Prevalent Human Cancers Research Articles

Decorated of silver nanoparticles over Arabic gum modified magnetic nanoparticles: Evaluation of its antioxidant and its therapeutic effects on cervical cancer

In the current work, we report the bio-inspired formulation of silver NPs fabricated over Arabic gum (AG) functionalized magnetic nanocomposite (Fe3O4@AG/Ag NPs) for the treatment of cervical cancer. In the stepwise modification approach, the pre-synthesized Fe3O4 NPs were encapsulated by the Arabic gum polar organomolecules, followed by the decoration of in-situ green synthesized silver NPs over the composite. The final bio-material was characterized by various analytical techniques such as XRD, EDX, ICP-OES, TEM, FE-SEM, and FT-IR. The FE-SEM findings validate the spherical shape of the Fe3O4@AG/Ag NPs, which range in size from 20 to 35 nm. An assessment was conducted on the characteristics of Fe3O4@AG/Ag NPs in relation to prevalent human cervical cancer cells. The DPPH free radical antioxidant assay demonstrates the notable antioxidant characteristics of Fe3O4@AG/Ag NPs. The Fe3O4@AG/Ag NPs exhibited IC50 values of 115, 90, 119, and 80 when tested against SiHa, C-33 A, Ca Ski, and LM-MEL-41 cells, respectively. The anti-human cervical cancer effect of Fe3O4@AG/Ag NPs appears to be a result of their antioxidant properties. According to the findings mentioned above, there is a potential for the newly created Fe3O4@AG/Ag NPs to be utilized as an innovative chemotherapeutic treatment or supplement for managing cervical cancer after the conclusion of clinical trials with human participants.

GSE1 promotes the proliferation and migration of lung adenocarcinoma cells by downregulating KLF6 expression.

Lung cancer is one of the most prevalent human cancers with a high lethality rate worldwide. In this study, we demonstrated that GSE1 (genetic suppressor element 1) expression is aberrantly upregulated in lung adenocarcinoma and that GSE1 depletion inhibits the proliferation and migration of both A549 and H1299 cells. Immunoprecipitation assays demonstrated that GSE1 interacts with histone deacetylase 1 (HDAC1) and other BRAF-HDAC complex (BHC) components in cells. The transcriptome of GSE1-knockdown A549 cells indicated that 207 genes were upregulated and 159 were downregulated based on a p-value < .05 and fold change ≥ 1.5. Bioinformatics analysis suggested that 140 differentially expressed genes harbor binding sites for HDAC1, including the tumor suppressor gene KLF6 (Kruppel-like factor 6). Indeed, quantitative reverse-transcription polymerase chain reaction and western blot analysis revealed that GSE1 could inhibit the transcription of KLF6 in lung cancer cells. In conclusion, GSE1 cooperates with HDAC1 to promote the proliferation and metastasis of non-small cell lung cancer cells through the downregulation of KLF6 expression.

The Prognostic and Therapeutic Roles of ARL-6 Gene in Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers. ARL-6, a member of the ADP ribosylation factor (like) (ARF) protein family, has gained attention as a potential therapeutic target in various malignancies and a prognostic biomarker. However, its specific roles in HCC, both prognostically and biochemically, remain largely unclear. Methods: To examine the functional relevance of ARL-6 in HCC, we acquired data from GEPIA, UALCAN, TIMER, TCGA, GeneMANIA, and Metascape databases. Then, we conducted immunohistochemistry on a replication sample comprising 26 HCC specimens to assess the efficacy of the ARL-6 gene. To unravel the mechanistic intricacies, we employed diverse assays such as the cell counting kit 8 (CCK8), flow cytometry, and transwell invasion assessment. Results: Our findings demonstrated the mRNA expression of ARL-6 was significantly upregulated in HCC compared to normal tissue, as evidenced by comprehensive database analysis. Immunohistochemistry further revealed that ARL-6 expression was remarkably higher in HCC than in para-carcinoma tissues. Moreover, ARL-6 expression exhibited noteworthy variations across diverse LIHC characteristics, including sample type, histological subtype, TP53 mutation status, nodal metastatic status, and cancer stage. In addition, high transcriptional levels of ARL-6 were correlated with diminished overall survival (OS) and disease-free survival (DFS) in HCC patients. Furthermore, our study indicated positive correlations between ARL-6 expression levels and the activities of tumor-infiltrating immune cells such as B cells, myeloid dendritic cells, macrophages, neutrophils, CD8+T cells, and CD4+T cells. Substantiating our findings, database analysis uncovered additional evidence of ARL-6 gene co-expression and its functional significance in HCC cases. Finally, we demonstrated the involvement of the ARL-6 gene in HCC cell invasion, proliferation, and apoptosis. Conclusions: In conclusion, our investigation sheds light on the pivotal role of ARL-6 in influencing HCC prognosis and treatment by modulating the biological activities of tumor cells. These discoveries hold promise for the development of predictive biomarkers and novel therapeutic avenues for affected patients.

HRGCNLDA: Forecasting of lncRNA-disease association based on hierarchical refinement graph convolutional neural network.

Long non-coding RNA (lncRNA) is considered to be a crucial regulator involved in various human biological processes, including the regulation of tumor immune checkpoint proteins. It has great potential as both a cancer biomolecular biomarker and therapeutic target. Nevertheless, conventional biological experimental techniques are both resource-intensive and laborious, making it essential to develop an accurate and efficient computational method to facilitate the discovery of potential links between lncRNAs and diseases. In this study, we proposed HRGCNLDA, a computational approach utilizing hierarchical refinement of graph convolutional neural networks for forecasting lncRNA-disease potential associations. This approach effectively addresses the over-smoothing problem that arises from stacking multiple layers of graph convolutional neural networks. Specifically, HRGCNLDA enhances the layer representation during message propagation and node updates, thereby amplifying the contribution of hidden layers that resemble the ego layer while reducing discrepancies. The results of the experiments showed that HRGCNLDA achieved the highest AUC-ROC (area under the receiver operating characteristic curve, AUC for short) and AUC-PR (area under the precision versus recall curve, AUPR for short) values compared to other methods. Finally, to further demonstrate the reliability and efficacy of our approach, we performed case studies on the case of three prevalent human diseases, namely, breast cancer, lung cancer and gastric cancer.

Blockade of the SRC/STAT3/BCL-2 Signaling Axis Sustains the Cytotoxicity in Human Colorectal Cancer Cell Lines Induced by Dehydroxyhispolon Methyl Ether.

Colorectal cancer (CRC) is the third most prevalent human cancer globally. 5-Fluorouracil (5-FU)-based systemic chemotherapy is the primary strategy for advanced CRC treatment, yet is limited by poor response rate. Deregulated activation of signal transducer and activator of transcription 3 (STAT3) is fundamental to driving CRC malignant transformation and a poor prognostic marker for CRC, underscoring STAT3 as a promising CRC drug target. Dehydroxyhispolon methyl ether (DHME) is an analog of Hispolon, an anticancer polyphenol abundant in the medicinal mushroom Phellinus linteus. Previously, we have established DHME's cytotoxic effect on human CRC cell lines by eliciting apoptosis through the blockade of WNT/β-catenin signaling, a preeminent CRC oncogenic pathway. Herein, we unraveled that compared with 5-FU, DHME is a more potent killer of CRC cells while being much less toxic to normal colon epithelial cells. DHME suppressed both constitutive and interleukin 6 (IL-6)-induced STAT3 activation represented by tyrosine 705 phosphorylation of STAT3 (p-STAT3 (Y705)); notably, DHME-induced CRC apoptosis and clonogenicity limitation were abrogated by ectopic expression of STAT3-C, a dominant-active STAT3 mutant. Additionally, we proved that BCL-2 downregulation caused by DHME-mediated STAT3 blockage is responsible for DHME-induced CRC cell apoptosis. Lastly, DHME inhibited SRC activation, and v-src overexpression restored p-STAT3 (Y705) levels along with lowering the levels of apoptosis in DHME-treated CRC cells. We conclude DHME provokes CRC cell apoptosis by blocking the SRC/STAT3/BCL-2 axis besides thwarting WNT/β-catenin signaling. The notion that DHME targets two fundamental CRC signaling pathways underpins the potential of DHME as a CRC chemotherapy agent.

Streamlined Intravital Imaging Approach for Long-Term Monitoring of Epithelial Tissue Dynamics on an Inverted Confocal Microscope.

Understanding normal and aberrant in vivo cell behaviors is necessary to develop clinical interventions to thwart disease initiation and progression. It is therefore critical to optimize imaging approaches that facilitate the observation of cell dynamics in situ, where tissue structure and composition remain unperturbed. The epidermis is the body's outermost barrier, as well as the source of the most prevalent human cancers, namely cutaneous skin carcinomas. The accessibility of skin tissue presents a unique opportunity to monitor epithelial and dermal cell behaviors in intact animals using noninvasive intravital microscopy. Nevertheless, this sophisticated imaging approach has primarily been achieved using upright multiphoton microscopes, which represent a significant barrier for entry for most investigators. This study presents a custom-designed, 3D-printed microscope stage insert suitable for use with inverted confocal microscopes, streamlining the long-term intravital imaging of ear skin in live transgenic mice. We believe this versatile invention, which may be customized to fit the inverted microscope brand and model of choice and adapted to image additional organ systems, will prove invaluable to the greater scientific research community by significantly enhancing the accessibility of intravital microscopy. This technological advancement is critical for bolstering our understanding of live cell dynamics in normal and disease contexts.

The role of USP1 deubiquitinase in the pathogenesis and therapy of cancer.

Ubiquitin-specific protease 1 (USP1) is an important deubiquitinating enzyme (DUB) involved in the maintenance of genome integrity, cell cycle, and cell homeostasis. USP1 overexpression is a characteristic feature of various cancers, correlating with a poor prognosis. The review summarizes the recent knowledge in understanding the role of deubiquitinase USP1 in the stabilization of oncoproteins and tumor suppressors, as a critical event in cancer development and progression. The putative mechanisms of USP1 involvement in some prevalent human cancers are discussed. The numerous data demonstrate that inhibition of USP1 suppresses the proliferation and viability of malignant cells, sensitizes them to radiation and increases their sensitivity to various chemo- therapeutic agents, which opens up new opportunities for combined therapy of malignant neoplasms.

ALIX promotes cell migration and invasion of head and neck squamous cell carcinoma by regulating the expression of MMP9, MMP14, VEGF-C

ObjectiveThe poor survival rate of head and neck squamous cell carcinoma (HNSCC), one of the most prevalent human cancer, is attributed to frequent locoregional recurrence and lymph node metastases. Though it is reported that the expression of ALG-2 interacting protein X (ALIX) closely correlates with the progression of various tumors, its role in HNSCC remains unclear. The present study aims to investigate the role of ALIX in the development of HNSCC. DesignWith immunohistochemical staining, the expression levels of ALIX and series of related functional proteins were compared in normal mucosal (n = 18), HNSCC tissues (n = 54), and metastatic lymph nodes (n = 11). Further, the correlation analysis was performed among the proteins detected. By knocking down ALIX in HNSCC cell lines, the correlation of ALIX with the proteins was verified in vitro. The role of ALIX in proliferation, migration, and invasion of HNSCC cells was further studied by flow cytometry, wounding healing, and transwell assays, respectively. ResultsHigher expression level of ALIX was revealed in HNSCC samples, especially in metastatic lymph nodes, than in normal mucosal tissues. Accordingly, increasing levels of MMP9, MMP14, and VEGF-C were also discovered in metastatic lymph nodes and significantly correlated with the expression of ALIX. In vitro assays demonstrated that the knockdown of ALIX reduced both the transcriptional and protein levels of MMP9, MMP14, and VEGF-C, together with suppressed migration and weakened invasion of HNSCC cell lines. ConclusionsALIX up-regulated the expression of MMP9, MMP14 and VEGF-C, and promoted migration and invasion of HNSCC cells.

Biomimetic synthesis and characterization of silver nanoparticles from Dipterygium glaucum extract and its anti-cancerous activities

The pharmaceutical research field dramatically benefits from using silver nanoparticles (AgNPs). In particular, AgNPs fabricated by plant extracts significantly impact biological processes, including antioxidant, antibacterial, and anticancer effects. In light of this, the current study examined the impact of AgNPs synthesized from Dipterygium glaucum Decne. plant extract on the three most prevalent human cancer cell lines, including HepG2, MCF-7, and HeLa. UV–visible spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS) characterized these nanoparticles. The approach was very efficient, cost-effective, and eco-friendly. These findings indicate that AgNPs exhibited exceptional cytotoxicity against all the cell lines, indicating a high therapeutic index value. In a concentration-dependent manner, these AgNPs induced cytotoxic activity against HepG-2 liver (IC50 2.21 µg/ml), HeLa cervical (IC50 2.14 µg/ml), and MCF-7 breast (IC50 1.1 µg/ml) cancer cell lines.

Human Skin Cancer: an Overview Of Animal, Ex Vivo, and In Vitro Models

Purpose of ReviewSkin cancer is the most prevalent human cancer and has presented a considerable world incidence rate increase over the last years. While animals offer highly complex systems to study skin cancer biology, ethical concerns and the differences found between the human and animal skin have promoted the development of alternative methods. In this review, we provide an overview of the most important skin cancer models and describe the advantages of in vitro substitutes over ex vivo and animal models. To facilitate understanding, an insight into the biology of skin cancer is also given. Recent FindingsCurrently, the study of cancer pathology and the development of therapeutic agents are mostly based on animal experiments. The methodologies used are based on mice genetic modifications and the induction of carcinogenesis by UV radiation, chemicals, or viruses. Skin explant models represent one alternative to animal models. These preserve the structure and composition of native skin and are therefore highly suitable. More recent studies have developed in vitro skin models composed of the epidermal and/or the dermal layers, which more faithfully mimic the human skin.SummaryVarious technologies have been studied to create improved skin substitutes. To better understand skin cancer biology, models that more faithfully mimic the human skin are needed. In vitro systems can recreate many of the typical features of both healthy and diseased skin and suggest that complex systems like full-thickness models are highly valuable tools to perform human skin studies.

Multiple function of lncRNA MALAT1 in cancer occurrence and progression.

Long non-coding RNAs (lncRNAs) have received particular attention in the last decade due to its engaging in carcinogenesis and tumorigenesis. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a lncRNA that plays physiological and pathological roles in many aspects of genome function as well as biological processes involved in cell development, differentiation, proliferation, invasion, and migration. In this article, we will review the effects of lncRNA MALAT1 on the progression of six prevalent human cancers by focusing on MALAT1 ability to regulate post-transcriptional modification and signaling pathways.

High expression of HOXB3 predicts poor prognosis and correlates with tumor immunity in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the most prevalent human cancers worldwide. The homeobox-B (HOXB) gene cluster has been reported to contribute to cancer development. Nevertheless, the expression status, clinical significance and biological role of HOXB genes in LUAD remain largely unclear. This study comprehensively investigated the transcriptional levels and prognostic values of the HOXB genes in LUAD based on The Cancer Genome Atlas (TCGA) database. Flow cytometry, CCK-8, and Transwell assays were used for detecting apoptosis, proliferation, and migration, respectively. We discovered that eight members of the HOXB cluster genes (HOXB2, HOXB3, HOXB4, HOXB6, HOXB7, HOXB8, HOXB9, and HOXB13) were dysregulated in LUAD tumor tissues. Increased expression of HOXB3, HOXB6, HOXB7, HOXB8, or HOXB9 was independently associated with unsatisfactory overall survival (OS) in LUAD patients. In addition, a high level of HOXB3 also predicted poor patient relapse-free survival (RFS), suggesting that HOXB3 may play a vital role in the progression of LUAD compared to other members of the HOXB cluster. Additionally, further analysis by TIMER and TISIDB algorithms revealed that HOXB3 was positively correlated with a panel of immune checkpoint molecules (ICMs), tumor-infiltrating lymphocytes (TILs), and tumor immune regulators (TIRs). Gene enrichment analysis based on KEGG showed that HOXB3 was closely associated with multiple tumor-related biological processes and signaling pathways. Functionally, the in vitro experiments revealed that depletion of HOXB3 significantly alleviated the resistance of LUAD cells to apoptosis, and suppressed cell proliferation and migration. Our study suggests that HOXB3 may play an oncogenic role in LUAD and correlate with tumor immunity.

Single-cell RNA sequencing in human lung cancer: Applications, challenges, and pathway towards personalized therapy.

Lung cancer is one of the most prevalent human cancers, and single-cell RNA sequencing (scRNA-seq) has been widely used to study human lung cancer at the cellular, genetic, and molecular level. Even though there are published reviews, which summarized the applications of scRNA-seq in human cancers like breast cancer, there is lack of a comprehensive review, which could effectively highlight the broad use of scRNA-seq in studying lung cancer. This review, therefore, was aimed to summarize the various applications of scRNA-seq in human lung cancer research based on the findings from different published in vitro, in vivo, and clinical studies. The review would first briefly outline the concept and principle of scRNA-seq, followed by the discussion on the applications of scRNA-seq in studying human lung cancer. Finally, the challenges faced when using scRNA-seq to study human lung cancer would be discussed, and the potential applications and challenges of scRNA-seq to facilitate the development of personalized cancer therapy in the future would be explored.

Overexpression of GSE1 Related to Trastuzumab Resistance in Gastric Cancer Cells.

Gastric cancer is one of the most prevalent human cancers with poor prognosis. Trastuzumab is a well-used targeted drug for gastric cancer with HER2 amplification. Trastuzumab resistance restrains the clinical use of trastuzumab. In this study, we reported human Gse1 coiled-coil protein (GSE1) promoted trastuzumab resistance in HER2-positive gastric cancer cells. Acquired trastuzumab-resistant gastric cancer cells overexpressed GSE1, and depletion of GSE1 decreased the trastuzumab resistance of trastuzumab-resistant gastric cancer cells. BCL-2 was a downstream gene positively regulated by GSE1 and also performed promoting the role of trastuzumab resistance in HER2-positive gastric cancer cells. A high level of GSE1 was associated with a high risk of tumor lymph node metastasis and higher clinical stage in HER2-positive gastric cancer patients. GSE1 was a potential target that could be used for HER2-positive gastric cancer therapy.

Construction and Validation of Novel Diagnostic and Prognostic DNA Methylation Signatures for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent life-threatening human cancers and the leading cause of cancer-related mortality, with increased global incidence within the last decade. Identification of effective diagnostic and prognostic biomarkers would enable reliable risk stratification and efficient screening of high-risk patients, thereby facilitating clinical decision-making. Herein, we performed a comprehensive, robust DNA methylation analysis based on genome-wide DNA methylation profiling. We constructed a diagnostic signature with five DNA methylation markers, which precisely distinguished HCC patients from normal controls. Cox regression and LASSO analysis were applied to construct a prognostic signature with four DNA methylation markers. A one-to-one correlation analysis was carried out between genes of the whole genome and our prognostic signature. Exploration of the biological function and the role of the underlying significantly correlated genes was conducted. A mixed dataset of 463 HCC patients and 253 normal controls, derived from six independent datasets, was used to valid the diagnostic signature. Results showed a specificity of 96.84% and sensitivity of 96.77%. Class scores for the diagnostic signature were significantly different between normal controls, individuals with liver diseases, and HCC patients. The present signature has the potential to serve as a biomarker to monitor health in normal controls. Additionally, HCC patients were successfully separated into low-risk and high-risk groups by the prognostic signature, with a better prognosis for patients in the low-risk group. Kaplan-Meier and ROC analysis confirmed that the prognostic signature performed well. We found eight of the top ten genes to positively correlate with risk scores of the prognostic signature, and to be involved in cell cycle regulation. This eight-gene panel also served as a prognostic signature. The robust evidence presented in this study therefore demonstrates the effectiveness of the prognostic signature. In summary, we constructed diagnostic and prognostic signatures, which have potential for use in diagnosis, surveillance, and prognostic prediction for HCC patients. Eight genes that were significantly and positively correlated with the prognostic signature were strongly associated with cell cycle processes. Therefore, the prognostic signature can be used as a guide by which to measure responsiveness to cell-cycle-targeting agents.

Switching Homes: How Cancer Moves to Bone.

Bone metastases (BM) are a very common complication of the most prevalent human cancers. BM are extremely painful and may be life-threatening when associated with hypercalcaemia. BM can lead to kidney failure and cardiac arrhythmias and arrest, but why and how do cancer cells decide to “switch homes” and move to bone? In this review, we will present what answers science has provided so far, with focus on the molecular mechanisms and cellular aspects of well-established findings, such as the concept of “vicious cycle” and “osteolytic” vs. “osteosclerotic” bone metastases; as well as on novel concepts, such as cellular dormancy and extracellular vesicles. At the molecular level, we will focus on hypoxia-associated factors and angiogenesis, the Wnt pathway, parathyroid hormone-related peptide (PTHrP) and chemokines. At the supramolecular/cellular level, we will discuss tumour dormancy, id est the mechanisms through which a small contingent of tumour cells coming from the primary site may be kept dormant in the endosteal niche for many years. Finally, we will present a potential role for the multimolecular mediators known as extracellular vesicles in determining bone-tropism and establishing a premetastatic niche by influencing the bone microenvironment.

Association of Additive Risk of Pioglitazone Use with the Presence of CYP1A1 Polymorphisms in the Occurrence of Bladder Cancer

Tumor of urinary bladder nowadays is regarded as one of the most prevalent human cancer allover our planet. Many predisposing factors play a crucial role in the pathogenesis of this tumor including endogenous and exogenous blamed causes. Certain polymorphism of CYP1A1 gene recently has been linked to the occurrence of bladder cancer. Pioglitazone that used for treatment of diabetes mellitus type II for long time carry a risk impact on induction of this tumor. Aim of this study: To evaluate the risk of using of pioglitazone in patients who carry CYP1A1 polymorphism to induce bladder carcinoma. Materials and method: This study was conducted from 2017 to 2019, 80 patients with bladder cancer after being medically diagnosed and were assessed if using of pioglitazone with presence of CYP1A1 polymorphisms associated with high risk of CA bladder. DNA was extracted and molecular detection was performed to detect single nucleotide polymorphisms (SNPs) at genetic sites using PCR and PCR-RFLP techniques. Results: There was additive risk by using of pioglitazone for long time (at least 1 year) in occurrence of CA bladder in individuals with CYP1A1 polymorphisms.

Long noncoding RNA HAND2-AS1 reduced the viability of hepatocellular carcinoma via targeting microRNA-300/SOCS5 axis

BackgroundHepatocellular carcinoma (HCC) is one of the most prevalent human cancers with high mortality. Long non-coding RNA heart and neural crest derivatives expressed 2 anti-sense 1 (HAND2-AS1) is down-regulated in several cancers including HCC, yet the precise mechanisms how HAND2-AS1 regulates cell survival in HCC remains poorly understood. MethodsThe expression levels of HAND2-AS1 and miR-300 were measured using quantitative real-time PCR. The protein levels of suppressor of cytokine signaling 5 (SOCS5), Bcl-2, Bax and cleaved caspase-3 were determined by Western blot. Cell viability and cell proliferation were assessed using cell counting kit-8 and clone formation assay, respectively. Cell apoptosis was detected using flow cytometry. The interactions between HAND2-AS1 and miR-300, miR-300 and SOCS5 were validated using luciferase reporter assay. ResultsHAND2-AS1 was down-regulated in HCC tissues and cell lines, and the expression level of HAND2-AS1 was positively correlated to patient survival. HAND2-AS1 over-expression reduced viability and proliferation in HCC cells. Elevated HAND2-AS1 level induced apoptosis in HCC cells, accompanied with increased Bax and cleaved caspase-3 levels and decreased Bcl-2 level. We also validated that HAND2-AS1 acted as a sponge of miR-300, and there was a negative correlation between expression levels of HAND2-AS1 and miR-300 in HCC tissues. Furthermore, we found that SOCS5 was a downstream target of miR-300. In addition, miR-300 mimics abolished HAND2-AS1-mediated inhibition of cell viability and proliferation. miR-300 mimics also reversed the HAND2-AS1-induced apoptosis in HCC cells. ConclusionlncRNA HAND2-AS1 inhibits proliferation in HCC through regulating miR-300/SOCS5 axis.

RYK, a receptor of noncanonical Wnt ligand Wnt5a, is positively correlated with gastric cancer tumorigenesis and potential of liver metastasis.

Gastric cancer (GC) is the most prevalent human cancer around the globe. In GC, Wnt signaling is deregulated, and receptor-like tyrosine kinase (RYK) coreceptors have been identified to interact with noncanonical Wnt ligand Wnt5a. We, therefore, aimed to evaluate the role of RYK in GC development and metastasis. GC tumor samples were collected from 250 GC patients. Expressions of RYK, as well as markers for the epithelial-mesenchymal transition (EMT), such as N-cadherin and E-cadherin, were subjected to correlation analysis with clinicopathological features. Endogenous RYK expression levels were compared in GC cell lines with ascending metastatic potentials followed by stable RYK knockdown. Effect of RYK knockdown on GC cell migration, invasion, and EMT phenotype were assessed in vitro, and on GC tumor growth in vivo in a xenograft rodent model. Particularly, liver metastasis potential of tail vein-injected GC cells was also analyzed following RYK knockdown. RYK was highly correlated with liver metastasis of GC tumors and the expression profiles of EMT markers toward the mesenchymal tendency. RYK expression was also positively correlated with the metastasis potential of GC cells. RYK knockdown not only inhibited migration, invasion, and EMT of GC cells in vitro, but also suppressed tumorigenesis and liver metastasis of GC cells in vivo using the mouse xenograft model. RYK is highly correlated with GC tumorigenesis and potential of liver metastasis, suggesting it may be a novel oncogenic factor of the noncanonical Wnt signaling pathway contributing to GC.NEW & NOTEWORTHY RYK is highly correlated with gastric cancer tumorigenesis and the potential of liver metastasis, suggesting it may be a novel oncogenic factor of the noncanonical Wnt signaling pathway contributing to gastric cancer.

Lipoxygenase Inhibitors as Cancer Chemopreventives: Discovery, Recent Developments and Future Perspectives.

Leukotrienes (LTs) constitute a bioactive group of Polyunsaturated Fatty Acid (PUFA) metabolites molded by the enzymatic activity of lipoxygenase (LO) and have a pivotal role in inflammation and allergy. Evidence is accumulating both by in vitro cell culture experiments and animal tumor model studies in support of the direct involvement of aberrant metabolism of arachidonic acid (ACD) in the development of several types of human cancers such as lung, prostate, pancreatic and colorectal malignancies. Several independent experimental data suggest a correlation between tumoral cells viability and LO gene expression, especially, 5-lipoxygenase (5-LO). Overexpressed 5-LO cells live longer, proliferate faster, invade more effectively through extracellular matrix destruction and activate the anti-apoptotic signaling mechanisms more intensively compared to the normal counterparts. Thus, some groups of lipoxygenase inhibitors may be effective as promising chemopreventive agents. A structured search of bibliographic databases for peer-reviewed research literature regarding the role of LO in the pathogenesis of cancer was performed. The characteristics of screened papers were summarized and the latest advances focused on the discovery of new LO inhibitors as anticancer agents were discussed. More than 180 papers were included and summarized in this review; the majority was about the newly designed and synthesized 5-LO inhibitors as anti-inflammatory and anticancer agents. The enzyme's structure, 5-LO pathway, 5-LO inhibitors structure-activity relationships as well as the correlation between these drugs and a number of most prevalent human cancers were described. In most cases, it has been emphasized that dual cyclooxygenase-2/5-lipoxygenase (COX-2/5-LO) or dual 5-lipoxygenase/microsomal prostaglandin E synthase-1 (5-LO/mPGES-1) inhibitors possess considerable inhibitory activities against their target enzymes as well as potent antiproliferative effects. Several papers disclosing 5-lipoxygenase activating protein (FLAP) antagonists as a new group of 5-LO activity regulators are also subject to this review. Also, the potential of 12-lipoxygenase (12- LO) and 15-lipoxygenase (15-LO) inhibitors as chemopreventive agents was outlined to expand the scope of new anticancer agents discovery. Some peptides and peptidomimetics with anti-LT activities were described as well. In addition, the cytotoxic effects of lipoxygenase inhibitors and their adverse effects were discussed and some novel series of natural-product-derived inhibitors of LO was also discussed in this review. This review gives insights into the novel lipoxygenase inhibitors with anticancer activity as well as the different molecular pharmacological strategies to inhibit the enzyme effectively. The findings confirm that certain groups of LO inhibitors could act as promising chemopreventive agents.