Search

Long noncoding (lnc)RNAs are reported to be key regulators of tumor progression, including hepatocellular carcinoma (HCC). The lncRNA long intergenic noncoding RNA 00673 (LINC00673) was indicated to play an important role in HCC progression, but the impacts of genetic variants (single-nucleotide polymorphisms, SNPs) of LINC00673 on HCC remain unclear. A TaqMan allelic discrimination assay was performed to analyze the genotypes of three tagging SNPs, viz., rs9914618 G > A, rs6501551 A > G, and rs11655237 C > T, of LINC00673 in 783 HCC patients and 1197 healthy subjects. Associations of functional SNPs of LINC00673 with HCC susceptibility and clinicopathologic variables were analyzed by logistic regression models. After stratification by confounding factor, we observed that elderly patients (≥60 years) with the LINC00673 rs9914618 A allele had an increased risk of developing HCC under a codominant model (p = 0.025) and dominant model (p = 0.047). Moreover, elderly patients carrying the GA + AA genotype of rs9914618 exhibited a higher risk of having lymph node metastasis compared to those who were homozygous for the major allele (p = 0.013). Genotype screening of rs9914618 in HCC cell lines showed that cells carrying the AA genotype expressed higher LINC00673 levels compared to the cells carrying the GG genotype. Further analyses of clinical datasets from the Cancer Genome Atlas (TCGA) showed that LINC00673 expressions were upregulated in HCC tissues compared to normal tissues, and were correlated with advanced clinical stages and poorer prognoses. In conclusions, our results suggested that the LINC00673 rs9914618 polymorphism may be a promising HCC biomarker, especially in elderly populations. [ABSTRACT FROM AUTHOR]

Background: Due to the difficulties in early diagnosing and treating hepatocellular carcinoma (HCC), prognoses for patients remained poor in the past decade. In this study, we established a screening model to discover novel prognostic biomarkers in HCC patients. Methods: Candidate biomarkers were screened by liquid chromatography with tandem mass spectrometry (LC-MS/MS) analyses of five HCC normal (N)/tumor (T) paired tissues and preliminarily verified them through several in silico database analyses. Expression levels and functional roles of candidate biomarkers were respectively evaluated by immunohistochemical staining in N/T paired tissue (n = 120) and MTS, colony formation, and transwell migration/invasion assays in HCC cell lines. Associations of clinicopathological features and prognoses with candidate biomarkers in HCC patients were analyzed from GEO and TCGA datasets and our recruited cohort. Results: We found that the transmembrane P24 trafficking protein 9 (TMED9) protein was elevated in HCC tissues according to a global proteomic analysis. Higher messenger (m)RNA and protein levels of TMED9 were observed in HCC tissues compared to normal liver tissues or pre-neoplastic lesions. The TMED9 mRNA expression level was significantly associated with an advanced stage and a poor prognosis of overall survival (OS, p = 0.00084) in HCC patients. Moreover, the TMED9 protein expression level was positively correlated with vascular invasion (p = 0.026), OS (p = 0.044), and disease-free survival (p = 0.015) in our recruited Taiwanese cohort. In vitro, manipulation of TMED9 expression in HCC cells significantly affected cell migratory, invasive, proliferative, and colony-forming abilities. Conclusions: Ours is the first work to identify an oncogenic role of TMED9 in HCC cells and may provide insights into the application of TMED9 as a novel predictor of clinical outcomes and a potential therapeutic target in patients with HCC. [ABSTRACT FROM AUTHOR]

The aldolase family members involved in metabolism and glycolysis are present in three isoforms: ALDOA , ALDOB , and ALDOC . Aldolases are differentially expressed in human tissues, and aberrant expression has been observed in several human diseases and cancer types. However, non-enzymatic functions through protein–protein interactions or epigenetic modifications have been reported in recent years. Using high-throughput screening and -omics database integration, aldolase has been validated as an independent clinical prognostic marker of human cancers. Therefore, the aim of this review was to provide potential clinical value from in silico predictions and also summarize well-known signaling axes or phenotypes in various cancer types. Finally, we discuss the role of aldolase in the treatment of human diseases and cancers. [ABSTRACT FROM AUTHOR]

Cancer cells encounter metabolic stresses such as hypoxia and nutrient limitations because they grow and divide more quickly than their normal counterparts. In response to glucose restriction, we found that nuclear translocation of the glycolic enzyme, pyruvate kinase M2 (PKM2), helped cancer cells survive under the metabolic stress. Restriction of glucose stimulated AMPK activation and resulted in co-translocation of AMPK and PKM2 through Ran-mediated nuclear transport. Nuclear PKM2 subsequently bound to Oct4 and promoted the expression of cancer stemness-related genes, which might enrich the cancer stem cell population under the metabolic stress. Nuclear PKM2 was also capable of promoting cancer metastasis in an orthotopic xenograft model. In summary, we found that cytosolic AMPK helped PKM2 carry out its nonmetabolic functions in the nucleus under glucose restriction and that nuclear PKM2 promoted cancer stemness and metastasis. These findings suggested a potential new targeting pathway for cancer therapy in the future. [ABSTRACT FROM AUTHOR]

Endocan is known to be a circulating dermatan sulfate proteoglycan that regulates endothelial cell function. Dysregulation of endocan expression is observed not only in the tumor vasculature but also in cancer cells. Accumulating evidence has revealed that disordered endocan facilitates cancer progression via enhancing cancer cell proliferation, cell mobility, and cancer stemness properties. Recently, various interacting proteins and diverse subcellular localizations of endocan were identified in cancer cells. Herein, we summarize the application of endocan in cancer diagnoses and prognoses using serum and tumor specimens. We further discuss that the aberrant molecular characteristics of endocan may be due to the mislocalization of endocan in cancer cells. Defining the specific cellular roles of endocan will provide a promising diagnostic factor and therapeutic target for cancer patients. • Critical roles of endocan have been revealed in the regulation of cancer cell behaviors during cancer progression. • Secretory endocan binds and affects signaling of growth factors, receptor tyrosine kinases, and adhesion molecules in a tumor. • Cytosolic endocan correlates with tumor progression while nuclear endocan acts as a transcriptional cofactor to promote cancer stemness. • Subpopulations such as EFGR-mutated NSCLC cells and prostate cancer stem cells were more sensitive to endocan targeting. • Understanding the roles of endocan in cancers can promote the development of diagnostic and therapeutic innovations. [ABSTRACT FROM AUTHOR]

Monoamine oxidases (MAOs) including MAOA and MAOB are enzymes located on the outer membranes of mitochondria, which are responsible for catalyzing monoamine oxidation. Recently, increased level of MAOs were shown in several cancer types. However, possible roles of MAOs have not yet been elucidated in the progression and prognosis of colorectal carcinoma (CRC). We therefore analyzed the importance of MAOs in CRC by an in silico analysis and tissue microarrays. Several independent cohorts indicated that high expression of MAOB, but not MAOA, was correlated with a worse disease stage and poorer survival. In total, 203 colorectal adenocarcinoma cases underwent immunohistochemical staining of MAOs, and associations with clinicopathological parameters and patient outcomes were evaluated. We found that MAOB is highly expressed in CRC tissues compared to normal colorectal tissues, and its expression was significantly correlated with a higher recurrence rate and a poor prognosis. Moreover, according to the univariate and multivariate analyses, we found that MAOB could be an independent prognostic factor for overall survival and disease-free survival, and its prognostic value was better than T and N stage. Furthermore, significant positive and negative correlations of MAOB with mesenchymal-type and epithelial-type gene expressions were observed in CRC tissues. According to the highlighted characteristics of MAOB in CRC, MAOB can be used as a novel indicator to predict the progression and prognosis of CRC patients. [ABSTRACT FROM AUTHOR]

Midlife women experience menopausal transition at different ages with a variety of symptoms. This study aimed to identify the effects of age, menopausal status, and symptoms in women on their actigraphy-based sleep patterns and circadian rhythms. A total of 87 women aged 45–60 from the community and a gynecology clinic in Taiwan who had their sleep and circadian rhythms recorded with a 7-day actigraphy were analyzed. Multiple linear regression was used to estimate the association of age, menopausal status, and symptoms with sleep parameters and circadian rhythms. A sleep efficiency below 85 % was observed in 46.0 % of women, and those with severe somatic-vegetative or psychological symptoms tended to have problems with sleep latency (β = 0.22 and β = 0.42, respectively) and efficiency (β = −0.26 and β = −0.36, respectively). Women with more severe urogenital symptoms only experienced significantly longer sleep latency (β = 0.33). There was a weak correlation between circadian rhythms and symptoms. Additionally, perimenopausal (β = 0.30 and β = 0.35, respectively) and late postmenopausal (β = 0.67 and β = 0.59, respectively) women had higher relative amplitude and stability in circadian rhythms than premenopausal women. Age had no significant effect on sleep parameters or circadian rhythms. Premenopausal women had the most unstable day-to-day rhythms compared to their peri- and postmenopausal counterparts. Women with higher somatic-vegetative, psychological, and urogenital symptoms showed greater sleep problems. Psychological symptoms (e.g., depression, irritability, anxiety, exhaustion) were the strongest predictors for all sleep parameters. The mechanisms underlying these associations warrant investigation. • Menopausal status was more strongly associated with circadian rhythms than age was. • Compared to age, symptoms showed a stronger correlation with sleep patterns. • Somatic and psychological symptoms are positively related to poor sleep efficiency. • Women with more severe urogenital symptoms tended to have difficulty falling asleep. • Psychological symptoms were the strongest predictors of sleep quality. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is considered one of the most prevalent malignancy globally, and metastasis is a major cause of death. Apigenin (API) is a dietary flavonoid which exerts an antimetastatic effect in various cancer types. Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) is a crucial modulator of tumor growth and metastasis in cancers. However, the role and underlying regulatory mechanisms of SPOCK1 in the API-mediated antimetastatic effects of PCa remain unclear. Methods: MTS, colony formation, wound-healing, and transwell assays were conducted to evaluate the effects of API on PCa cell proliferative, migratory, and invasive potentials. In vivo orthotopic bioluminescent xenograft model were employed to determine antitumor activity of API. PCa cells were transfected with either Snail-, Slug-, SPOCK1-overexpressing vector, or small hairpin (sh)SPOCK1 to determine the invasive abilities and expression levels of SPOCK1 and epithelial-to-mesenchymal transition (EMT) biomarkers in response to API treatment. Immunohistochemical (IHC) assays were carried out to evaluate the expression level of SPOCK1 in PCa xenografts and a PCa tissue array. Associations of SPOCK1 expression with clinicopathological features and prognoses of patients with PCa were analyzed by GEO or TCGA RNA-sequencing data. Results: API significantly suppressed in vitro PCa cell proliferation, migration, and invasion and inhibited in vivo PCa tumor growth and metastasis. Moreover, survival times of animals were also prolonged after API treatment. Mechanistic studies revealed that API treatment resulted in downregulation of SPOCK1, which was accompanied by reduced expressions of mesenchymal markers and subsequent attenuation of invasive abilities of PCa cells. Overexpression of SPOCK1 in PCa xenografts resulted in significant promotion of tumor progression and relieved the anticancer activities induced by API, whereas knockdown of SPOCK1 had opposite effects. In clinical, SPOCK1 levels were higher in tumor tissues compared to non-tumor tissues, which was also significantly correlated with shorter disease-free survival in PCa patients. Conclusions: Levels of SPOCK1 increase with the progression of human PCa which suggests that SPOCK1 may act as a prognostic marker or therapeutic target for patients with PCa. Suppression of SPOCK1-mediated EMT signaling contributes to the antiproliferative and antimetastatic activities of API in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-small-cell lung cancer (NSCLC) is a typical inflammation-associated cancer and epidermal growth factor (EGF) receptor (EGFR) mutations are the most common driver mutations of NSCLC. The aim of our study was to evaluate the impacts of the proinflammatory cytokine, interleukin (IL)-17A, on EGFR-mediated progression of NSCLC. In NSCLC cells with mutant EGFR, we found that the IL-17A/IL-17 receptor C (IL-17RC) axis enhanced phosphorylation of EGFR and Met, thereby promoting proliferation and resistance to EGFR-tyrosine kinase inhibitors (TKIs). In NSCLC cells with wild-type (WT) EGFR, we found that the IL-17A/IL-17RC axis enhanced EGF-induced EGFR activation and cell proliferation through causing an impairment of EGF-induced EGFR lysosomal degradation. Our results indicated that developing therapeutic strategies against IL-17A/IL-17RC would be valuable for NSCLC treatment. Non-small-cell lung cancer (NSCLC) is a typical inflammation-associated cancer, and lung adenocarcinoma (LUAD) is the most common pathological subtype. Epidermal growth factor (EGF) receptor (EGFR) mutations are the most common driver mutations of LUAD, and they have been identified as important therapeutic targets by EGFR-tyrosine kinase inhibitors (TKIs). The proinflammatory cytokine, interleukin (IL)-17A, and IL-17A-producing cells were reported to be elevated in the tumor microenvironment and peripheral blood of NSCLC patients and to be correlated with tumor progression and poor prognoses. However, the pathophysiological role of IL-17A in NSCLC remains unclear, although some studies suggested its involvement in cancer cell invasion and metastasis. Herein, we observed that expressions of IL-17A and its receptor, IL-17 receptor C (IL-17RC), were elevated in LUAD tissues and were correlated with poor survival in different lung cancer cohorts. In LUAD cells with mutant EGFR, the IL-17A/IL-17RC axis was shown to enhance phosphorylation of EGFR and Met, thereby promoting proliferation and resistance to EGFR-TKIs such as afatinib. In LUAD cells with wild-type (WT) EGFR, we found that the IL-17A/IL-17RC axis enhanced EGF-induced EGFR activation and cell proliferation through causing impairment of EGF-induced EGFR lysosomal degradation. Collectively, our results indicated diverse impacts of the IL-17A/IL-17RC axis on EGFR activation in LUAD cells with WT and mutant EGFR and suggested that developing therapeutic strategies against IL-17A/IL-17RC would be valuable for LUAD treatment. [ABSTRACT FROM AUTHOR]

N-α-Acetyltransferase 10 protein (Naa10p) mediates N-terminal acetylation of nascent proteins. Oncogenic or tumor suppressive roles of Naa10p were reported in cancers. Here, we report an oncogenic role of Naa10p in promoting metastasis of osteosarcomas. Higher NAA10 transcripts were observed in metastatic osteosarcoma tissues compared to non-metastatic tissues and were also correlated with a worse prognosis of patients. Knockdown and overexpression of Naa10p in osteosarcoma cells respectively led to decreased and increased cell migratory/invasive abilities. Re-expression of Naa10p, but not an enzymatically inactive mutant, relieved suppression of the invasive ability in vitro and metastasis in vivo imposed by Naa10p-knockdown. According to protease array screening, we identified that matrix metalloproteinase (MMP)-2 was responsible for the Naa10p-induced invasive phenotype. Naa10p was directly associated with MMP-2 protein through its acetyltransferase domain and maintained MMP-2 protein stability via NatA complex activity. MMP-2 expression levels were also significantly correlated with Naa10p levels in osteosarcoma tissues. These results reveal a novel function of Naa10p in the regulation of cell invasiveness by preventing MMP-2 protein degradation that is crucial during osteosarcoma metastasis. [ABSTRACT FROM AUTHOR]

Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) has been reported to play an oncogenic role in certain cancer types; however, the role of SPOCK1 in the progression of clear cell renal cell carcinoma (ccRCC) remains elusive. Here, higher SPOCK1 transcript and protein levels were observed in ccRCC tissues compared to normal tissues and correlated with advanced clinical stages, larger tumor sizes, and lymph node and distal metastases. Knockdown and overexpression of SPOCK1 in ccRCC cells led to decreased and increased cell clonogenic and migratory/invasive abilities in vitro as well as lower and higher tumor growth and invasion in vivo, respectively. Mechanistically, the gene set enrichment analysis (GSEA) database was used to identify the gene set of epithelial-to-mesenchymal transition (EMT) pathways enriched in ccRCC samples with high SPOCK1 expression. Further mechanistic investigations revealed that SPOCK1 triggered the Snail/Slug–matrix metalloproteinase (MMP)-2 axis to promote EMT and cell motility. Clinical ccRCC samples revealed SPOCK1 to be an independent prognostic factor for overall survival (OS), and positive correlations of SPOCK1 with MMP-2 and mesenchymal-related gene expression levels were found. We observed that patients with SPOCK1high/MMP2high tumors had the shortest OS times compared to others. In conclusion, our findings reveal that SPOCK1 can serve as a useful biomarker for predicting ccRCC progression and prognosis, and as a promising target for treating ccRCC. [ABSTRACT FROM AUTHOR]

Purpose: Metastasis of lung adenocarcinoma (LADC) is a crucial factor determining patient survival. Repurposing of the antipsychotic agent penfluridol has been found to be effective in the inhibition of growth of various cancers. As yet, however, the anti-metastatic effect of penfluridol on LADC has rarely been investigated. Herein, we addressed the therapeutic potential of penfluridol on the invasion/metastasis of LADC cells harboring different epidermal growth factor receptor (EGFR) mutation statuses. Methods: MTS viability, transwell migration and invasion, and tumor endothelium adhesion assays were employed to determine cytotoxic and anti-metastatic effects of penfluridol on LADC cells. Protease array, Western blot, immunohistochemistry (IHC), immunofluorescence (IF) staining, and expression knockdown by shRNA or exogenous overexpression by DNA plasmid transfection were performed to explore the underlying mechanisms, both in vitro and in vivo. Results: We found that nontoxic concentrations of penfluridol reduced the migration, invasion and adhesion of LADC cells. Protease array screening identified matrix metalloproteinase-12 (MMP-12) as a potential target of penfluridol to modulate the motility and adhesion of LADC cells. In addition, we found that MMP-12 exhibited the most significantly adverse prognostic effect in LADC among 39 cancer types. Mechanistic investigations revealed that penfluridol inhibited the urokinase plasminogen activator (uPA)/uPA receptor/transforming growth factor-β/Akt axis to downregulate MMP-12 expression and, subsequently, reverse MMP-12-induced epithelial–mesenchymal transition (EMT). Subsequent analysis of clinical LADC samples revealed a positive correlation between MMP12 and mesenchymal-related gene expression levels. A lower survival rate was found in LADC patients with a SNAl1high/MMP12high profile compared to those with a SNAl1low/MMP12low profile. Conclusions: Our results indicate that MMP-12 may serve as a useful biomarker for predicting LADC progression and as a promising penfluridol target for treating metastatic LADC. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeting epigenetic alterations in hepatocellular carcinoma (HCC) provides therapeutic options in addition to traditional treatments. The aim of our study was to evaluate the potential of targeting histone methyltransferase G9a in the development of a therapeutic target. We confirmed the prognostic values of mRNA and protein levels of G9a expression in HCC respectively from public database and tissue microarray. We also confirmed the aggressive phenotypes supported by G9a in both HBV+ and HBV− HCC cells. The identification of a regulation axis between liver-specific tumor suppressor miR-122 and G9a further supported the important roles of G9a during the tumorigenesis and progression of HCC. Combination of lower miR-122 and higher G9a levels may provide prognostic potential for poor clinical outcomes and therapeutic potential for epigenetic targeting therapies. Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers, which is the second most lethal tumor worldwide. Epigenetic deregulation is a common trait observed in HCC. Recently, increasing evidence suggested that the G9a histone methyltransferase might be a novel regulator of HCC development. However, several HCC cell lines were recently noted to have HeLa cell contamination or to have been derived from non-hepatocellular origin, suggesting that functional validation of G9a in proper HCC models is still required. Herein, we first confirmed that higher G9a messenger RNA and protein expression levels were correlated with poor overall survival (OS) and disease-free survival (DFS) rates of HCC patients from The Cancer Genome Atlas (TCGA) dataset and our recruited HCC cohort. In an in vitro functional evaluation of HCC cells, HCC36 (hepatitis B virus-positive (HBV+) and Mahlavu (HBV−)) cells showed that G9a participated in promoting cell proliferation, colony formation, and migration/invasion abilities. Moreover, orthotopic inoculation of G9a-depleted Mahlavu cells in NOD-SCID mice also resulted in a significantly decreased tumor burden compared to the control group. Furthermore, after surveying microRNA (miRNA; miR) prediction databases, we identified the liver-specific miR-122 as a G9a-targeting miRNA. In various HCC cell lines, we observed that miR-122 expression levels tended to be inversely correlated to G9a expression levels. In clinical HCC specimens, a significant inverse correlation of miR-122 and G9a mRNA expression levels was also observed. Functionally, the colony formation and invasive ability were attenuated in miR-122-overexpressing HCC cells. HCC patients with low miR-122 and high G9a expression levels had the worst OS and DFS rates compared to others. Together, our results confirmed the importance of altered G9a expression during HCC progression and discovered that a novel liver-specific miR-122-G9a regulatory axis exists. [ABSTRACT FROM AUTHOR]

Wnt/β‐catenin signaling is frequently activated in advanced prostate cancer and contributes to therapy resistance and metastasis. However, activating mutations in the Wnt/β‐catenin pathway are not common in prostate cancer, suggesting alternative regulations may exist. Here, we report that the expression of endothelial cell‐specific molecule 1 (ESM1), a secretory proteoglycan, is positively associated with prostate cancer stemness and progression by promoting Wnt/β‐catenin signaling. Elevated ESM1 expression correlates with poor overall survival and metastasis. Accumulation of nuclear ESM1, instead of cytosolic or secretory ESM1, supports prostate cancer stemness by interacting with the ARM domain of β‐catenin to stabilize β‐catenin–TCF4 complex and facilitate the transactivation of Wnt/β‐catenin signaling targets. Accordingly, activated β‐catenin in turn mediates the nuclear entry of ESM1. Our results establish the significance of mislocalized ESM1 in driving metastasis in prostate cancer by coordinating the Wnt/β‐catenin pathway, with implications for its potential use as a diagnostic or prognostic biomarker and as a candidate therapeutic target in prostate cancer. SYNOPSIS: Aberrant activation of the Wnt/β‐catenin pathway can promote stem cell self‐renewal and expansion in cancer. Here, mislocalized secretory proteoglycan ESM1 is implicated in the nuclear coordination of Wnt/β‐catenin signaling, thus supporting prostate cancer (PCa) stemness and metastasis. Nuclear ESM1 regulates PCa metastasis by promoting cancer stem cell properties.ESM1 associates with β‐catenin to stabilize the β‐catenin/TCF4 complex and promote Wnt activation.A positive feed‐forward loop between activated β‐catenin and nuclear ESM1 maintains Wnt‐mediated PCa stemness. [ABSTRACT FROM AUTHOR]

A disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) family are widely implicated in tissue remodeling events manifested in cancer development. ADAMTS1, the most fully characterized ADAMTS, plays conflicting roles in different cancer types; however, the role of ADAMTS1 in renal cell carcinoma (RCC) remains unclear. Herein, we found that ADAMTS1 is highly expressed in RCC tissues compared to normal renal tissues, and its expression was correlated with an advanced stage and a poor prognosis of RCC patients. In vitro, we observed higher expression of ADAMTS1 in metastatic (m)RCC cells compared to primary cells, and manipulation of ADAMTS1 expression affected cell invasion and clonogenicity. Results from protease array showed that ADAMTS1 is modulated by melatonin through mechanisms independent of the MT1 receptor in mRCC cells, and overexpression of ADAMTS1 relieved the invasion/clonogenicity and growth/metastasis inhibition imposed by melatonin treatment in vitro and in an orthotopic xenograft model. The human microRNA (miR) OneArray showed that miR‐181d and miR‐let‐7f were induced by melatonin and, respectively, targeted the 3'‐UTR and non‐3'‐UTR of ADAMTS1 to suppress its expression and mRCC invasive ability. Clinically, RCC patients with high levels of miR‐181d or miR‐let‐7f and a low level of ADAMTS1 had the most favorable prognoses. In addition, ubiquitin/proteasome‐mediated degradation of ADAMTS1 can also be triggered by melatonin. Together, our study indicates that ADAMTS1 may be a useful biomarker for predicting RCC progression. The novel convergence between melatonin and ADAMTS1 post‐transcriptional and post‐translational regulation provides new insights into the role of melatonin‐induced molecular regulation in suppressing RCC progression. [ABSTRACT FROM AUTHOR]

Demethoxycurcumin (DMC) is a curcumin analogue with better stability and higher aqueous solubility than curcumin after oral ingestion and has the potential to treat diverse cancers, including oral squamous cell carcinoma (OSCC). The aim of this study was to investigate the anticancer effects and underlying mechanisms of DMC against OSCC. We found that DMC suppressed cell proliferation via simultaneously inducing G2/M-phase arrest and cell apoptosis. Mechanistic investigations found that the downregulation of cellular IAP 1 (cIAP1)/X-chromosome-linked IAP (XIAP) and upregulation of heme oxygenase-1 (HO-1) were critical for DMC-induced caspase-8/-9/-3 activation and apoptotic cell death. Moreover, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK)1/2 were activated by DMC treatment in OSCC cells, and only the inhibition of p38 MAPK significantly abolished DMC-induced HO-1 expression and caspase-8/-9/-3 activation. The analyses of clinical datasets revealed that patients with head and neck cancers expressing high HO-1 and low cIAP1 had the most favorable prognoses. Furthermore, a combinatorial treatment of DMC with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib, significantly enhanced the inhibitory effect of gefitinib on the proliferation of OSCC cells. Overall, the current study supported a role for DCM as part of a therapeutic approach for OSCC through suppressing IAPs and activating the p38-HO-1 axis. [ABSTRACT FROM AUTHOR]

Background: Cisplatin is the first-line chemotherapy used against most upper aerodigestive tract carcinomas. In head and neck cancer, sensitivity to cisplatin remains the key issue in treatment response and outcome. Genetic heterogeneity and aberrant gene expression may be the intrinsic factors that cause primary cisplatin-resistance. Methods: Combination of the HNSCC gene expression data and the cisplatin sensitivity results from public database. We found that aldo-keto reductase family 1 member C1 (AKR1C1) may be associated with cisplatin sensitivity in HNSCC treatment of naïve cells. We examined the AKR1C1 expression and its correlation with cisplatin IC50 and prognosis in patients. The in vitro and in vivo AKR1C1 functions in cisplatin-resistance through overexpression or knockdown assays, respectively. cDNA microarrays were used to identify the upstream regulators that modulate AKR1C1-induced signaling in HNSCC. Finally, we used the cigarette metabolites to promote AKR1C1 expression and ruxolitinib to overcome AKR1C1-induced cisplatin-resistance. Results: AKR1C1 positively correlates to cisplatin-resistance in HNSCC cells. AKR1C1 is a poor prognostic factor for recurrence and death of HNSCC patients. Silencing of AKR1C1 not only reduced in vitro IC50 but also increased in vivo cisplatin responses and vise versa in overexpression cells. Cigarette metabolites also promote AKR1C1 expression. Transcriptome analyses revealed that STAT1 and STAT3 activation enable AKR1C1-induced cisplatin-resistance and can be overcome by ruxolitinib treatment. Conclusions: AKR1C1 is a crucial regulator for cisplatin-resistance in HNSCC and also poor prognostic marker for patients. Targeting the AKR1C1-STAT axis may provide a new therapeutic strategy to treat patients who are refractory to cisplatin treatment. [ABSTRACT FROM AUTHOR]

Background: Metastasis rather than the primary cancer determines the survival of cancer patients. Activation of Akt plays a critical role in the epithelial-to-mesenchymal transition (EMT), the initial step in lung cancer metastasis. Apigenin (API), a flavonoid with a potent Akt-inhibitory effect, shows oncostatic activities in various cancers. However, the effects of API on metastasis of non-small cell lung cancer (NSCLC) remain unclear. Methods: NSCLC cell lines with different epidermal growth factor receptor (EGFR) statuses and in vivo orthotopic bioluminescent xenograft model were employed to determine antitumor activity of API. Western blot and genetic knockdown by shRNA or genetic overexpression by DNA plasmids were performed to explore the underlying mechanisms. The Cancer Genome Atlas (TCGA) database was used to investigate the prognosis of API-targeted genes. Results: API was demonstrated to inhibit the migration/invasion of NSCLC cells harboring different EGFR statuses via suppressing the Snail/Slug-mediated EMT. Mechanistic investigations showed that CD26/dipeptidyl peptidase IV (DPPIV) was downregulated by API following suppressive interplay of Akt and Snail/Slug signaling to modulate the EMT and the invasive ability of NSCLC cells. CD26 expression was positively correlated with the invasive abilities of NSCLC cells and a worse prognosis of lung cancer patients. Furthermore, we observed that patients with CD26high/Akthigh tumors had the shortest recurrence-free survival times. In vivo, API drastically reduced the growth and metastasis of A549 xenografts through targeting CD26. Conclusions: CD26 may be a useful biomarker for predicting NSCLC progression. API effectively suppressed lung cancer progression by targeting the CD26-Akt-Snail/Slug signaling pathway. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma ( RCC) is the most lethal of all urological malignancies because of its potent metastasis potential. Melatonin exerts multiple tumor-suppressing activities through antiproliferative, proapoptotic, and anti-angiogenic actions and has been tested in clinical trials. However, the antimetastastic effect of melatonin and its underlying mechanism in RCC are unclear. In this study, we demonstrated that melatonin at the pharmacologic concentration (0.5-2 m m) considerably reduced the migration and invasion of RCC cells (Caki-1 and Achn). Furthermore, we found that melatonin suppressed metastasis of Caki-1 cells in spontaneous and experimental metastasis animal models. Mechanistic investigations revealed that melatonin transcriptionally inhibited MMP-9 by reducing p65 - and p52 - DNA -binding activities. Moreover, the Akt-mediated JNK1/2 and ERK1/2 signaling pathways were involved in melatonin-regulated MMP-9 transactivation and cell motility. Clinical samples revealed an inverse correlation between melatonin receptor 1A ( MTNR1A) and MMP-9 expression in normal kidney and RCC tissues. In addition, a higher survival rate was found in MTNR1Ahigh/ MMP-9low patients than in MTNR1Alow/ MMP-9high patients. Overall, our results provide new insights into the role of melatonin-induced molecular regulation in suppressing RCC metastasis and suggest that melatonin has potential therapeutic applications for metastastic RCC. [ABSTRACT FROM AUTHOR]

Graphene has shown many attractive properties while the difficulties in the fabrication of high-quality graphene have been a significant bottleneck in its applications. Here we report the discovery of high-quality graphene obtained from the solidified equiatomic CrFeCoNiC high-entropy alloy. Graphite flakes can be peeled off from the surface of the as-cast CrFeCoNiC high-entropy alloy, and single or multilayer graphene can be further exfoliated. The mechanical properties of the graphene are investigated by an atomic force microscope, and the result confirms the discovery of high-quality graphene. The transmission electron microscopy and Raman spectroscopy are applied to further characterize the quality of the graphene and show that the graphene has high-quality with few defects, comparable to the graphene obtained from highly oriented pyrolytic graphite. The thermodynamic calculation is applied to investigate the solidification process of the high-entropy alloy and reveals the mechanism of the formation of graphite on the surface. [Display omitted] • The CrFeCoNiC high-entropy alloy is prepared with graphite on the surface. • Graphene can be peeled off from the surface, and the quality of the graphene is excellent. • The thermodynamic mechanism for the formation of graphene is revealed. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is a typical inflammation-associated cancer, and lung adenocarcinoma (LUAD) is the most common histopathological subtype. Epidermal growth factor receptor (EGFR) mutations are the most common driver mutations of LUAD, and they have been identified as important therapeutic targets by EGFR tyrosine kinase inhibitors. Interleukin (IL)-17A secreted by T-helper 17 lymphocytes is a proinflammatory cytokine that plays an important role in cancer pathogenesis. The present study was designed to investigate the possible associations among IL-17A genetic polymorphisms, EGFR mutation status, and the clinicopathologic development of LUAD in a Taiwanese population. Our study population consisted of 277 LUAD patients harboring the wild-type (WT) EGFR or a mutant (MT) EGFR. Four single-nucleotide polymorphisms (SNPs) of IL-17A in the peripheral blood, including rs8193036(C > T), rs8193037(G > A), rs2275913(G > A), and rs3748067(C > T) loci, were genotyped using a TaqMan allelic discrimination assay. Our results showed that none of these IL-17A SNPs were correlated with the risk of developing mutant EGFR. However, patients with a smoking habit who carried the GA genotype of IL-17A rs8193037 had a significantly lower susceptibility to EGFR mutations (adjusted odds ratio (AOR): 0.225; 95% confidence interval (CI): 0.056~0.900, p = 0.035). Moreover, compared to individuals carrying the CC genotype of rs8193036 at IL-17A, T-allele carriers (CT + TT) were at higher risk of developing more-advanced stages (stage III or IV; p = 0.020). In the WT EGFR subgroup analysis, IL-17A rs8193036 T-allele carriers had higher risks of developing an advanced tumor stage (p = 0.016) and lymphatic invasion (p = 0.049). Further analyses of clinical datasets revealed correlations of IL-17 receptor A (IL-17RA) and IL-17RC expressions with a poor prognosis of LUAD patients with a smoking history or with higher levels of tumor-infiltrating lymphocytes. In conclusion, our results suggested that two functional promoter polymorphisms of IL-17A, i.e., rs8193036 and rs8193037, were associated with the EGFR mutation status and progression in LUAD patients, indicating that these two genetic variants might act as possible markers for predicting patients' clinical prognoses. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma (LADC) is a major subtype of lung cancer, particularly among populations of East Asia. The epidermal growth factor receptor (EGFR) is the most frequently mutated oncogene promoting LADC progression and can serve as a therapeutic target in LADC. The tissue inhibitor of metalloproteinases (TIMP)-3 is a major regulator of extracellular matrix turnover via targeting of matrix metalloproteinases (MMPs), and thus, plays a critical role in tumor development and progression. The purpose of this study was to investigate potential associations among TIMP-3 genetic polymorphisms, EGFR statuses, and cancer clinicopathologic development in patients with LADC. In this study, 277 LADC patients with different EGFR statuses were recruited to dissect the allelic discrimination of TIMP-3 -1296 T>C (rs9619311), TIMP3 249T>C (rs9862), and TIMP3 261C>T (rs11547635) polymorphisms using a TaqMan allelic discrimination assay. Our data showed that compared to those LADC patients with wild-type CC homozygotes of TIMP-3 rs9862, patients harboring TT homozygotes of rs9862 were at a higher risk of developing mutant EGFR (adjusted odds ratio (AOR) = 2.530; 95% confidence interval (CI): 1.230–5.205; p = 0.012), particularly the EGFR L858R point mutation (AOR = 2.975; 95% CI: 1.182–7.488; p = 0.021). Moreover, we observed that TIMP-3 TT homozygotes of rs9862 were correlated with the incidence of EGFR mutations in patients with a smoking habit (p = 0.045). Within male patients harboring a mutant EGFR, TIMP-3 rs9862 T (CT+TT) allele carriers were at higher risk of developing an advanced stage (p = 0.025) and lymph node metastasis (p = 0.043). Further analyses of clinical datasets revealed correlations of TIMP-3 expression with a favorable prognosis in patients with LADC. In conclusion, the data suggest that TIMP-3 rs9862 polymorphisms may contribute to identify subgroups of lung cancer patients at high risk for tumor progression, among carriers of LADC-bearing mutant EGFR. [ABSTRACT FROM AUTHOR]

The long noncoding (lnc)RNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), plays a crucial role in the development of hepatocellular carcinoma (HCC). However, potential genetic variants (single nucleotide polymorphisms, SNPs) in MALAT1 that affect the susceptibility and progression of HCC have rarely been explored. Three tagging SNPs, viz., rs3200401 C > T, rs619586 A > G, and rs1194338 C > A, in MALAT1 were genotyped by a TaqMan allelic discrimination assay in 394 HCC patients and 1199 healthy controls. A stratified analysis showed that younger patients (<55 years) with the MALAT1 rs619586 G allele had a decreased risk of HCC under a codominant model (AOR = 0.289, 95% CI: 0.108–0.773, p = 0.013) and dominant model (AOR = 0.286, 95% CI: 0.107–0.765, p = 0.013). Female patients and patients with a smoking habit who carried the CA + AA genotype of rs1194338 had a lower risk of developing vascular invasion (p = 0.049) and a high Child–Pugh grade (B or C) (p = 0.036), respectively. Under the dominant model, smokers with the MALAT1 rs3200401 CT + TT genotype had a higher frequency of hepatitis B virus (HBV) infection (p = 0.034). Moreover, the aspartate aminotransferase was higher in patients with the rs3200401 CT + TT genotype. Furthermore, analyses of clinical datasets revealed that MALAT1 expression level was gradually unregulated during HCC development from normal liver, cirrhotic liver, dysplastic liver to HCC and correlated with poor survival rates in HCC patients, especially in the hepatitis virus-infected population. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy is the main treatment for acute myeloid leukemia (AML), but the cure rates for AML patients remain low, and the notorious adverse effects of chemotherapeutic drugs drastically reduce the life quality of patients. Penfluridol, a long-acting oral antipsychotic drug, has an outstanding safety record and exerts oncostatic effects on various solid tumors. Until now, the effect of penfluridol on AML remains unknown. Methods: AML cell lines harboring wild-type (WT) Fms-like tyrosine kinase 3 (FLT3) and internal tandem duplication (ITD)-mutated FLT3 were used to evaluate the cytotoxic effects of penfluridol by an MTS assay. A flow cytometric analysis and immunofluorescence staining were employed to determine the cell-death phenotype, cell cycle profile, and reactive oxygen species (ROS) and acidic vesicular organelle (AVO) formation. Western blotting and chemical inhibitors were used to explore the underlying mechanisms involved in penfluridol-mediated cell death. Results: We observed that penfluridol concentration-dependently suppressed the cell viability of AML cells with FLT3-WT (HL-60 and U937) and FLT3-ITD (MV4–11). We found that penfluridol treatment not only induced apoptosis as evidenced by increases of nuclear fragmentation, the sub-G1 populations, poly (ADP ribose) polymerase (PARP) cleavage, and caspase-3 activation, but also triggered autophagic responses, such as the light chain 3 (LC3) turnover and AVO formation. Interestingly, blocking autophagy by the pharmacological inhibitors, 3-methyladenine and chloroquine, dramatically enhanced penfluridol-induced apoptosis, indicating the cytoprotective role of autophagy in penfluridol-treated AML cells. Mechanistically, penfluridol-induced apoptosis occurred through activating protein phosphatase 2A (PP2A) to suppress Akt and mitogen-activated protein kinase (MAPK) activities. Moreover, penfluridol's augmentation of intracellular ROS levels was critical for the penfluridol-induced autophagic response. In the clinic, we observed that patients with AML expressing high PP2A had favorable prognoses. Conclusions: These findings provide a rationale for penfluridol being used as a PP2A activator for AML treatment, and the combination of penfluridol with an autophagy inhibitor may be a novel strategy for AML harboring FLT3-WT and FLT3-ITD. [ABSTRACT FROM AUTHOR]

Background: The epidermal growth factor receptor (EGFR) plays important roles in cell survival, growth, differentiation, and tumorigenesis. Dysregulation of the EGFR is a common mechanism in cancer progression especially in non-small cell lung cancer (NSCLC). Main body: Suppression of the EGFR-mediated signaling pathway is used in cancer treatment. Furthermore, reactive oxygen species (ROS)-induced oxidative stress from mitochondrial dysfunction or NADPH oxidase (NOX) overactivation and ectopic expression of antioxidative enzymes were also indicated to be involved in EGFR-mediated tumor progression (proliferation, differentiation, migration, and invasion) and drug resistance (EGFR tyrosine kinase inhibitor (TKI)). The products of NOX, superoxide and hydrogen peroxide, are considered to be major types of ROS. ROS are not only toxic materials to cells but also signaling regulators of tumor progression. Oxidation of both the EGFR and downstream phosphatases by ROS enhances EGFR-mediated signaling and promotes tumor progression. This review primarily focuses on the recent literature with respect to the roles of the EGFR and ROS and correlations between ROS and the EGFR in tumor progression and EGFR TKI resistance. Short conclusion: The evidence discussed in this article can serve as a basis for basic and clinical research to understand how to modulate ROS levels to control the development and drug resistance of cancers. [ABSTRACT FROM AUTHOR]