vitro. Furthermore, induced deletion of Cdk2 in spermatocytes results in increased expression of many NRF1 target genes including Ehmt1 We hypothesize that the regulation of NRF1 transcriptional activity by CDK2 may allow the modulation of Ehmt1 expression, therefore controlling the dynamic methylation of H3K9 during meiotic prophase.

Established and novel Cdk/cyclin complexes regulating the cell cycle and development.

The identification of new members in the Cdk and cyclin families, functions for many of which are still emerging, has added new facets to the cell cycle regulatory network. With roles extending beyond the classical regulation of cell cycle progression, these new players are involved in diverse processes such as transcription, neuronal function, and ion transport. Members closely related to Cdks and cyclins such as the Speedy/RINGO proteins offer fresh insights and hope for filling in the missing gaps in our understanding of cell division. This chapter will present a broad outlook on the cell cycle and its key regulators with special emphasis on the less-studied members and their emerging roles.