Regulation of the P53 tumor suppressor gene and the Mcl-2 oncogene expression by an active herbal component delivered through a smart thermo-pH-sensitive PLGA carrier to improve Osteosarcoma treatment.

Osteosarcoma (OS), a lethal malignancy, has witnessed an escalating incidence rate. Contemporary therapeutic strategies for this cancer have proven to be inadequate, primarily due to their extensive side effects and the lack of specificity in targeting the molecular pathways implicated in this disease. Consequently, this project is aimed to manufacture and characterize Poly (Lactic-co-glycolic acid) embodying curcumin, a phytocompound devoid of adverse effects which not only exerts an anti-neoplastic influence but also significantly modulates the genetic pathways associated with this malignancy. In this investigation, multiple formulations of PLGA-Cur were synthesized, and the choice of optimal formula was made considering the efficiency of nanoparticle encapsulation and the drug dispersion rate from synthesized PLGA. The selected formulation's physical and chemical attributes, such as its dimension, polydispersity index of the formulation, surface electrical charge, physical-spatial structure, and stability, were examined using methods, including Dynamic light scattering (DLS), Scanning Electron Microscopy (SEM), Atomic Force Microscopy (AFM), and spectrophotometry. Subsequently, the absence of interaction between the drug and the system was assessed using Fourier Transform Infrared Spectroscopy (FT-IR), and cellular uptake was evaluated using fluorescence microscopy. The smart system's responsiveness to environmental stimuli was determined using the dialysis bag method and its anti-tumor properties were investigated on the SAOS-2 cell line. Finally, to evaluate the system's genetic impact on bone cancer, the molecular quantification of the P53 tumor suppressor gene and the oncogene MCL-2 was analyzed using real-time PCR and their protein expression levels were also examined. The PLGAs synthesized in this study exhibited an encapsulation rate of 91.5 ± 1.16% and a maximum release rate of 71 ± 1%, which were responsive to various stimuli. The size of the PLGAs was 12.5 ± 321.2 nm, with an electric charge of -38.9 ± 2.6 mV and a PDI of 0.107, indicating suitable morphology and stability. Furthermore, both the system and the drug retained their natural properties after inoculation. The system was readily absorbed by cancer cells and effectively exerted its anti-cancer properties. Notably, the system had a significant impact on the mentioned genes' expression. The produced nanosystem, possessing optimal physicochemical properties, has the potential to enhance the anti-cancer efficacy of curcumin. This is achieved by altering molecular and genetic pathways within cancer cells, thereby positioning it as a viable adjunctive treatment modality and also synthesizing of this herbal base drug system consider as a completely novel method for cancer therapy that can efficiently modulate genetical pathways involved.

Antiproliferative efficacy of the antioxidant bioactive compounds of defatted seeds of Azadirachta indica and Momordica charantia against the regulatory function of tumor suppressor gene inducing oral carcinoma.

The present study focuses on the antiproliferative activity of polyphenolic flavonoids found in defatted seeds of Azadirachta indica and Momordica charantia with the regulatory function of tumor suppressor genes inducing Oral Squamous Cell Carcinoma. Polyphenolic flavonoid in extracts was characterized using chromatographic analysis and has confirmed the presence of quercetin, rutin and tannic acid in the extracts of A. indica and M. charantia. According to DPPH assay and reducing power assays, free radical scavenging was found to be high in ethanolic extract of defatted seeds. Antiproliferative efficacies of defatted seed extracts against KB cell line (mouth) were studied by MTT assay and revealed that aqueous extract of defatted seeds of M. charantia has exhibited maximum antiproliferative activity against KB cells. Antioxidant activity of defatted seed extracts were observed on treated KB cells by determining enzymatic activity (SOD, Cat, and GST) and nonenzyme content (GSH and MDA Content). Using the AutoDock tool, quercetin, rutin and tannin acid revealed that mutant p53, TWIST related protein, TGF-ß and Snail I have the best binging energy results. MD simulation was observed on best docking results between the molecule and identified flavonoid by Desmond V 5.9 package . This leads to the conclusion that bioactive extracts with antiproliferative activity, antioxidant capacity and polyphenols with binding efficacy against tumor suppressor gene regulatory function could be used as a herbal remedy.Communicated by Ramaswamy H. Sarma.

Microrna-96 In Human Cancers.

MicroRNAs (miRNAs) are small non-coding RNAs 19-25 nucleotides in size involved in gene regulation and diverse processes in tumor cells. Abnormal expression of miRNAs is closely related to carcinogenesis. MiR-96 is a salient cancer-related miRNA in a variety of tumors. Recent evidence indicates that miR-96 has been observed to be wrapped in exosome and associated with drug resistance or radio-chemosensitivity in cancers. miR-96 is also inextricably linked with the competing endogenous RNAs (ceRNAs) in cancers. Notably, miR-96 plays both a tumor suppressor role and plays a carcinogenic role in the same cancers. This review summarizes the critical role of cancer-related miR-96 in drug resistance or radio-chemosensitivity and ceRNA mechanisms of miR-96 in cancer. And we innovatively propose that miR-96 has a yin-yang effect in cancers. Based on these several major roles of miR-96 in cancer as described above, we speculate that the abnormal expression of miR-96 is likely to be novel potential therapeutic targets in cancers. It is expected to solve the treatment problems such as low chemoradiotherapy sensitivity, poor prognosis quality of life and easy recurrence in cancer patients.

Anticancer Effect of Puerarin on Ovarian Cancer Progression Contributes to the Tumor Suppressor Gene Expression and Gut Microbiota Modulation.

Ovarian cancer (OC) causes more deaths than any other cancer of the female reproductive system due to its late presentation and malignant nature. Although significant progress has been made in the diagnosis and treatment of OC over the last decade, chemotherapeutic drug resistance and cancer recurrence remain serious challenges in OC management. In the field of cancer therapy, traditional Chinese herbal medicines and their active compounds have been widely reported to have favorable therapeutic effects on cancer. Recent studies have also revealed the protective effect of puerarin in cancer, but the exact role and underlying mechanism of puerarin in OC remain unclear. Here, we established in vivo and in vitro OC models to evaluate the anticancer effect of puerarin. It was found that puerarin significantly inhibited OC cell viability and proliferation and induced cell apoptosis. In OC model mice, puerarin treatment suppressed tumor formation and modulated the gut microbiome. In addition, the expression of tumor suppressor genes was activated by puerarin in vitro and in vivo. These findings add to the existing knowledge on the usefulness of herbal active ingredients for the prevention and treatment of OC and provide a new perspective regarding the therapeutic potential of puerarin in cancer.

Hypothalamic kisspeptin and kisspeptin receptors: Species variation in reproduction and reproductive behaviours.

Kisspeptin, encoded by the KISS1 gene, was first discovered as a potential metastasis suppressor gene. The prepro-kisspeptin precursor is cleaved into shorter mature bioactive peptides of varying sizes that bind to the G protein-coupled receptor GPR54 (=KISS1R). Over the last two decades, multiple types of Kiss and KissR genes have been discovered in mammalian and non-mammalian vertebrate species, but they are remarkably absent in birds. Kiss neuronal populations are distributed mainly in the hypothalamus. The KissRs are widely distributed in the brain, including the hypothalamic and non-hypothalamic regions, such as the hippocampus, amygdala, and habenula. The role of KISS1-KISS1R in humans and Kiss1-Kiss1R in rodents is associated with puberty, gonadal maturation, and the reproductive axis. However, recent gene deletion studies in zebrafish and medaka have provided controversial results, suggesting that the reproductive role of kiss is dispensable. This review highlights the evolutionary history, localisation, and significance of Kiss-KissR in reproduction and reproductive behaviours in mammalian and non-mammalian vertebrates.

Combined effects of cigarette smoking, DNA methyltransferase 3B genetic polymorphism, and DNA damage on lung cancer.

BACKGROUND: Smoking increases DNA methylation and DNA damage, and DNA damage acts as a vital cause of tumor development. The DNA methyltransferase 3B (DNMT3B) enhances promoter activity and methylation of tumor suppressor genes. Tea polyphenols may inhibit DNMT activity. We designed a case-control study to evaluate the combined effects of smoking, green tea consumption, DNMT3B - 149 polymorphism, and DNA damage on lung cancer occurrence. METHODS: Questionnaires were administered to obtain demographic characteristics, life styles, and family histories of lung cancer from 190 primary lung cancer cases and 380 healthy controls. Genotypes and cellular DNA damage were determined by polymerase chain reaction and comet assay, respectively. RESULTS: The mean DNA tail moment for lung cancer cases was significantly higher than that for healthy controls. Compared to nonsmokers carrying the DNMT3B - 149 CT genotype, smokers carrying the TT genotype had a greater lung cancer risk (odds ratio [OR]: 2.83, 95% confidence interval [CI]: 1.62-4.93). DNA damage levels were divided by the tertile of the healthy controls' values. Compared to nonsmokers with low DNA damage, smokers with moderate DNA damage (OR: 2.37, 95% CI: 1.54-3.63) and smokers with high DNA damage (OR: 3.97, 95% CI: 2.63-5.98) had elevated lung cancer risks. Interaction between smoking and DNA damage significantly affected lung cancer risk. CONCLUSIONS: Our study suggested that the DNMT3B - 149 TT genotype, which has higher promoter activity, can increase the lung cancer risk elicited by smoking, and DNA damage may further promote smoking related lung cancer development.

A novel tumor suppressor CECR2 down regulation links glutamine metabolism contributes tumor growth in laryngeal squamous cell carcinoma.

PURPOSE: Glutamine plays an important role in tumor metabolism and progression. This research aimed to find out how Gln exert their effects on laryngeal squamous cell carcinoma (LSCC). METHODS: Cell proliferation was measured by CCK8 and EdU assay, mitochondrial bioenergetic activity was measured by mitochondrial stress tests. Gene expression profiling was revealed by RNA sequencing and validated by RT-qPCR. In LSCC patients, protein expression in tumor and adjacent tissues was examined and scored by IHC staining. RNAi was performed by stably expressed shRNA in TU177 cells. In vivo tumor growth analysis was performed using a nude mouse tumorigenicity model. RESULTS: Gln deprivation suppressed TU177 cell proliferation, which was restored by αKG supplementation. By transcriptomic analysis, we identified CECR2, which encodes a histone acetyl-lysine reader, as the downstream target gene for Gln and αKG. In LSCC patients, the expression of CECR2 in tumors was lower than adjacent tissues. Furthermore, deficiency of CECR2 promoted tumor cell growth both in vitro and in vivo, suggesting it has tumor suppressor effects. Besides, cell proliferation inhibited by Gln withdrawal could be restored by CECR2 depletion, and the proliferation boosted by αKG supplementation could be magnified either, suggested that CECR2 feedback suppressed Gln and αKG's effect on tumor growth. Transcriptomic profiling revealed CECR2 regulated the expression of a series of genes involved in tumor progression. CONCLUSION: We confirmed the Gln-αKG-CECR2 axis contributes to tumor growth in LSCC. This finding provided a potential therapeutic opportunity for the use of associated metabolites as a potential treatment for LSCC.

Clocks, cancer, and chronochemotherapy.

The circadian clock coordinates daily rhythmicity of biochemical, physiologic, and behavioral functions in humans. Gene expression, cell division, and DNA repair are modulated by the clock, which gives rise to the hypothesis that clock dysfunction may predispose individuals to cancer. Although the results of many epidemiologic and animal studies are consistent with there being a role for the clock in the genesis and progression of tumors, available data are insufficient to conclude that clock disruption is generally carcinogenic. Similarly, studies have suggested a circadian time-dependent efficacy of chemotherapy, but clinical trials of chronochemotherapy have not demonstrated improved outcomes compared with conventional regimens. Future hypothesis-driven and discovery-oriented research should focus on specific interactions between clock components and carcinogenic mechanisms to realize the full clinical potential of the relationship between clocks and cancer.

Role of Kisspeptin in Regulation of Reproductive and Immune Reactions.

The work is focused on physiological role of the hormone kisspeptin produced by neurons of the hypothalamus anterior zone, which is a key regulator of reproduction processes. Role of the hormone in transmission of information on metabolic activity and induction of the secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus that determines gestation processes involving fertilization, placentation, fetal development, and child birth is considered. The literature data on molecular mechanisms and effects of kisspeptin on reproductive system including puberty initiation are summarized and analyzed. In addition, attention is paid to hormone-mediated changes in the cardiovascular system in pregnant women. For the first time, the review examines the effect of kisspeptin on functional activity of immune system cells presenting molecular mechanisms of the hormone signal transduction on the level of lymphoid cells that lead to the immune tolerance induction. In conclusion, a conceptual model is presented that determines the role of kisspeptin as an integrator of reproductive and immune functions during pregnancy.

Cellular and molecular properties of neural progenitors in the developing mammalian hypothalamus.

The neuroendocrine hypothalamus is the central regulator of vital physiological homeostasis and behavior. However, the cellular and molecular properties of hypothalamic neural progenitors remain unexplored. Here, hypothalamic radial glial (hRG) and hypothalamic mantle zone radial glial (hmRG) cells are found to be neural progenitors in the developing mammalian hypothalamus. The hmRG cells originate from hRG cells and produce neurons. During the early development of hypothalamus, neurogenesis occurs in radial columns and is initiated from hRG cells. The radial glial fibers are oriented toward the locations of hypothalamic subregions which act as a scaffold for neuronal migration. Furthermore, we use single-cell RNA sequencing to reveal progenitor subtypes in human developing hypothalamus and characterize specific progenitor genes, such as TTYH1, HMGA2, and FAM107A. We also demonstrate that HMGA2 is involved in E2F1 pathway, regulating the proliferation of progenitor cells by targeting on the downstream MYBL2. Different neuronal subtypes start to differentiate and express specific genes of hypothalamic nucleus at gestational week 10. Finally, we reveal the developmental conservation of nuclear structures and marker genes in mouse and human hypothalamus. Our identification of cellular and molecular properties of neural progenitors provides a basic understanding of neurogenesis and regional formation of the non-laminated hypothalamus.

Circadian Oscillations Persist in Cervical and Esophageal Cancer Cells Displaying Decreased Expression of Tumor-Suppressing Circadian Clock Genes.

There is accumulating evidence for a link between circadian clock disruption and cancer progression. In this study, the circadian clock was investigated in cervical and esophageal cancers, to determine whether it is disrupted in these cancer types. Oncomine datamining revealed downregulation of multiple members of the circadian clock gene family in cancer patient tissue compared with matched normal epithelium. Real-time RT-PCR analysis confirmed significant downregulation of CLOCK, PER1, PER2, PER3, CRY1, CRY2, REV-ERBα, and RORα in esophageal tumor tissue. In cell line models, expression of several circadian clock genes was significantly decreased in transformed and cancer cells compared with noncancer controls, and protein levels were dysregulated. These effects were mediated, at least in part, by methylation, where CLOCK, CRY1, and RORα gene promoter regions were found to be methylated in cancer cells. Overexpression of CLOCK and PER2 in cancer cell lines inhibited cell proliferation and activation of RORα and REV-ERBα using agonists resulted in cancer cell death, while having a lesser effect on normal epithelial cells. Despite dysregulated circadian clock gene expression, cervical and esophageal cancer cells maintain functional circadian oscillations after Dexamethasone synchronization, as revealed using real-time bioluminescence imaging, suggesting that their circadian clock mechanisms are intact. IMPLICATIONS: This study is a first to describe dysregulated, yet oscillating, circadian clock gene expression in cervical and esophageal cancer cells, and knowledge of circadian clock functioning in these cancer types has the potential to inform chronotherapy approaches, where the timing of administration of chemotherapy is optimized on the basis of the circadian clock.

[Research on Analysis of Final Diagnosis and Prognostic Factors, and Development of New Therapeutic Drugs for Malignant Tumors (Especially Malignant Pediatric Tumors)].

Outcomes of treatment for malignant pediatric tumors including leukemia are improving by conventional multimodal treatment with strong chemotherapy, surgical resection, radiotherapy, and bone marrow transplantation. However, patients with advanced neuroblastoma, metastatic Ewing's sarcoma family of tumor (ESFT), and metastatic osteosarcoma continue to have an extremely poor prognosis. Therefore novel therapeutic strategies are urgently needed to improve their survival. Apoptotic cell death is a key mechanism for normal cellular homeostasis. Intact apoptotic mechanisms are pivotal for embryonic development, tissue remodeling, immune regulation, and tumor regression. Genetic aberrations disrupting programmed cell death often underpin tumorigenesis and drug resistance. Moreover, it has been suggested that apoptosis or cell differentiation proceeds to spontaneous regression in early stage neuroblastoma. Therefore apoptosis or cell differentiation is a critical event in this cancer. We extracted many compounds from natural plants (Angelica keiskei, Alpinia officiarum, Lycaria puchury-major, Brassica rapa) or synthesized cyclophane pyridine, indirubin derivatives, vitamin K3 derivatives, burchellin derivatives, and GANT61, and examined their effects on apoptosis, cell differentiation, and cell cycle in neuroblastoma and ESFT cell lines compared with normal cells. Some compounds were very effective against these tumor cells. These results suggest that they may be applicable as an efficacious and safe drug for the treatment of malignant pediatric tumors.

6-Gingerol stabilized the p-VEGFR2/VE-cadherin/ß-catenin/actin complex promotes microvessel normalization and suppresses tumor progression.

BACKGROUND: Anti-angiogenic therapies demonstrate anti-tumor effects by decreasing blood supply to tumors and inhibiting tumor growth. However, anti-angiogenic therapy may leads to changes in tumor microenvironment and increased invasiveness of tumor cells, which in turn promotes distant metastasis and increased drug resistance. METHODS: The CO-IP assays, N-STORM and cytoskeleton analysis were used to confirm the mechanism that p-VEGFR2/VE-cadherin/ß-catenin/actin complex regulates vascular remodeling and improves the tumor microenvironment. 6-gingerol (6G), the major bioactive component in ginger, stabilized this complex by enhancing the binding of VEGFa to VEGFR2 with non-pathway dependent. Biacore, pull down and molecular docking were employed to confirm the interaction between 6G and VEGFR2 and enhancement of VEGFa binding to VEGFR2. RESULTS: Here, we report that microvascular structural entropy (MSE) may be a prognostic factor in several tumor types and have potential as a biomarker in the clinic. 6G regulates the structural organization of the microvascular bed to decrease MSE via the p-VEGFR2/VE-cadherin/ß-catenin/actin complex and inhibit tumor progression. 6G promotes the normalization of tumor vessels, improves the tumor microenvironment and decreases MSE, facilitating the delivery of chemotherapeutic agents into the tumor core and thereby reducing tumor growth and metastasis. CONCLUSIONS: This study demonstrated the importance of vascular normalization in tumor therapy and elucidated the mechanism of action of ginger, a medicinal compound that has been used in China since ancient times.

Expanding the Biotherapeutics Realm via miR-34a: "Potent Clever Little" Agent in Breast Cancer Therapy.

BACKGROUND: One of the most prevalent cancers befell to women is considered to be breast cancer (BC). It is also the deadliest among the female population after lung cancer. Additionally, several studies have demonstrated that there is an association between microRNA34-a and breast cancer. METHODS: We searched PubMed, Web of Science, and Google Scholar up to December 2018. Those studies which have been studied miR-34a and its tumor-suppressing capabilities were considered as the most important topics. Moreover, we extracted articles which were solely focused on microRNA-34a in breast cancer therapy. Finally, 80 articles were included. RESULTS: In comparison with the normal tissues, down-regulation of miR-34a expression is shown considerably in tumor cells. Overexpression of miR-34a acts as a tumor suppressor by transcriptional regulating one of the signaling pathways (TP53), NOTCH, and transforming growth factor beta (TGF-ß), Bcl- 2 and SIRT1genes, HDAC1 and HDAC7, Fra-1, TPD52, TLR Via CXCL10. Moreover, drug resistance declines which lead to the apoptosis, cell cycle arrest and senescence. As a result, the proliferation, invasion and metastasis of the tumor are suppressed. The Mrx34 drug contains miR-34a mimic and a lipid vector. MiR-34a as the active ingredient portrays the role of a tumor suppressor. This drug has recently entered the clinical trials studies. CONCLUSION: These findings suggest a robust cause for developing miR-34a as a therapeutic agent to target BC. In that scenario, miR-34a is strongly useful to introduce new therapeutic goals for BC. Moreover, this review aims to confirm the signal pathways, therapeutic and diagnostic values of miR- 34a in BC and beyond.

Peroxynitrite supports a metabolic reprogramming in merlin-deficient Schwann cells and promotes cell survival.

Neurofibromatosis type 2 (NF2) is an autosomal-dominant disorder characterized by the development of bilateral vestibular schwannomas. The NF2 gene encodes the tumor suppressor merlin, and loss of merlin activity promotes tumorigenesis and causes NF2. Cellular redox signaling has been implicated in different stages of tumor development. Among reactive nitrogen species, peroxynitrite is the most powerful oxidant produced by cells. We recently showed that peroxynitrite-mediated tyrosine nitration down-regulates mitochondrial metabolism in tumor cells. However, whether peroxynitrite supports a metabolic shift that could be exploited for therapeutic development is unknown. Here, we show that vestibular schwannomas from NF2 patients and human, merlin-deficient (MD) Schwann cells have high levels of endogenous tyrosine nitration, indicating production of peroxynitrite. Furthermore, scavenging or inhibiting peroxynitrite formation significantly and selectively decreased survival of human and mouse MD-Schwann cells. Using multiple complementary methods, we also found that merlin deficiency leads to a reprogramming of energy metabolism characterized by a peroxynitrite-dependent decrease of oxidative phosphorylation and increased glycolysis and glutaminolysis. In MD-Schwann cells, scavenging of peroxynitrite increased mitochondrial oxygen consumption and membrane potential, mediated by the up-regulation of the levels and activity of mitochondrial complex IV. This increase in mitochondrial activity correlated with a decrease in the glycolytic rate and glutamine dependence. This is the first demonstration of a peroxynitrite-dependent reprogramming of energy metabolism in tumor cells. Oxidized proteins constitute a novel target for therapeutic development not only for the treatment of NF2 schwannomas but also other tumors in which peroxynitrite plays a regulatory role.

One hundred years of Drosophila cancer research: no longer in solitude.

When Mary Stark first described the presence of tumours in the fruit fly Drosophila melanogaster in 1918, would she ever have imagined that flies would become an invaluable organism for modelling and understanding oncogenesis? And if so, would she have expected it to take 100 years for this model to be fully accredited? This Special Article summarises the efforts and achievements of Drosophilists to establish the fly as a valid model in cancer research through different scientific periods.

MicroRNA-520c-3p functions as a novel tumor suppressor in lung adenocarcinoma.

Lung cancer is a malignancy with one of the highest incidence rates, and it is the leading cause of cancer-related death. To gain further insights into the underlying mechanisms of tumor growth and metastasis, we investigated the role and expression of microRNAs in lung adenocarcinoma (LUAD). We discovered a significantly lower expression level of microRNA-520c-3p (miR-520c-3p) in LUAD tissues than in nontumor tissues. miR-520c-3p is known to regulate multiple biological functions and cellular behaviors. In this study, we show that AKT1 and AKT2 are key direct targets of miR-520c-3p, which are required for its biological roles in LUAD. Mechanistically, downregulation of miR-520c-3p in LUAD is due to DNA methylation of the miR-520c-3p promoter region. Conversely, the activity of the transcription factor Yin Yang 1 (YY1) results in the upregulation of miR-520c-3p. Taken together, our results reveal methylation/YY1/miR-520c-3p/AKT1/AKT2 as a molecular axis with a potent biological function and highlight miR-520c-3p as a novel potent tumor suppressor in LUAD.

The Yin and Yang of cancer genes.

Cancer is caused by malfunctioning of genes that normally regulate cardinal processes including various nuclear functions, cell division and survival, cell surface to nucleus signaling cascades, etc. Cancer associated genes are often classified as oncogenes (OCGs) or tumor suppressor genes (TSGs) depending on whether they promote or suppress tumorigenesis, respectively. Such strict classification of cancer genes may however be an over-simplification. Several studies have highlighted a dual role for cancer genes, often impacting the same facet of tumorigenesis. Knowledge of a possible dichotomy of a cancer gene (particularly an OCG) is imperative when evaluating its possible utility as a therapeutic target. Though previous studies have extensively evaluated specific examples of cancer genes exhibiting a dual nature, efforts to unravel the molecular basis for such contrasting functions have been fewer. The current review is an attempt to delineate molecular events underlying the functional dichotomy of cancer genes at the DNA (mutations, gene fusions, etc.), RNA (alternative splicing, regulation through non-coding RNAs, etc.) and protein (isoforms, mis-localisation, post-translational modifications, proteolytic cleavage, etc.) levels.

Autophagy as a molecular target for cancer treatment.

Autophagy is an evolutionarily conserved catabolic mechanism, by which eukaryotic cells recycle or degrades internal constituents through membrane-trafficking pathway. Thus, autophagy provides the cells with a sustainable source of biomolecules and energy for the maintenance of homeostasis under stressful conditions such as tumor microenvironment. Recent findings revealed a close relationship between autophagy and malignant transformation. However, due to the complex dual role of autophagy in tumor survival or cell death, efforts to develop efficient treatment strategies targeting the autophagy/cancer relation have largely been unsuccessful. Here we review the two-faced role of autophagy in cancer as a tumor suppressor or as a pro-oncogenic mechanism. In this sense, we also review the shared regulatory pathways that play a role in autophagy and malignant transformation. Finally, anti-cancer therapeutic agents used as either inhibitors or inducers of autophagy have been discussed.

Involvement of PLAGL1/ZAC1 in hypocretin/orexin transcription.

The hypocretin/orexin neuropeptide system coordinates the regulation of various physiological processes. Our previous study reported that a reduction in the expression of pleomorphic adenoma gene­like 1 (Plagl1), which encodes a C2H2 zinc­finger transcription factor, occurs in hypocretin neuron­ablated transgenic mice, suggesting that PLAGL1 is co­expressed in hypocretin neurons and regulates hypocretin transcription. The present study examined whether canonical prepro­hypocretin transcription is functionally modulated by PLAGL1. Double immunostaining indicated that the majority of hypocretin neurons were positive for PLAGL1 immunoreactivity in the nucleus. Notably, PLAGL1 immunoreactivity in hypocretin neurons was altered in response to several conditions affecting hypocretin function. An uneven localization of PLAGL1 was detected in the nuclei of hypocretin neurons following sleep deprivation. Chromatin immunoprecipitation revealed that endogenous PLAGL1 may bind to a putative PLAGL1­binding site in the proximal region of the hypocretin gene, in the murine hypothalamus. In addition, electroporation of the PLAGL1 expression vector into the fetal hypothalamus promoted hypothalamic hypocretin transcription. These results suggested that PLAGL1 may regulate hypothalamic hypocretin transcription.